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1
Gams, Polona, Zvezdana Dolenc Stražar, Maja Šoštarič, Matic Bošnjak, and Juš Kšela. "Cardiac Melanoma Metastasis with ERBB2 Gene Amplification: A Potential for Future Targeted Therapy." Case Reports in Oncology 14, no. 1 (March 29, 2021): 622–27. http://dx.doi.org/10.1159/000514981.
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Cardiac tumors are rare, and their treatment differs interindividually regarding the histopathological proprieties and the stage of disease. Authors present a case of symptomatic cardiac melanoma metastasis that expressed an <i>ERBB2</i> (<i>HER2</i>) gene amplification in a course of the disease that has not yet been reported. The frail patient with a history of pulmonary and renal carcinoma, was admitted to the hospital due to a symptomatic left atrial tumor mass. The patient underwent a tumor-resecting cardiac surgery. At first mistaken for myxoma on echocardiography, the histopathological examination of the tumor revealed a melanoma of acral or mucosal origin. The melanoma metastasis was negative for common genetic mutations in <i>BRAF</i>, <i>NRAS</i> or <i>KIT</i> genes, and for the presence of <i>NTRK</i> genes fusions, but carried <i>ERBB2</i> (<i>HER2</i>) gene amplification. The absence of standard gene mutations rendered it unresponsive to treatment with BRAF and MEK inhibitors. This molecular finding is rare in melanomas and represented a therapeutic target for off-label systemic treatment with drugs, primarily aimed at ERBB2 positive breast, gastric, and gastroesophageal junction cancers. A rare finding like this justifies molecular genetic analysis of unusual tumor specimen and guarantees optimal treatment for uncommon types of cardiac metastatic tumors.
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Tsai, Katy K., Iwei Yeh, Adil Daud, and Ari Oglesby. "Phase II study of binimetinib with imatinib in patients with unresectable KIT-mutant melanoma." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS9594. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps9594.
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TPS9594 Background: Immune checkpoint inhibitors (ICI) have transformed treatment for patients (pts) with advanced melanoma, as have BRAF/MEK inhibitors for pts with BRAF V600-mutant melanoma. However, pts with acral or mucosal melanomas are in particular need of more options given a lower objective response rate (ORR) to ICI, and lower incidence of BRAF V600 driver mutation. Such BRAF mutations are found in only 5-10% of acral/mucosal melanomas, while KIT mutations/amplifications are found in 10-20%. Even when present, a KIT alteration does not guarantee response to KIT inhibition, with only about one-third responding as previously shown in 3 phase II studies. A significant number of KIT-mutant melanomas have been shown to demonstrate NF1 or SPRED1 loss, with recent preclinical work showing that such alterations are associated with the loss of negative suppression of RAS, resulting in RAS activation and MEK dependence. We hypothesize that NF1 or SPRED1 loss cooperates with KIT mutations to drive melanomagenesis and resistance to KIT inhibition, and propose to target this vulnerability with a combination approach to targeted therapy. This phase II study will be the first to evaluate the efficacy and safety of binimetinib plus imatinib in pts with KIT-mutant melanoma. Methods: This is an investigator-initiated phase II study of binimetinib in combination with imatinib in pts with BRAF V600 WT, KIT-mutant unresectable melanoma who have progressed on or who are ineligible for ICI (NCT04598009). Pts will be ≥18 yo with performance status ECOG 0-2, and have unresectable Stage IIIB/C/D or Stage IV melanoma that is BRAF V600 WT and KIT-mutant by CLIA-certified testing platform. Pts will have progressed on prior ICI or other standard-of-care (SOC) therapies, or be ineligible for or unable to tolerate SOC therapies. Pts with brain metastasis will be eligible if clinically stable and determination made that no CNS-specific treatment is required prior to study start. Pts previously treated with a MEK inhibitor will be excluded. A Simon 2-stage Minimax design will be used; the null hypothesis that the true response rate is 0.1 will be tested against a one-sided alternative. 15 pts will be accrued in the first stage. If there are £1 responses, the study will be stopped. Otherwise, 10 additional pts will be accrued for a total of 25. The null hypothesis that the true response rate is 0.1 will be rejected if ≥6 responses are observed. This yields a type I error rate of 0.05 and power of 0.8017 when the true response rate is 0.3.Primary endpoint: ORR (RECIST). Secondary endpoints: duration of response, progression-free survival, overall survival, clinical benefit rate (CR, PR, or SD ≥16 weeks), safety profile (CTCAE). Exploratory objectives to include investigations of association between clinical response and baseline NF1 and SPRED1 status, and of pathologic correlates of acquired resistance. Study began enrolling pts in December 2020 and is ongoing. Clinical trial information: NCT04598009.
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Yeh, Iwei, Eric Jorgenson, Ling Shen, Mengshu Xu, Jeffrey P. North, A. Hunter Shain, David Reuss, et al. "Targeted Genomic Profiling of Acral Melanoma." JNCI: Journal of the National Cancer Institute 111, no. 10 (January 18, 2019): 1068–77. http://dx.doi.org/10.1093/jnci/djz005.
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Abstract Background Acral melanoma is a rare type of melanoma that affects world populations irrespective of skin color and has worse survival than other cutaneous melanomas. It has relatively few single nucleotide mutations without the UV signature of cutaneous melanomas, but instead has a genetic landscape characterized by structural rearrangements and amplifications. BRAF mutations are less common than in other cutaneous melanomas, and knowledge about alternative therapeutic targets is incomplete. Methods To identify alternative therapeutic targets, we performed targeted deep-sequencing on 122 acral melanomas. We confirmed the loss of the tumor suppressors p16 and NF1 by immunohistochemistry in select cases. Results In addition to BRAF (21.3%), NRAS (27.9%), and KIT (11.5%) mutations, we identified a broad array of MAPK pathway activating alterations, including fusions of BRAF (2.5%), NTRK3 (2.5%), ALK (0.8%), and PRKCA (0.8%), which can be targeted by available inhibitors. Inactivation of NF1 occurred in 18 cases (14.8%). Inactivation of the NF1 cooperating factor SPRED1 occurred in eight cases (6.6%) as an alternative mechanism of disrupting the negative regulation of RAS. Amplifications recurrently affected narrow loci containing PAK1 and GAB2 (n = 27, 22.1%), CDK4 (n = 27, 22.1%), CCND1 (n = 24, 19.7%), EP300 (n = 20, 16.4%), YAP1 (n = 15, 12.3%), MDM2 (n = 13, 10.7%), and TERT (n = 13, 10.7%) providing additional and possibly complementary therapeutic targets. Acral melanomas with BRAFV600E mutations harbored fewer genomic amplifications and were more common in patients with European ancestry. Conclusion Our findings support a new, molecularly based subclassification of acral melanoma with potential therapeutic implications: BRAFV600E mutant acral melanomas with characteristics similar to nonacral melanomas that could benefit from BRAF inhibitor therapy, and non-BRAFV600E mutant acral melanomas. Acral melanomas without BRAFV600E mutations harbor a broad array of therapeutically relevant alterations. Expanded molecular profiling would increase the detection of potentially targetable alterations for this subtype of acral melanoma.
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Teixido, Cristina, Paola Castillo, Clara Martinez-Vila, Ana Arance, and Llucia Alos. "Molecular Markers and Targets in Melanoma." Cells 10, no. 9 (September 5, 2021): 2320. http://dx.doi.org/10.3390/cells10092320.
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Melanoma develops as a result of several genetic alterations, with UV radiation often acting as a mutagenic risk factor. Deep knowledge of the molecular signaling pathways of different types of melanoma allows better characterization and provides tools for the development of therapies based on the intervention of signals promoted by these cascades. The latest World Health Organization classification acknowledged the specific genetic drivers leading to melanoma and classifies melanocytic lesions into nine distinct categories according to the associate cumulative sun damage (CSD), which correlates with the molecular alterations of tumors. The largest groups are melanomas associated with low-CSD or superficial spreading melanomas, characterized by frequent presentation of the BRAFV600 mutation. High-CSD melanomas include lentigo maligna type and desmoplastic melanomas, which often have a high mutation burden and can harbor NRAS, BRAFnon-V600E, or NF1 mutations. Non-CSD-associated melanomas encompass acral and mucosal melanomas that usually do not show BRAF, NRAS, or NF1 mutations (triple wild-type), but in a subset may have KIT or SF3B1 mutations. To improve survival, these driver alterations can be treated with targeted therapy achieving significant antitumor activity. In recent years, relevant improvement in the prognosis and survival of patients with melanoma has been achieved, since the introduction of BRAF/MEK tyrosine kinase inhibitors and immune checkpoint inhibitors. In this review, we describe the current knowledge of molecular pathways and discuss current and potential therapeutic targets in melanoma, focusing on their clinical relevance of development.
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Rodrigues, Ana Sofia, and Ana Brinca. "Treatment of BRAF-Mutated Metastatic Melanoma: Immunotherapy or Target Therapy?" Journal of the Portuguese Society of Dermatology and Venereology 79, no. 2 (June 25, 2021): 103–11. http://dx.doi.org/10.29021/spdv.79.2.1342.
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Metastatic melanoma has been associated with a poor prognosis, with overall survival rates at 5 years of 10%. Until 2011, the only treatments available for metastatic melanoma were chemotherapy and immunotherapy with interleukin-2. The more in-depth knowledge about the molecular biology of melanoma and the identification of BRAF mutations, which are the most frequently found, allowed us to find new therapeutic targets that came to modify the prognosis of these patients. Currently, the treatments available for metastatic melanoma with BRAF mutation are immunotherapy with immunological checkpoint inhibitors (anti-PD-1 to anti-CTLA-4) and targeted therapy with BRAF inhibitors and MEK inhibitors. However, the first-line therapy to be instituted in these patients remains unknown.
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Jebali, Ahlem, Maxime Battistella, Céleste Lebbé, and Nicolas Dumaz. "RICTOR Affects Melanoma Tumorigenesis and Its Resistance to Targeted Therapy." Biomedicines 9, no. 10 (October 19, 2021): 1498. http://dx.doi.org/10.3390/biomedicines9101498.
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The network defined by phosphatidylinositol-3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR) plays a major role in melanoma oncogenesis and has been implicated in BRAF inhibitor resistance. The central role of RICTOR (rapamycin-insensitive companion of mTOR) in this pathway has only recently begun to be unraveled. In the present study, we assessed the role of mTORC2/RICTOR in BRAF-mutated melanomas and their resistance to BRAF inhibition. We showed that RICTOR was significantly overexpressed in melanoma and associated with bad prognoses. RICTOR overexpression stimulated melanoma-initiating cells (MICs) with ‘stemness’ properties. We also showed that RICTOR contributed to melanoma resistance to BRAF inhibitors and rendered the cells very sensitive to mTORC2 inhibition. We highlighted a connection between mTORC2/RICTOR and STAT3 in resistant cells and revealed an interaction between RAS and RICTOR in resistant melanoma, which, when disrupted, impeded the proliferation of resistant cells. Therefore, as a key signaling node, RICTOR contributes to BRAF-dependent melanoma development and resistance to therapy and, as such, is a valuable therapeutic target in melanoma.
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Fattore, Luigi, Rita Mancini, Mario Acunzo, Giulia Romano, Alessandro Laganà, Maria Elena Pisanu, Debora Malpicci, et al. "miR-579-3p controls melanoma progression and resistance to target therapy." Proceedings of the National Academy of Sciences 113, no. 34 (August 8, 2016): E5005—E5013. http://dx.doi.org/10.1073/pnas.1607753113.
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Therapy of melanoma patients harboring activating mutations in the BRAF (V-raf murine sarcoma viral oncogene homolog B1) oncogene with a combination of BRAF and MEK inhibitors is plagued by the development of drug resistance. Mutational events, as well as adaptive mechanisms, contribute to the development of drug resistance. In this context we uncover here the role of a miRNA, miR-579-3p. We first show that low expression of miR-579-3p is a negative prognostic factor correlating with poor survival. Expression levels of miR-579-3p decrease from nevi to stage III/IV melanoma samples and even further in cell lines resistant to BRAF/MEK inhibitors. Mechanistically, we demonstrate that miR-579-3p acts as an oncosuppressor by targeting the 3′UTR of two oncoproteins: BRAF and an E3 ubiquitin protein ligase, MDM2. Moreover miR-579-3p ectopic expression impairs the establishment of drug resistance in human melanoma cells. Finally, miR-579-3p is strongly down-regulated in matched tumor samples from patients before and after the development of resistance to targeted therapies.
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Pizzimenti, Stefania, Simone Ribero, Marie Angele Cucci, Margherita Grattarola, Chiara Monge, Chiara Dianzani, Giuseppina Barrera, and Giuliana Muzio. "Oxidative Stress-Related Mechanisms in Melanoma and in the Acquired Resistance to Targeted Therapies." Antioxidants 10, no. 12 (December 3, 2021): 1942. http://dx.doi.org/10.3390/antiox10121942.
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Melanoma is a highly aggressive cancer with the poorest prognosis, representing the deadliest form of skin cancer. Activating mutations in BRAF are the most frequent genetic alterations, present in approximately 50% of all melanoma cases. The use of specific inhibitors towards mutant BRAF variants and MEK, a downstream signaling target of BRAF in the MAPK pathway, has significantly improved progression-free and overall survival in advanced melanoma patients carrying BRAF mutations. Nevertheless, despite these improvements, resistance still develops within the first year of therapy in around 50% of patients, which is a significant problem in managing BRAF-mutated advanced melanoma. Understanding these mechanisms is one of the mainstreams of the research on BRAFi/MEKi acquired resistance. Both genetic and epigenetic mechanisms have been described. Moreover, in recent years, oxidative stress has emerged as another major force involved in all the phases of melanoma development, from initiation to progression until the onsets of the metastatic phenotype and chemoresistance, and has thus become a target for therapy. In the present review, we discuss the current knowledge on oxidative stress and its signaling in melanoma, as well as the oxidative stress-related mechanisms in the acquired resistance to targeted therapies.
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Rossi, Ernesto, Giovanni Schinzari, Francesco Cellini, Mario Balducci, Mariangela Pasqualoni, Brigida Anna Maiorano, Bruno Fionda, et al. "Dabrafenib-Trametinib and Radiotherapy for Oligoprogressive BRAF Mutant Advanced Melanoma." Biomedicines 11, no. 2 (January 29, 2023): 394. http://dx.doi.org/10.3390/biomedicines11020394.
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The clinical management of metastatic melanoma has been changed by BRAF (BRAFi) and MEK inhibitors (MEKi), which represent a standard treatment for BRAF-mutant melanoma. In oligoprogressive melanoma patients with BRAF mutations, target therapy can be combined with loco-regional radiotherapy (RT). However, the association of BRAF/MEK inhibitors and RT needs to be carefully monitored for potential increased toxicity. Despite the availability of some reports regarding the tolerability of RT + target therapy, data on simultaneous RT and BRAFi/MEKi are limited and mostly focused on the BRAFi vemurafenib. Here, we report a series of metastatic melanoma patients who received fractioned RT regimens for oligoprogressive disease in combination with the BRAFi dabrafenib and the MEKi trametinib, which have continued beyond progression. None of the cases developed relevant adverse events while receiving RT or interrupted dabrafenib and trametinib administration. These cases suggest that a long period of dabrafenib/trametinib interruption during radiotherapy for oligoprogressive disease can be avoided. Prospective trials are warranted to assess the efficacy and safety of the contemporary administration of BRAF/MEK inhibitors and radiotherapy for oligoprogressive disease.
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Pavlick, Anna C., Leslie Fecher, Paolo A. Ascierto, and Ryan J. Sullivan. "Frontline Therapy forBRAF-Mutated Metastatic Melanoma: How Do You Choose, and Is There One Correct Answer?" American Society of Clinical Oncology Educational Book, no. 39 (May 2019): 564–71. http://dx.doi.org/10.1200/edbk_243071.
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Genetic analysis of melanoma has allowed us to identify a population of patients who have more aggressive disease and harbor the driver mutation BRAF. This mutation is found in approximately 50% of metastatic disease and provides a target for focused therapies to control this disease. These responses are usually brisk; however, they lack the durability of immunotherapy. Frontline therapy for patients with BRAF-mutated melanoma is not as straightforward as prescribing BRAF/MEK inhibitors. Prior trials of combination immunotherapy demonstrate similar responses and durability of responses in patients with BRAF wild-type as well as BRAF-mutated disease. Decisions about immunotherapy, targeted therapy, or the combination of immunotherapy with targeted therapy require an oncologist to evaluate multiple factors to select which treatment option is best for the patient. Trials for metastatic melanoma have included biomarkers as secondary endpoints and aim to identify some way to predict a response, or lack thereof, to therapy. Here, we discuss the utility and reliability of biomarkers in determining therapy for patients with BRAF-mutated metastatic melanoma and discuss combination immunotherapy with targeted therapy versus sequential immunotherapy/targeted therapy as well as which regimen should be implemented as initial therapy.
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Ice, Ryan J., Michelle Chen, Max Sidorov, Tam Le Ho, Rinette W. L. Woo, Aida Rodriguez-Brotons, Tri Luu, et al. "Drug responses are conserved across patient-derived xenograft models of melanoma leading to identification of novel drug combination therapies." British Journal of Cancer 122, no. 5 (December 20, 2019): 648–57. http://dx.doi.org/10.1038/s41416-019-0696-y.
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Abstract Background Patient-derived xenograft (PDX) mouse tumour models can predict response to therapy in patients. Predictions made from PDX cultures (PDXC) would allow for more rapid and comprehensive evaluation of potential treatment options for patients, including drug combinations. Methods We developed a PDX library of BRAF-mutant metastatic melanoma, and a high-throughput drug-screening (HTDS) platform utilising clinically relevant drug exposures. We then evaluated 34 antitumor agents across eight melanoma PDXCs, compared drug response to BRAF and MEK inhibitors alone or in combination with PDXC and the corresponding PDX, and investigated novel drug combinations targeting BRAF inhibitor-resistant melanoma. Results The concordance of cancer-driving mutations across patient, matched PDX and subsequent PDX generations increases as variant allele frequency (VAF) increases. There was a high correlation in the magnitude of response to BRAF and MEK inhibitors between PDXCs and corresponding PDXs. PDXCs and corresponding PDXs from metastatic melanoma patients that progressed on standard-of-care therapy demonstrated similar resistance patterns to BRAF and MEK inhibitor therapy. Importantly, HTDS identified novel drug combinations to target BRAF-resistant melanoma. Conclusions The biological consistency observed between PDXCs and PDXs suggests that PDXCs may allow for a rapid and comprehensive identification of treatments for aggressive cancers, including combination therapies.
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Andronova, N. V., L. F. Morozova, I. N. Mikhailova, A. A. Lushnikova, D. A. Ponkratova, N. T. Raychlin, I. A. Bukaeva, U. A. Borisova, S. M. Sitdikova, and H. M. Treshalina. "MODELING OF A SUBCUTANEOUS XENOGRAFT OF HUMAN SKIN MELANOMA MEL CHER WITH V600E BRAF MUTATION IN IMMUNODEFICIENT MICE FOR PRECLINICAL STUDY THE TARGETING ANTICANCER DRUGS." Russian Journal of Biotherapy 15, no. 4 (December 30, 2016): 65–71. http://dx.doi.org/10.17650/1726-9784-2016-15-4-65-71.
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Introduction. Development of new models of a human disseminated skin melanoma of the with molecular-genetic targets for specific therapy increases productivity of the preclinical researches new the anti-melanoma drugs or their combinations in vitro and in vivo. Such opportunity is realized by adaptation in vivo of the original human pigmented skin melanoma cell line mel Cher and receiving subcutaneous (s. c.) xenograft under monitoring of transplant, morphological, molecular-genetic (V600E BRAF mutation) and chemotherapeutic (sensitivity for the inhibitor of BRAF kinases to a vemurafenib) characteristics. Objective: receiving from the cell line mel Cher s. c. xenogratft of the human pigmented skin melanoma with V600E BRAF mutation and sensitive to specific target therapy. Materials and methods. Human pigmented skin melanoma cell line mel Cher from the Collection of Russian Cancer Research Center and immunodeficient Balb/c nude female mice cultivated in Russian Cancer Research Center was used. Required characteristics are defined by multiple s. c. transplanting in vivo by methods of transplant biology, a light microscopy, molecular-genetics and the experimental chemotherapy. Sensitivity to a BRAF kinase inhibitor to a vemurafenib was estimated under monitoring of the tumor growth rate (Vt/V0) on indexes, adequate for patients: existence of the complete remission and possibility of recurrence. Results. When s. c. transplantation of 107 cell of mel Cher line cytological identical intertwined s. c. xenografts with a stable growth kinetics on 4-9 passages (a latent phase 8 days, exponential - to 14 days, stationary - to 24 days) and existence of a mutation of V600E BRAF have been recieved. Vemurafenib in a single dose of 75 mg/kg caused the complete remission during a 15-day course and within 7 days after its cancellation - with the subsequent recurrence. Conclusion: receiving from the cell line mel Cher s. c. xenogratft of a human pigmented melanoma of skin with a mutation of V600E BRAF and sensitive to specific target therapy is suitable for preclinical studying of the new anti-melanoma drugs specific for this target.
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Moiseyenko, Fedor V., Vitaliy V. Egorenkov, Mikhail M. Kramchaninov, Elizaveta V. Artemieva, Svetlana N. Aleksakhina, Maxim M. Holmatov, Vladimir M. Moiseyenko, and Evgeny N. Imyanitov. "Lack of Response to Vemurafenib in Melanoma Carrying BRAF K601E Mutation." Case Reports in Oncology 12, no. 2 (May 16, 2019): 339–43. http://dx.doi.org/10.1159/000500481.
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Vemurafenib has been developed to target common BRAF mutation V600E. It also exerts activity towards some but not all rare BRAF substitutions. Proper cataloguing of drug-sensitive and -insensitive rare mutations remains a challenge, due to low occurrence of these events and inability of commercial PCR-based diagnostic kits to detect the full spectrum of BRAF gene lesions. We considered the results of BRAF exon 15 testing in 1872 consecutive melanoma patients. BRAF mutation was identified in 1,090 (58.2%) cases. While drug-sensitive codon 600 substitutions constituted the majority of BRAF gene lesions (V600E: 962 [51.4%]; V600K: 86 [4.6%]; V600R: 17 [0.9%]), the fourth common BRAF allele was K601E accounting for 9 (0.5%) melanoma cases. The data on BRAF inhibitor sensitivity of tumors with K601E substitution are scarce. We administered single-agent vemurafenib to a melanoma patient carrying BRAF K601E mutation as the first-line treatment. Unfortunately, this therapy did not result in a tumor response. Taken together with already published data, this report indicates lack of benefit from conventional BRAF inhibitors in patients with BRAF K601E mutated melanoma.
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Porumb-Andrese, Elena, Ramona Gabriela Ursu, Iuliu Ivanov, Irina-Draga Caruntu, Vlad Porumb, Dan Ferariu, Costin Damian, Delia Ciobanu, Cristina Terinte, and Luminita Smaranda Iancu. "The BRAF V600E Mutation Detection by quasa Sensitive Real-Time PCR Assay in Northeast Romania Melanoma Patients." Applied Sciences 11, no. 20 (October 13, 2021): 9511. http://dx.doi.org/10.3390/app11209511.
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Background: The prevalence of melanoma in Romanian patients is underestimated. There is a need to identify the BRAF V600E mutation to accurately treat patients with the newest approved BRAF inhibitor therapy. This is a pilot study in which we first aimed to choose the optimal DNA purification method from formalin fixation and paraffin embedding (FFPE) malignant melanoma skin samples to assess the BRAF mutation prevalence and correlate it with clinical pathological parameters. Methods: 30 FFPE samples were purified in parallel with two DNA extraction kits, a manual and a semi-automated kit. The extracted DNA in pure and optimum quantity was tested for the BRAF V600E mutation using the quantitative allele-specific amplification (quasa) method. quasa is a method for the sensitive detection of mutations that may be present in clinical samples at low levels. Results: The BRAF V600E mutation was detected in 60% (18/30) samples in patients with primary cutaneous melanoma of the skin. BRAFV600E mutation was equally distributed by gender and was associated with age >60, nodular melanoma, and trunk localization. Conclusions: The high prevalence of BRAF V600E mutations in our study group raises awareness for improvements to the national reporting system and initiation of the target therapy for patients with malignant melanoma of the skin.
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McKenna, Stephanie, and Lucía García-Gutiérrez. "Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing?" International Journal of Molecular Sciences 22, no. 10 (May 12, 2021): 5115. http://dx.doi.org/10.3390/ijms22105115.
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Melanoma is one of the most aggressive forms of skin cancer and is therapeutically challenging, considering its high mutation rate. Following the development of therapies to target BRAF, the most frequently found mutation in melanoma, promising therapeutic responses were observed. While mono- and combination therapies to target the MAPK cascade did induce a therapeutic response in BRAF-mutated melanomas, the development of resistance to MAPK-targeted therapies remains a challenge for a high proportion of patients. Resistance mechanisms are varied and can be categorised as intrinsic, acquired, and adaptive. RASSF1A is a tumour suppressor that plays an integral role in the maintenance of cellular homeostasis as a central signalling hub. RASSF1A tumour suppressor activity is commonly lost in melanoma, mainly by aberrant promoter hypermethylation. RASSF1A loss could be associated with several mechanisms of resistance to MAPK inhibition considering that most of the signalling pathways that RASSF1A controls are found to be altered targeted therapy resistant melanomas. Herein, we discuss resistance mechanisms in detail and the potential role for RASSF1A reactivation to re-sensitise BRAF mutant melanomas to therapy.
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Hu-Lieskovan, Siwen, Lidia Robert, Blanca Homet Moreno, and Antoni Ribas. "Combining Targeted Therapy With Immunotherapy in BRAF-Mutant Melanoma: Promise and Challenges." Journal of Clinical Oncology 32, no. 21 (July 20, 2014): 2248–54. http://dx.doi.org/10.1200/jco.2013.52.1377.
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Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAFV600-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non–BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.
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Tímár, József, and Andrea Ladányi. "Molecular Pathology of Skin Melanoma: Epidemiology, Differential Diagnostics, Prognosis and Therapy Prediction." International Journal of Molecular Sciences 23, no. 10 (May 11, 2022): 5384. http://dx.doi.org/10.3390/ijms23105384.
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Similar to other malignancies, TCGA network efforts identified the detailed genomic picture of skin melanoma, laying down the basis of molecular classification. On the other hand, genome-wide association studies discovered the genetic background of the hereditary melanomas and the susceptibility genes. These genetic studies helped to fine-tune the differential diagnostics of malignant melanocytic lesions, using either FISH tests or the myPath gene expression signature. Although the original genomic studies on skin melanoma were mostly based on primary tumors, data started to accumulate on the genetic diversity of the progressing disease. The prognostication of skin melanoma is still based on staging but can be completed with gene expression analysis (DecisionDx). Meanwhile, this genetic knowledge base of skin melanoma did not turn to the expected wide array of target therapies, except the BRAF inhibitors. The major breakthrough of melanoma therapy was the introduction of immune checkpoint inhibitors, which showed outstanding efficacy in skin melanoma, probably due to their high immunogenicity. Unfortunately, beyond BRAF, KIT mutations and tumor mutation burden, no clinically validated predictive markers exist in melanoma, although several promising biomarkers have been described, such as the expression of immune-related genes or mutations in the IFN-signaling pathway. After the initial success of either target or immunotherapies, sooner or later, relapses occur in the majority of patients, due to various induced genetic alterations, the diagnosis of which could be developed to novel predictive genetic markers.
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Yilmaz, Mesut, and Şermin Güven Meşe. "Treatment exceeds expectations with vemurafenib monotherapy in a patient with BRAFV600E-mutant metastatic melanoma." Journal of Oncology Pharmacy Practice 26, no. 7 (March 29, 2020): 1754–58. http://dx.doi.org/10.1177/1078155220906011.
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Introduction Patients with distant metastatic melanoma has a poor prognosis, with a reported median survival time of six to eight months. In modern era, survival has prolonged with the immunotherapy and targeted therapy options. Potent and selective BRAF inhibitors have been developed that specifically inhibit mutated BRAF over other RAF kinases. Vemurafenib was the first selective tyrosine kinase inhibitor developed to target the V600E allele of BRAF-mutant melanoma. Case Report In this report, we present a case of BRAFV600E-mutant metastatic melanoma, which is being treated with vemurafenib monotherapy with complete response for about seven years. Management and Outcome The patient is still being treated with vemurafenib and radiologic complete response is ongoing for about seven years. Discussion Patients treated with BRAF inhibitors monotherapy had promising response rates and improvement in the progression-free survival and overall survival, but melanoma cells became resistant very quickly, affecting the progression. In this case, we present a case that has permanent response to vemurafenib monotherapy.
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Ruggiero, Ciro Francesco, Debora Malpicci, Luigi Fattore, Gabriele Madonna, Vito Vanella, Domenico Mallardo, Domenico Liguoro, et al. "ErbB3 Phosphorylation as Central Event in Adaptive Resistance to Targeted Therapy in Metastatic Melanoma: Early Detection in CTCs during Therapy and Insights into Regulation by Autocrine Neuregulin." Cancers 11, no. 10 (September 25, 2019): 1425. http://dx.doi.org/10.3390/cancers11101425.
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In recent years the introduction of target therapies with BRAF and MEK inhibitors (MAPKi) and of immunotherapy with anti-CTLA-4 and anti-PD-1 monoclonal antibodies have dramatically improved survival of metastatic melanoma patients. Despite these changes drug resistance remains a major hurdle. Several mechanisms are at the basis of drug resistance. Particular attention has been devoted over the last years to unravel mechanisms at the basis of adaptive/non genetic resistance occurring in BRAF mutated melanomas upon treatment with to MAPKi. In this paper we focus on the involvement of activation of ErbB3 receptor following early exposure of melanoma cells to BRAF or MEK inhibitors, and the following induction of PI3K/AKT pathway. Although different mechanisms have been invoked in the past at the basis of this activation we show here with a combination of approaches that autocrine production of neuregulin by melanoma cells is a major factor responsible for ErbB3 phosphorylation and downstream AKT activation. Interestingly the kinetic of neuregulin production and of the ensuing ErbB3 phosphorylation is different in different melanoma cell lines which underscores the high degree of tumor heterogeneity. Moreover, heterogeneity is further highlighted by the evidence that in different cell lines neuregulin upregulation can occur at the transcriptional or at the post-transcritpional level. Finally we complement our study by showing with a liquid biopsy assay that circulating tumor cells (CTCs) from melanoma patients undergo upregulation of ErbB3 phosphorylation in vivo shortly after initiation of therapy.
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Lau, Peter Kar Han, Carleen Cullinane, Susan Jackson, Rachael Walker, Lorey K. Smith, Alison Slater, Laura Kirby, et al. "Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma." Cancers 13, no. 24 (December 17, 2021): 6342. http://dx.doi.org/10.3390/cancers13246342.
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Despite the success of immune checkpoint inhibitors that target cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed-cell-death-1 (PD-1) in the treatment of metastatic melanoma, there is still great need to develop robust options for patients who are refractory to first line immunotherapy. As such there has been a resurgence in interest of adoptive cell transfer (ACT) particularly derived from tumor infiltrating lymphocytes. Moreover, the addition of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) have been shown to greatly extend duration of response in combination with BRAF-MEK inhibitors (BRAF-MEKi) in pre-clinical models of melanoma. We therefore investigated whether combinations of BRAF-MEK-CDK4/6i and ACT were efficacious in murine models of melanoma. Triplet targeted therapy of BRAF-MEK-CDK4/6i with OT-1 ACT led to sustained and robust anti-tumor responses in BRAFi sensitive YOVAL1.1. We also show that BRAF-MEKi but not CDK4/6i enhanced MHC Class I expression in melanoma cell lines in vitro. Paradoxically CDK4/6i in low concentrations of IFN-γ reduced expression of MHC Class I and PD-L1 in YOVAL1.1. Overall, this work provides additional pre-clinical evidence to pursue combination of BRAF-MEK-CDK4/6i and to combine this combination with ACT in the clinic.
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Becco, Paolo, Susanna Gallo, Stefano Poletto, Mirko Pio Manlio Frascione, Luca Crotto, Alessandro Zaccagna, Luca Paruzzo, Daniela Caravelli, Fabrizio Carnevale-Schianca, and Massimo Aglietta. "Melanoma Brain Metastases in the Era of Target Therapies: An Overview." Cancers 12, no. 6 (June 21, 2020): 1640. http://dx.doi.org/10.3390/cancers12061640.
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Malignant melanoma is the third most common type of tumor that causes brain metastases. Patients with cerebral involvement have a dismal prognosis and their treatment is an unmet medical need. Brain involvement is a multistep process involving several signaling pathways such as Janus kinase/signal Transducer and Activator of Transcription (JAK/STAT), Phosphoinositide 3-kinase/Protein Kinase B (PI3K/AKT), Vascular Endothelial Growth Factor and Phosphatase and Tensin Homolog (PTEN). Recently therapy that targets the MAPK signaling (BRAF/MEK inhibitors) and immunotherapy (anti-CTLA4 and anti-PD1 agents) have changed the therapeutic approaches to stage IV melanoma. In contrast, there are no solid data about patients with brain metastases, who are usually excluded from clinical trials. Retrospective data showed that BRAF-inhibitors, alone or in combination with MEK-inhibitors have interesting clinical activity in this setting. Prospective data about the combinations of BRAF/MEK inhibitors have been recently published, showing an improved overall response rate. Short intracranial disease control is still a challenge. Several attempts have been made in order to improve it with combinations between local and systemic therapies. Immunotherapy approaches seem to retain promising activity in the treatment of melanoma brain metastasis as showed by the results of clinical trials investigating the combination of anti-CTL4 (Ipilimumab) and anti-PD1(Nivolumab). Studies about the combination or the sequential approach of target therapy and immunotherapy are ongoing, with immature results. Several clinical trials are ongoing trying to explore new approaches in order to overcome tumor resistance. At this moment the correct therapeutic choices for melanoma with intracranial involvement is still a challenge and new strategies are needed.
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Karki, Prashant, Shayne Sensenbach, Vahideh Angardi, and Mehmet A. Orman. "BRAF-Inhibitor-Induced Metabolic Alterations in A375 Melanoma Cells." Metabolites 11, no. 11 (November 14, 2021): 777. http://dx.doi.org/10.3390/metabo11110777.
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Acquired drug tolerance has been a major challenge in cancer therapy. Recent evidence has revealed the existence of slow-cycling persister cells that survive drug treatments and give rise to multi-drug-tolerant mutants in cancer. Cells in this dynamic persister state can escape drug treatment by undergoing various epigenetic changes, which may result in a transient metabolic rewiring. In this study, with the use of untargeted metabolomics and phenotype microarrays, we characterize the metabolic profiles of melanoma persister cells mediated by treatment with vemurafenib, a BRAF inhibitor. Our findings demonstrate that metabolites associated with phospholipid synthesis, pyrimidine, and one-carbon metabolism and branched-chain amino acid metabolism are significantly altered in vemurafenib persister cells when compared to the bulk cancer population. Our data also show that vemurafenib persisters have higher lactic acid consumption rates than control cells, further validating the existence of a unique metabolic reprogramming in these drug-tolerant cells. Determining the metabolic mechanisms underlying persister cell survival and maintenance will facilitate the development of novel treatment strategies that target persisters and enhance cancer therapy.
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Nepote, Alessandro, Gianluca Avallone, Simone Ribero, Francesco Cavallo, Gabriele Roccuzzo, Luca Mastorino, Claudio Conforti, et al. "Current Controversies and Challenges on BRAF V600K-Mutant Cutaneous Melanoma." Journal of Clinical Medicine 11, no. 3 (February 4, 2022): 828. http://dx.doi.org/10.3390/jcm11030828.
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About 50% of melanomas harbour a BRAF mutation. Of these 50%, 10% have a V600K mutation. Although it is the second most common driver mutation after V600E, no specific studies have been conducted to identify a clinical and therapeutic gold standard for this patient subgroup. We analysed articles, including registrative clinical trials, to identify common clinical and biological traits of the V600K melanoma population, including different adopted therapeutic strategies. Melanoma V600K seems to be more frequent in Caucasian, male and elderly populations with a history of chronic sun damage and exposure. Prognosis is poor and no specific prognostic factor has been identified. Recent findings have underlined how melanoma V600K seems to be less dependent on the ERK/MAPK pathway, with a higher expression of PI3KB and a strong inhibition of multiple antiapoptotic pathways. Both target therapy with BRAF inhibitors + MEK inhibitors and immunotherapy with anti-checkpoint blockades are effective in melanoma V600K, although no sufficient evidence can currently support a formal recommendation for first line treatment choice in IIIC unresectable/IV stage patients. Still, melanoma V600K represents an unmet medical need and a marker of poor prognosis for cutaneous melanoma.
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Testori, Alessandro A. E., Silvia Chiellino, and Alexander C. J. van Akkooi. "Adjuvant Therapy for Melanoma: Past, Current, and Future Developments." Cancers 12, no. 7 (July 21, 2020): 1994. http://dx.doi.org/10.3390/cancers12071994.
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This review describes the progress that the concept of adjuvant therapies has undergone in the last 50 years and focuses on the most recent development where an adjuvant approach has been scientifically evaluated in melanoma clinical trials. Over the past decade the development of immunotherapies and targeted therapies has drastically changed the treatment of stage IV melanoma patients. These successes led to trials studying the same therapies in the adjuvant setting, in high risk resected stage III and IV melanoma patients. Adjuvant immune checkpoint blockade with anti-CTLA-4 antibody ipilimumab was the first drug to show an improvement in recurrence-free and overall survival but this was accompanied by high severe toxicity rates. Therefore, these results were bypassed by adjuvant treatment with anti-PD-1 agents nivolumab and pembrolizumab and BRAF-directed target therapy, which showed even better recurrence-free survival rates with more favorable toxicity rates. The whole concept of adjuvant therapy may be integrated with the new neoadjuvant approaches that are under investigation through several clinical trials. However, there is still no data available on whether the effective adjuvant therapy that patients finally have at their disposal could be offered to them while waiting for recurrence, sparing at least 50% of them a potentially long-term toxic side effect but with the same rate of overall survival (OS). Adjuvant therapy for melanoma has radically changed over the past few years—anti-PD-1 or BRAF-directed therapy is the new standard of care.
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Fattore, Luigi, Virginia Campani, Ciro Francesco Ruggiero, Valentina Salvati, Domenico Liguoro, Lorena Scotti, Gerardo Botti, et al. "In Vitro Biophysical and Biological Characterization of Lipid Nanoparticles Co-Encapsulating Oncosuppressors miR-199b-5p and miR-204-5p as Potentiators of Target Therapy in Metastatic Melanoma." International Journal of Molecular Sciences 21, no. 6 (March 12, 2020): 1930. http://dx.doi.org/10.3390/ijms21061930.
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Uncontrolled MAPK signaling is the main oncogenic driver in metastatic melanomas bearing mutations in BRAF kinase. These tumors are currently treated with the combination of BRAF/MEK inhibitors (MAPKi), but this therapy is plagued by drug resistance. In this context we recently discovered that several microRNAs are involved in the development of drug resistance. In particular miR-204-5p and miR-199b-5p were found to function as antagonists of resistance because their enforced overexpression is able to inhibit melanoma cell growth in vitro either alone or in combination with MAPKi. However, the use of miRNAs in therapy is hampered by their rapid degradation in serum and biological fluids, as well as by the poor intracellular uptake. Here, we developed lipid nanoparticles (LNPs) encapsulating miR-204-5p, miR-199b-5p individually or in combination. We obtained LNPs with mean diameters < 200 nm and high miRNA encapsulation efficiency. These formulations were tested in vitro on several melanoma cell lines sensitive to MAPKi or rendered drug resistant. Our results show that LNPs encapsulating combinations of the two oncosuppressor miRNAs are highly efficient in impairing melanoma cell proliferation and viability, affect key signaling pathways involved in melanoma cell survival, and potentiate the efficacy of drugs inhibiting BRAF and MEK. These results warrant further assessment of the anti-tumor efficacy of oncosuppressor miRNAs encapsulating LNPs in in vivo tumor models.
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Valpione, Sara, Luca G. Campana, Jacopo Pigozzo, and Vanna Chiarion-Sileni. "Consolidation electrochemotherapy with bleomycin in metastatic melanoma during treatment with dabrafenib." Radiology and Oncology 49, no. 1 (March 1, 2015): 71–74. http://dx.doi.org/10.2478/raon-2014-0035.
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Abstract Background. Small molecules that inhibit V600 mutated BRAF protein, such as vemurafenib and dabrafenib, are effective in treatment of metastatic melanoma. Case report. We here describe the clinical course of a V600E BRAF mutated metastatic melanoma patient with systemic disease, who developed tumor progression on superficial soft-tissue metastases during treatment with dabrafenib. Bleomycin electrochemotherapy during dabrafenib treatment was administered to control the soft-tissue progressing metastases and ensured sustained local control without significant toxicity. Conclusions. The new combined approach maintained the patient quality of life and allowed for the prosecution of the target therapy, which proved to be still effective on systemic disease, up to 17 months
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Sarnaik, Amod, Sajeve Samuel Thomas, Diwakar Davar, John M. Kirkwood, Harriet M. Kluger, Jose Lutzky, Melissa Wilson, et al. "Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients previously treated with at least one prior systemic therapy." Journal of Clinical Oncology 37, no. 8_suppl (March 10, 2019): 136. http://dx.doi.org/10.1200/jco.2019.37.8_suppl.136.
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136 Background: While immunotherapies including checkpoint inhibitors and targeted therapies (BRAF/MEK inhibitors) are options for patients with metastatic melanoma, many patients still develop progressive disease. These patients have few treatment options available including high dose IL-2 and chemotherapy with reported second line response rates of 4-10%. Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) is recognized as an effective treatment in metastatic melanoma, able to elicit durable and complete responses in even heavily pretreated patients. We provide preliminary data for lifileucel TIL (LN-144) in heavily pre-treated metastatic melanoma patients who progressed on multiple checkpoint and BRAF/MEK inhibitors. Methods: C-144-01 is an ongoing global Phase 2, open-label, multicenter study of efficacy and safety of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 47) patients who received cryopreserved lifileucel. Tumors resected at local institutions were processed at central GMP facilities in a 22-day manufacturing process. The final product was cryopreserved and shipped to sites. Patients received a one week cyclophosphamide/fludarabine preconditioning lymphodepletion regimen, a single lifileucel infusion, followed by up to 6 doses of iv IL-2 (600,000 IU/kg). Results: Patients with Stage IIIC/IV melanoma had 3.3 mean prior therapies (range: 1-9) and high baseline tumor burden, reflected by a mean sum of diameters of target lesions of 112 mm. Preliminary efficacy results: ORR = 38% (1 CR, 13 PR, 4 uPR), DCR = 77%, and median DOR 6.4 mo (range: 1.3 to 13.7) with median follow-up 6.0 mo. Longer follow-up led to improved responses in some patients including the CR. Frequency of AEs decreased over time, a potentially important benefit of one-time TIL treatment. Conclusions: Preliminary data support lifileucel TIL as an efficacious and well-tolerated therapeutic option for patients with metastatic melanoma who have failed multiple lines of prior therapies including checkpoint inhibitors and BRAF/MEK inhibitors. Clinical trial information: NCT02360579.
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Sarnaik, Amod, Nikhil I. Khushalani, Jason Alan Chesney, Harriet M. Kluger, Brendan D. Curti, Karl D. Lewis, Sajeve Samuel Thomas, et al. "Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients who progressed on multiple prior therapies including anti-PD-1." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 2518. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2518.
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2518 Background: Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable long-term responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel (LN-144), a centrally manufactured autologous TIL therapy are presented. Methods: C-144-01 is a global Phase 2 open-label, multicenter study of the efficacy and safety of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 55) patients who received cryopreserved lifileucel. Tumors resected at local institutions were processed in central GMP facilities for TIL production in a 22-day process. Final TIL infusion product was cryopreserved and shipped to sites. Patients received one week of cyclophosphamide/fludarabine preconditioning lymphodepletion, a single lifileucel infusion, followed by up to 6 doses of IL-2. Results: In 55 patients with Stage IIIC/IV unresectable melanoma, 3.1 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 24%), high baseline tumor burden (110 mm mean target lesion sum of diameters), ORR was 38% (2 CR, 18 PR, 1 uPR). Of 21 responders, 4 have progressed to date with median follow up of 7.4 months. Overall disease control was 76%. Improved responses in some patients were observed with longer follow up. Most (54) patients progressed on prior anti-PD1 and those with PD-L1 negative status (TPS < 5%) were among responders. Mean cells infused was 28 x109. Median IL-2 doses administered was 6.0. Adverse events resolved to baseline, 2 weeks post TIL infusion, a potentially important benefit of one-time TIL therapy. Conclusions: Lifileucel treatment results in 38% ORR in heavily pretreated metastatic melanoma patients with high baseline disease burden who received prior anti-PD1 and BRAF/MEK inhibitor if BRAF mutated. Based on these data, a new Cohort 4 in C-144-01 has been initiated to support lifileucel registration. Clinical trial information: NCT02360579.
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Dzienis, Marcin Radoslaw, and Victoria Atkinson. "Response rate to vemurafenib in BRAF-positive melanoma brain metastases." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 9081. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.9081.
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9081 Background: Brain is a common site for melanoma metastases. Responses to dabrafenib have already been reported in over 50% of patients. We aimed at assessing response rate (RR) to vemurafenib (Vem). Methods: Patients with BRAF positive melanoma and asymptomatic brain metastases at initiation of Vem were eligible. Records were analysed retrospectively to calculate RR (at least 30% decrease in the sum of diameters of target lesions), duration of response and time to CNS progression (TTP). Results: 18 patients with CNS metastasis received Vem (M/F=8/10; median age 50); 9 received no prior therapy to the brain (group A), 6 had previous surgery and/or radiotherapy with residual disease (group B; n=6), 3 patients had prior "brain therapy" but with evidence of progression in CNS before the start of Vem and were added to group A (n=9+3=12). 50% RR was observed in group A; 5 had no prior therapy, 1 relapsed after resection/WBRT. Duration of response was: 8, 8, 8, 16, 32 weeks and 1 not reached yet. Similarly, 50% RR was observed in group B; however contribution of Vem to CNS control in this group was more difficult to assess. Duration of responses: 4, 26, 33 weeks. All except 2 patients progressed in CNS before, or at the time of, systemic progression. Median TTP in group A was: 21 weeks (16-41) in responding patients and 12 weeks (4-22) in those without a response (includes SD). Median TTP in group B = 44 weeks (16-60) in responders, 8 weeks (3-16) in non-responders. Conclusions: Vemurafenib resulted in 50% CNS response rate. Prospective comparison to dabrafenib may be warranted.
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Algazi, Alain Patrick, Christian Posch, Susana Ortiz-Urda, Alyson Cockerill, Pamela N. Munster, and Adil Daud. "BKM120 combined with vemurafenib in vemurafenib-refractory BRAF mutant metastatic melanoma: Two cases." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e20010-e20010. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e20010.
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e20010 Background: PTEN loss and PI3K activation are common in BRAF mutant metastatic melanoma, and PI3K activation has been implicated as a cause of acquired resistance to BRAF inhibitors. Two vemurafenib refractory were treated with the potent BRAF inhibitor, vemurafenib, and the pan-class I PI3K inhibitor BKM120. Methods: The study enrolled BRAF-V600E/K mutant metastatic melanoma patients with an ECOG PS ≥ 2 and adequate organ function. Vemurafenib refractory BRAF-V600E/K mutant melanoma patients started both vemurafenib twice daily and BKM120 daily on cycle 1, day 1 after a vemurafenib washout of at least 14 days. Serial biopsies prior to treatment, on cycle 1 day 15, and at progression were obtained for pharmacodynamics analysis in patients with visible or palpable tumors. Results: 3 BRAF inhibitor refractory patients were treated on study with vemurafenib 720 mg PO bid and BKM120 60 mg PO daily. One patient was inevaluable due to non-compliance and had minimal exposure to study drug. Pre-treatment biopsy specimens were available in the remaining 2 vemurafenib-refractory patients. Both patient expressed PTEN at baseline and had demonstrable pAKT and pS6 staining. One patient had a mixed response to treatment with a 35.9% reduction in target lesions and two new small subcutaneous lesions. This patient also developed dose limiting febrile neutropenia on trial. The second patient tolerated treatment well but had widespread disease progression at 8 weeks. Conclusions: Combination therapy with vemurafenib and BKM120 in BRAF-V600E/K mutant melanoma led to substantial regression of several tumors in a PTEN+ patient with prior disease progression on vemurafenib alone. A phase I dose escalation trial in ongoing. Clinical trial information: NCT01512251.
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Bernocchi, Ottavia, Marianna Sirico, Silvia Paola Corona, Carla Strina, Manuela Milani, Maria Rosa Cappelletti, Giuseppina Ferrero, et al. "Tumor Type Agnostic Therapy Carrying BRAF Mutation: Case Reports and Review of Literature." Pharmaceuticals 14, no. 2 (February 16, 2021): 159. http://dx.doi.org/10.3390/ph14020159.
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Background: Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting genomic alterations, regardless of tumor origin. In this context, novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape in solid tumors have been investigated. Case presentation, Case 1: The first case is chemotherapy-refractory, BRAF V600E mutated intrahepaticcholangiocarcinoma treated with vemurafenib and cobimetinib as third line therapy. In this setting the dual BRAF and MEK inhibition resulted in improved progression-free survival and quality of life; Case 2: The second case shows aBRAF G466A mutated Bellini duct carcinoma (BDC), treated with dabrafenib and trametinib in second line therapy. The disease remained under control for 11 months after the first relapse. Discussion: In the literature there is strong evidence that melanoma, colorectal cancer, non small cell lung cancer and anaplastic thyroid cancer with BRAF mutations are good targets for BRAF/MEK pathway inhibitors. The VE-BASKET and ROAR basket trials explored the efficacy of vemurafenib and the combination of dabrafenib/trametinib, respectively, in BRAF V600 mutation-positive cancers other than melanoma, papillary thyroid cancer, colorectal cancer and non small cell lung cancer. Within the concept of tumor type agnostic therapy, we decided to treat our BRAF-mutated tumors with the association of BRAF and MEK inhibitors. Conclusions: Our results confirm the emerging importance of molecular tumor profiling for the successful management of cancer, and the potential of BRAF-targeted therapy in the treatment of rare solid tumors with poor prognosis and no clinical benefit from systemic therapies with.
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Homicsko, Krisztian Gyuta, Veronica Aedo, Edoardo Missiaglia, Bettina Bisig, and Olivier Michielin. "Targeting MAP2K1 mutation with trametinib in a triple wild-type melanoma patient." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e21027-e21027. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e21027.
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e21027 Background: MAP2K1 inhibitors combined with BRAF inhibitors provide a prolonged progression-free survival for BRAF mutant patients. However, the impact of MEK inhibition of MAP2K1 mutant and BRAF/NRAS/NF1 wild type melanoma patients remains elusive. Methods: We performed next-generation sequencing using an in-house developed 400 full exon panel for one of our triple wild type (BRAF/NRAS/NF1) melanoma patient. The patient received off-label, trametinib at a dose of 2 mg o.d. We performed additional sequencing at progression. After progression, the patient was treated off-label with combined trametinib and palbociclib therapy. Furthermore, we screened the TCGA melanoma and MSK-IMPAKT databases for patients with similar mutation profiles. Results: Our patient presented with dual somatic MAP2K1 mutations at Cys121Ser and Pro124Arg with a 68% allele frequency. The tumor also harbored a minor EGFR mutant clone (11% allele frequency) and a complete loss of the CDKN2A locus. The patient received trametinib and after two months presented a partial response as per RECIST1.1. However, after two additional months, the patient progressed. A new biopsy was performed, and the treatment was modified to combine trametinib and palbociclib to co-target MAP2K1 and the loss of the CKDN2A locus. The patient progressed under dual trametinib/palbociclib therapy without any objective benefit. The on-progression biopsy showed the absence of a gatekeeper mutation of MAP2K1 and the persistence of the loss of the CDKN2A locus. We detected a large number of novel copy number variations, most notable amplification of MITF (9x), FGFR1 (10X) and of MDM2 (16x). We also detected a loss of the minor, EGFR mutant clone. The analysis of large-scale state transitions (LSTs) for deficiency in homolog recombination (HRDness) was negative in pre and post-treatment biopsies. Conclusions: Our patient provides unique evidence to target solitary MAP2K1 mutations in triple wild melanoma by MEK1 inhibitors. Resistance to MEK1 inhibition developed rapidly and likely involved FGFR1 and MDM2, which have not been previously associated with resistance to MEK inhibitor monotherapy. The addition of palbociclib could not rescue these potential resistance mechanisms.
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Fattore, Luigi, Rita Mancini, and Gennaro Ciliberto. "Cancer Stem Cells and the Slow Cycling Phenotype: How to Cut the Gordian Knot Driving Resistance to Therapy in Melanoma." Cancers 12, no. 11 (November 13, 2020): 3368. http://dx.doi.org/10.3390/cancers12113368.
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Cancer stem cells (CSCs) have historically been defined as slow cycling elements that are able to differentiate into mature cells but without dedifferentiation in the opposite direction. Thanks to advances in genomic and non-genomic technologies, the CSC theory has more recently been reconsidered in a dynamic manner according to a “phenotype switching” plastic model. Transcriptional reprogramming rewires this plasticity and enables heterogeneous tumors to influence cancer progression and to adapt themselves to drug exposure by selecting a subpopulation of slow cycling cells, similar in nature to the originally defined CSCs. This model has been conceptualized for malignant melanoma tailored to explain resistance to target therapies. Here, we conducted a bioinformatics analysis of available data directed to the identification of the molecular pathways sustaining slow cycling melanoma stem cells. Using this approach, we identified a signature of 25 genes that were assigned to four major clusters, namely (1) kinases and metabolic changes, (2) melanoma-associated proteins, (3) Hippo pathway and (4) slow cycling/CSCs factors. Furthermore, we show how a protein−protein interaction network may be the main driver of these melanoma cell subpopulations. Finally, mining The Cancer Genome Atlas (TCGA) data we evaluated the expression levels of this signature in the four melanoma mutational subtypes. The concomitant alteration of these genes correlates with the worst overall survival (OS) for melanoma patients harboring BRAF-mutations. All together these results underscore the potentiality to target this signature to selectively kill CSCs and to achieve disease control in melanoma.
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Jamme, Philippe, Guillaume Delzenne, Laurent Mortier, Olivier Farchi, and Marie Boileau. "Relevance of detection of RAF fusion in pan-negative melanoma in routine practice." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e21500-e21500. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e21500.
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e21500 Background: Pan-negative melanomas (i.e. without MAPK kinase pathway alteration and C-kit wild type) account for 30% of melanomas (according to the AACR GENIE database). In case of immunotherapy failure, therapeutic options are limited. Oncogene fusions represent a target of interest in many solid cancers (NSCLC, Cholangiocarcinoma, Glioma, GIST, pancreatic acinar carcinoma, thyroid, and prostate cancers). In melanoma, the frequency of oncogene fusion is not well documented and not routinely investigated. Methods: We conducted a single-center retrospective study. The objective was to determine the frequency of oncogene fusion detected by RNA sequencing (Archer Fusion pLex) performed in routine practice, in patients with advanced or metastatic pan negative melanoma. Data on clinical, pathological, and molecular characteristics and patient outcomes were collected. Analysis was carried out on the genetic material available for the diagnosis of the disease except for 1 patient who benefited from a new anatomopathological sample during an unfavorable evolution. In parallel, an extended molecular alteration search was performed using extended targeted NGS (OncoMine Comprehensive Assay panel). Results: We identified 48 patients with an advanced pan negative melanoma between January 2021 and January 2022 with a median age at diagnosis of 63 years. It was a cutaneous melanoma in 72,9 % (35/48) of the cases, a mucous melanoma in 14,5% (7/48) of the cases and a melanoma of unknown primary site in 12,5% (6/48) of the cases. The detection of fusion transcript was made in 89,5 % (43/48) of the cases. We identified 6 patients with a RAF fusion, including 4 BRAF gene fusion (MKLN1-BRAF, AGK-BRAF, SNX29-BRAF, PTPRJ-BRAF) and 2 RAF1 fusion (MAP4-RAF1, EFCC1-RAF1). Of the other molecular alterations, NF1 mutation was the most frequent molecular alteration identified (25 % (12/48) of patients). At lower frequencies, 6,8 % (3/48) of patients had a PI3K mutation, and 8,3 % (4/48) of patients had NOTCH, PTCH1, GNAQ mutations. Among the 6 patients with RAF fusions, all the patients initially received treatment with anti-PD1+/- anti-CTLA4 immunotherapy. After immunotherapy failure, 4 patients benefited from second-line targeted therapy (2 with BRAF and MEK inhibitors combination, 2 MEK inhibitors alone). One patient presented an objective imaging response, the other three patients have not yet benefited from reassessment imaging. Conclusions: In a population of pan negative melanoma, we detected 12,5 % (6/48) of RAF fusion. Fusion detection allowed the introduction of a second line of targeted therapy, in the absence of a validated therapeutic option in 66,6 % (4/6) of cases This study suggests the relevance of detecting RAF fusion in a selected population.
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Tawbi, Hussein A., Celine Boutros, David Kok, Caroline Robert, and Grant McArthur. "New Era in the Management of Melanoma Brain Metastases." American Society of Clinical Oncology Educational Book, no. 38 (May 2018): 741–50. http://dx.doi.org/10.1200/edbk_200819.
Full textAbstract:
The remarkable advances in the systemic therapy of metastatic melanoma have now extended the 1-year overall survival rate from 25% to nearing 85%. Systemic treatment in the form of BRAF-targeted therapy and immunotherapy is slowly but surely proving its efficacy in the treatment of metatstatic brain metastases (MBM). Single-agent BRAF inhibitors provide an intracranial response rate of 25% to 40%, whereas the combination of BRAFi/MEKi leads to responses in up to 58%. However, the durability of responses induced by BRAFi/MEKi seems to be even shorter than in extracranial disease. On the other hand, single-agent ipilimumab provides comparable clinical benefit in MBMs as it does in extracranial metastases. Single-agent PD-1 anitbodies induce response rates of approximately 20%, and those responses appear durable. Similarly the combination of CTLA-4+ PD-1 antibodies induces durable responses at an impressive rate of 55% and is safe to administer. Although the local treatment approaches with radiation and surgery remain important and are critically needed in the management of MBM, systemic therapy offers a new dimension that can augment the impact of those therapies and come at a potentially lower cost of neurocognitive impairment. Considerations for combining those modalities are direly needed, in addition to considering novel systemic combinations that target mechanisms specific to MBM. In this report, we will discuss the underlying biology of melanoma brain metastases, the clinical outcomes from recent clinical trials of targeted and immunotherapy, and their impact on clinical practice in the context of existing local therapeutic modalities.
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Rager, Taylor, Adam Eckburg, Meet Patel, Rong Qiu, Shahina Gantiwala, Katrina Dovalovsky, Kelly Fan, et al. "Treatment of Metastatic Melanoma with a Combination of Immunotherapies and Molecularly Targeted Therapies." Cancers 14, no. 15 (August 3, 2022): 3779. http://dx.doi.org/10.3390/cancers14153779.
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Melanoma possesses invasive metastatic growth patterns and is one of the most aggressive types of skin cancer. In 2021, it is estimated that 7180 deaths were attributed to melanoma in the United States alone. Once melanoma metastasizes, traditional therapies are no longer effective. Instead, immunotherapies, such as ipilimumab, pembrolizumab, and nivolumab, are the treatment options for malignant melanoma. Several biomarkers involved in tumorigenesis have been identified as potential targets for molecularly targeted melanoma therapy, such as tyrosine kinase inhibitors (TKIs). Unfortunately, melanoma quickly acquires resistance to these molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been employed and have been shown to improve the prognosis of melanoma patients compared to monotherapy. This review discusses several combination therapies that target melanoma biomarkers, such as BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K. Several of these regimens are already FDA-approved for treating metastatic melanoma, while others are still in clinical trials. Continued research into the causes of resistance and factors influencing the efficacy of these combination treatments, such as specific mutations in oncogenic proteins, may further improve the effectiveness of combination therapies, providing a better prognosis for melanoma patients.
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Comunanza, Valentina, Chiara Gigliotti, Gabriella Doronzo, Valentina Martin, Anna Gattuso, Dario Sangiolo, Federica Di Nicolantonio, and Federico Bussolino. "Abstract B17: VEGF removal delays the onset of acquired resistance to target therapy and increases the efficacy of immune checkpoint inhibitors in BRAF-mutated melanoma." Cancer Research 80, no. 19_Supplement (October 1, 2020): B17. http://dx.doi.org/10.1158/1538-7445.mel2019-b17.
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Abstract The introduction of BRAF inhibitors (BRAFi) has improved response rate and overall survival of metastatic melanoma patients compared to standard chemotherapy. However, acquired drug resistance occurs in nearly all patients. The comprehension of cellular and molecular mechanisms underlying BRAFi resistance could help to identify novel actionable pathways in the treatment of BRAF-dependent tumors. VEGFA is an attractive target for combinatorial cancer therapy, and we have recently demonstrated in melanoma and CRC xenografts that targeting VEGFA enhanced the antitumor effect of BRAFi by normalizing the tumor vasculature, recruiting M1 macrophages, and inducing a remodeling of the extracellular matrix characterized by a reduction in collagen I and in cancer-associated fibroblasts (Comunanza et al., EMBO Mol Med 2017). Based on our previous proof of concept, obtained within an immunodeficient model, here we investigated the therapeutic effect of VEGFA targeting in association with PLX4720 (BRAFi) in a dedicated immune-competent model. D4M cells, a BRAFV600E-mutant melanoma murine cell line, were subcutaneously injected in syngeneic C57BL/6J mice. We demonstrated that the association of BRAFi with DC101 (antibody anti-VEGFR2) had a weak activity while we observed a synergistic antitumor effect when combined with B20 (murine anti-VEGFA neutralizing antibody). Although targeted inhibition of either BRAF or VEGFA delayed the tumor growth, only combined inhibition of both pathways resulted in the regression of initial tumor size, with an evident apoptotic effect, and delayed the onset of acquired resistance to the BRAF inhibition. Since the immune-suppressive role of VEGFA in tumors has been well characterized, we further investigated whether contrasting the VEGF effect along with simultaneous BRAF inhibition can turn into a promotion of both innate and adaptive immunity. Immune phenotype analysis revealed that the combinatorial regimen activated the host immune system, inducing the tumor infiltration of macrophages with tumor-suppressive features, NKs, CD4+ and CD8+ lymphocytes. Most of the infiltrating CD8+ lymphocytes in D4M tumors expressed high levels of PD-1 and none of the treatments significantly modulated PD-1 expression on T cells, suggesting a sustained T-cell exhaustion. We then postulated that the therapeutic effect obtained by the combinatorial VEGF blockade and BRAFi could be further enhanced by the association with an immune-checkpoint inhibitor targeting PD-1. Interestingly, we observed that the addition of anti-PD-1 blocking antibody boosted the antitumor effect and induced striking tumor volume regression in mice receiving the triplet therapy (BRAFi+anti-VEGFA+anti-PD1-1). Our findings provide biologic rationale to explore the association of immunotherapy in novel combinatorial approaches that could improve the clinical outcome exerted by oncogene-targeted therapy, and further investigation is warranted. Citation Format: Valentina Comunanza, Chiara Gigliotti, Gabriella Doronzo, Valentina Martin, Anna Gattuso, Dario Sangiolo, Federica Di Nicolantonio, Federico Bussolino. VEGF removal delays the onset of acquired resistance to target therapy and increases the efficacy of immune checkpoint inhibitors in BRAF-mutated melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B17.
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Musi, Alice, and Laura Bongiovanni. "Extracellular Vesicles in Cancer Drug Resistance: Implications on Melanoma Therapy." Cancers 15, no. 4 (February 8, 2023): 1074. http://dx.doi.org/10.3390/cancers15041074.
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Extracellular vesicles (EVs) are involved in the pathogenesis of neoplastic diseases. Their role in mediating drug resistance has been widely described in several types of cancers, including melanoma. EVs can mediate drug resistance through several different mechanisms, such as drug-sequestration, transfer of pro-survival proteins and RNA, induction of cancer stem cell-like features and interaction with cells of the tumor microenvironment and immune-system. Melanoma is a highly immunogenic tumor originating from the malignant transformation of melanocytes. Several therapeutic strategies currently used in the treatment of melanoma and the combination of BRAF and MEK-inhibitors, as well as immune check-point inhibitors (ICI), have consistently improved the overall survival time of melanoma patients. However, the development of resistance is one of the biggest problems leading to a poor clinical outcome, and EVs can contribute to this. EVs isolated from melanoma cells can contain “sequestered” chemotherapeutic drugs in order to eliminate them, or bioactive molecules (such as miRNA or proteins) that have been proven to play a crucial role in the transmission of resistance to sensitive neoplastic cells. This leads to the hypothesis that EVs could be considered as resistance-mediators in sensitive melanoma cells. These findings are a pivotal starting point for further investigations to better understand EVs’ role in drug resistance mechanisms and how to target them. The purpose of this review is to summarize knowledge about EVs in order to develop a deeper understanding of their underlying mechanisms. This could lead to the development of new therapeutic strategies able to bypass EV-mediated drug-resistance in melanoma, such as by the use of combination therapy, including EV release inhibitors.
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Sosman, Jeffrey A. "Abstract IA24: Are there nonimmune targets in the BRAFV600 WT melanoma patient?" Cancer Research 80, no. 19_Supplement (October 1, 2020): IA24. http://dx.doi.org/10.1158/1538-7445.mel2019-ia24.
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Abstract Molecular targeting of melanoma beyond the BRAFV600 mutation has been a frustrating and largely unsuccessful pursuit. The dominant driver in many of these cases is the gain of function NRAS mutations, while a smaller subset are in part driven by NF1 loss of function genetic alterations, and lastly a subset (WT) with a variety of mutations, most of which activate the MAPK pathway such as mutations in c-Kit, MEK, KRAS, HRAS, and alternate non-V600 BRAF mutations. This effort has concentrated on the inhibition of the activated MAPK pathway with MEK inhibitors and targeted NRAS tumors, which make at least 1/3 of the non-BRAF V600 mutant melanoma. As a single agent this approach has been disappointing, but preclinical data support the need for combination therapy, including MEK inhibition with inhibition of alternate pathways such as the PI3/Akt pathway, the cell cycle pathway with CDK4/6 inhibitors, or MDM2 inhibitors to restore functional p53 driven apoptosis. These approaches have been frequently plagued by significant toxicity. Many of these approaches continue to be pursued in the clinic in the hope that different schedules will be more effective and less toxic. An obvious target has been inhibition of downstream pERK which has shown some limited clinical activity. Attacking other pathways looks promising, including targeting mitotic kinases, such as PLK1 and Aurora kinase A. Either inhibiting autophagy or enhancing Bim-directed apoptosis is also under investigation. Finally, we now have a better understanding about the interaction between the targeted agent and the tumor microenvironment. Preclinical and clinical studies show that MEK inhibition can actually enhance the T-cell response at the site of the tumor by selectively eliminating naïve T cells; CDK4/6 inhibition can influence PD-L1 expression and induce retroviral sequences, which then induce an inflammatory (hot) tumor microenvironment. On the other hand, there is further evidence that the microenvironment may be critical for targeted therapy to be effective. This supports an approach combining targeted agents with immune checkpoint inhibitors even in BRAF WT melanoma. While immunotherapy approaches dominate treatment of BRAF WT melanoma, it is critical that we do not lose focus on defining targets, developing better agents, and learning to administer them by an optimal schedule. Citation Format: Jeffrey A. Sosman. Are there nonimmune targets in the BRAFV600 WT melanoma patient? [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA24.
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Gatalica, Zoran, Kathleen D. Danenberg, Matthew Jerome McGinniss, Anatole Ghazalpour, Ryan P. Bender, Raheela Ashfaq, David Arguello, Brian Wright, Nicole Griffin, and Gargi D. Basu. "Molecular profiling of uveal melanoma patients." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 10630. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10630.
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10630 Background: Although uveal melanoma represents only 5% of all melanomas, it is the most common primary intraocular malignancy of the adult eye. Approximately 50% of patients will develop metastases which are resistant to medical interventions. There is a great need for improved therapy as the prognosis is poor for advanced stages. Our study was undertaken to investigate the presence of novel therapeutic targets. Methods: We analyzed 49 uveal melanoma patients with immunohistochemistry for 16 markers including cKIT, PDGFR, cMET, PTEN and IGF1R. Further, microarray analysis was performed on 29 samples using the Illumina platform. We also investigated amplification of EGFR and mutational analysis of cKIT, BRAF, KRAS and NRAS on a smaller patient subset. Results: Overexpression of KIT at the protein and RNA level was 74% (28 out of 38) and 45% (13 out of 29), respectively. Expression of cKIT did not correlate with gain-of-function cKIT mutations in any of the 34 samples tested. In our study, MET was overexpressed in 15 out of 17 cases at the RNA level and IGF1R was high in 4 out of 6 patients indicating poor prognosis. PTEN expression by IHC was present in 90% (36 out of 40) patients indicating the PI3K pathway is not activated in the majority of uveal melanoma patients. BRAF was wildtype in all 42 patients tested. Similarly, no KRAS or NRAS mutations were detected. Protein and RNA expression of PDGFR were low in our patients. MGMT was lost in 16 out of 40 patients at the protein level and 10 out of 29 patients at the RNA level. EGFR expression, copy number and protein levels were low in the patients tested. Conclusions: Our data on cKIT suggests that it is a promising target in uveal melanoma. Low expression of MGMT in about a third of our patients may indicate the likelihood of favorable response to dacarbazine and temozolomide. There are currently several clinical trials investigating various cKIT inhibitors, as well as temozolomide in advanced uveal melanoma patients. Our findings highlight the importance of molecular profiling uveal melanoma patients.
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Mikhaylova, I. N., E. M. Treshalina, L. F. Morozova, N. V. Andronova, I. Zh Shubina, and A. A. Lushnikova. "Cell lines of human melanoma and their xenograft with braf or nras mutations a targets for targeted therapy. Reviews." Russian Journal of Biotherapy 17, no. 4 (January 11, 2019): 27–35. http://dx.doi.org/10.17650/1726-9784-2018-17-4-27-35.
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The review presents a discussion on articles and patents, describing new in vitro and in vivo models of pigmented or non-pigmented human cutaneous melanoma, received in NMRCO from the patients» metastases. Molecular genetic characteristics of the new models is supported by the arguments in addition to the given data and visual materials. The subjects of the discussed publications are 3 polyclonal cell lines, 2 subclones and 4 subcutaneous (s/c) xenografts in immunodeficient mice Balb/c nude. All the models are stored in Cryo Collection with xenografts at N.N. Blokhin NMRCO as well as in the Russian Collection of Cell Cultures of Vertebrae (RCCCV, St. Petersburg). This mini-collection is recommended for use in basic research of cutaneous melanoma and pre-clinical studies of anti-melanoma agents. The basis for these studies are the appropriate characteristics of the models, including cytological, immunologic, transplantation and molecular-genetic ones, as well as in vivo drug sensitivity to the corresponding target therapy.
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Sarnaik, Amod, Nikhil Khushalani, Jason Chesney, Harriet Kluger, Brendan Curti, Karl Lewis, Theresa Medina, et al. "P865 Safety & efficacy of lifileucel (LN-144) tumor infiltrating lymphocyte therapy in metastatic melanoma patients after progression on multiple therapies – independent review committee data update." Journal for ImmunoTherapy of Cancer 8, Suppl 1 (April 2020): A12. http://dx.doi.org/10.1136/lba2019.18.
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BackgroundTreatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel, a centrally manufactured cryopreserved autologous TIL therapy assessed by both investigator and an independent review committee (IRC), are presented.MethodsC-144-01 is a global Phase 2 open-label, multicenter study of the safety and efficacy of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 66) patients with Stage IIIC/IV unresectable melanoma who received lifileucel. Tumors resected at local institutions were processed in central GMP facilities for TIL production in a 22-day process. Final TIL infusion product was cryopreserved and shipped to sites. Patients received one week of cyclophosphamide/fludarabine preconditioning lymphodepletion, a single lifileucel infusion, followed by up to 6 doses of IL-2. All responses were assessed by RECIST 1.1.Results66 patients had the following baseline characteristics: 3.3 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 23%), relatively high tumor burden (106 mm mean target lesion sum of diameters), 44% with liver and/or brain lesions, median LDH 244 U/L. Objective Response Rate (ORR) by investigator was 36.4% (2 CR, 22 PR, 1 previously confirmed PR is now changed to SD) and Disease Control Rate (DCR) of 80.3%. At a median follow up of 9.7 months, median Duration of Response (DOR) has not been reached. The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens.The ORR per IRC was 34.8% (2 CR, 21 PR) and DCR was 72.7%. At a median follow up of 6.9 months, the median IRC DOR has not been reached. Overall concordance rate of investigator and IRC read of response was 89.4%. The concordance compares favorably with literature reports in a metastatic disease.1ConclusionsLifileucel treatment resulted in a 36.4% ORR in heavily pretreated metastatic melanoma patients with high baseline disease burden who had received prior anti-PD1 and BRAF/MEK inhibitors, if tumor BRAF mutated. The high concordance of 89.4% between investigator and IRC confirms the original assessment of lifileucel efficacy in metastatic melanoma.2AcknowledgementsThe authors would like to thank the patients and their families for participation in the study.The authors would also like to acknowledge the support and dedication of all investigators and site team members from all participating clinical trial institutions.Trial RegistrationClinicalTrials. gov Identifier: NCT02360579Ethics ApprovalEthics Approval This trial was approved by Western Institutional Review Board - IRB Tracking Number: 20160198.ReferencesGhiorghiu DC, et al. Comparison of central and site review of RECIST data in an open randomised phase II trial in advanced melanoma. 10.1594.ecr 2009/C-075.Sarnaik A, et al. Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients who progressed on multiple prior therapies including anti-PD-1. J Clin Oncol 2019;37:2518–2518.
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Kendra, Kari Lynn, Ryan Watson, and Gregory B. Lesinski. "Selinexor, a selective inhibitor of nuclear export (SINE), in patients with unresectable melanoma." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e21014-e21014. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e21014.
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e21014 Background: Limited effective therapies exist for patients with melanoma after progression on immune- and targeted-therapies. Treatment with selinexor, a potent small molecule inhibitor of exportin-1 (CRM/XPO1), results in nuclear retention of major tumor suppressor proteins and cell cycle regulators, leads to growth arrest and apoptosis in vitro, in xenograft models (BRAF +/-), and Phase I solid tumor trial. (Yang et al PLOS One, 2014, Razak et al JCO, 2016). Methods: Objectives of this single institution trial were to determine: the safety in melanoma patients, the clinical benefit rate, and efficacy at the MTD as measured by PFS. Patients received prior immunotherapy and a BRAF inhibitor (mutation positive). Lead-in phase is completed. Median number of prior systemic therapies = 2 (2 – 4). Selinexor (50 mg/m2) was orally administered twice weekly, with 2-3 days off between doses. Toxicities were evaluated every 28-days. Tumor biopsies were collected for correlative analysis. Results: As of Jan 2017, 7 patients (0/7 BRAF mutant) were enrolled. Drug related AEs: neutropenia (grade 4) (1/7 patients), hyponatremia (grade 3) (1/7 patients), thrombocytopenia (Grade 3) (3/7 patients), anemia (Grade 3) (1/7 patients), and thromboembolic events (Grade 3) (1/7 patients). There were no DLT’s. Four patients experienced stable disease (SD); one patient had a minor response, for a disease control rate (DCR) of 71% (5/7). Mean duration of response was 207 days (70 – 335). One patient, removed from therapy due to a CNS met, continued with stable systemic disease off therapy for 177 days. Another patient, taken off therapy due to a non-drug related adverse event, remained SD for 127 days. Conclusions: These preliminary results demonstrate that selinexor is well tolerated with supportive care, is safe for melanoma patients dosed at the 50 mg/m2, and has the potential to control disease progression as a single agent in patients with prior BRAF inhibitor and immunotherapy. Patients are currently enrolling at a flat 60 mg dose. Correlative studies including evaluation of selinexor target engagement and exploratory markers of drug response are underway. Clinical trial information: NCT02120222. Clinical trial information: NCT02120222.
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Sarnaik, Amod, Nikhil I. Khushalani, Jason Alan Chesney, Karl D. Lewis, Theresa Michelle Medina, Harriet M. Kluger, Sajeve Samuel Thomas, et al. "Long-term follow up of lifileucel (LN-144) cryopreserved autologous tumor infiltrating lymphocyte therapy in patients with advanced melanoma progressed on multiple prior therapies." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 10006. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.10006.
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10006 Background: Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) leverages and enhances the body’s natural defense against cancer and has shown durable responses in heavily pretreated melanoma patients. Methods: C-144-01 is a global Phase 2 open-label, multicenter study of efficacy & safety of lifileucel in patients with unresectable metastatic melanoma who have progressed on checkpoint inhibitors and BRAF/MEK inhibitors, if BRAFv600 mutant. We report on Cohort 2 (N = 66) patients who have received TIL. Tumors were resected at local institutions, processed in central GMP facilities for TIL production, manufactured, cryopreserved & shipped back to sites in a 22-day process. Therapy consisted of one week of lymphodepletion, a single lifileucel infusion, and up to 6 IL-2 doses. ORR was based on RECIST v1.1 by investigator assessment. Data cutoff was Feb 2, 2020. Results: Baseline characteristics: 3.3 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 23%), high baseline tumor burden (106 mm mean target lesion sum of diameters), 44% liver/brain lesions, 40.9% LDH > ULN. ORR by investigator was 36.4% (2 CR, 22 PR) and DCR was 80.3%. Mean time to response was 1.9 months (range: 1.3-5.6). After a median study follow-up of 17.0 months, median DOR (mDOR) was still not reached. Six responders have progressed, 2 have died and 2 started other anti-cancer therapy without progression. The adverse event profile was consistent with the underlying advanced disease and the lymphodepletion and IL-2 regimens. Additional follow-up data will be available for presentation. Conclusions: Lifileucel treatment results in a 36.4% ORR and mDOR was not reached at 17.0 months of median study follow up in a heavily pretreated metastatic melanoma patients with high baseline disease burden who progressed on multiple prior therapies, including anti-PD1 and BRAF/MEK inhibitors, if BRAFv600 mutant. Clinical trial information: NCT02360579.
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Rebecca, Vito W., Jianglan Liu, Thomas Connelly, Keith Flaherty, Ze’ev Ronai, and Meenhard Herlyn. "Abstract PR18: Comparative screening of skin-derived NCSCs, melanocytes, and melanoma developmental programs reveals LPAR1 in MAPKi resistance." Cancer Research 80, no. 19_Supplement (October 1, 2020): PR18. http://dx.doi.org/10.1158/1538-7445.mel2019-pr18.
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Abstract Despite the high efficacy of BRAFi/MEKi in BRAF-MT melanomas, resistance arises in the majority of cases. Melanoma hijacks developmental pathways that drive aggressiveness; however, gene signatures shared by melanocyte progenitor cells and melanoma cells remain poorly understood. Here, we define common dependencies in neural crest stem cells (NCSCs) and melanoma cells not present in melanocytes through computational transcriptome analyses and targeted siRNA screens against shared developmental genes. Secondary validation coupled with Ingenuity Pathway Analysis identified the LPAR1-RAPGEF5-RAP1A axis as the top pathway critical for stem cell maintenance and melanoma aggressiveness. Genome-wide gene expression data in the CCLE demonstrates LPAR1 correlates with the MITFlo/AXLhi intrinsic MAPKi resistance signature. In agreement, LPAR1 is elevated in MAPKi-resistant PDX models, and in a subset of post-treatment tumor biopsies from patients who relapsed on MAPKi, relative to respective paired pretreatment biopsies. Melanocytes and fibroblasts express low levels of LPAR1 and are not sensitive to LPAR1i. In contrast, genetic silencing of LPAR1 and pharmacologic inhibition of LPAR1 with HA130, an upstream LPAR1 inhibitor, triggers cell cycle arrest and antitumor activity in MAPKi-resistant cells in vivo. Mechanistically, genetic and pharmacologic targeting of LPAR1 downregulates genes involved in the PI3K/mTOR and Hippo/YAP. Concurrent depletion of YAP and S6K cells significantly impairs melanoma viability relative to knockdown of YAP or S6K alone, suggesting that Hippo/YAP and mTOR/S6K pathways are main downstream effectors of LPAR1 signaling in melanoma. Our data identify novel pathways responsible for the escape of BRAF mutant melanoma from MAPKi therapy, and our hypothesis is that concurrent BRAFi/MEKi/LPAR1i may have therapeutic efficacy. This abstract is also being presented as Poster B02. Citation Format: Vito W. Rebecca, Jianglan Liu, Thomas Connelly, Keith Flaherty, Ze’ev Ronai, Meenhard Herlyn. Comparative screening of skin-derived NCSCs, melanocytes, and melanoma developmental programs reveals LPAR1 in MAPKi resistance [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR18.
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Betoff, Allison, Jonathan Zippin, Taha Merghoub, Paul B. Chapman, and Jedd Wolchok. "Abstract IA10: Targeting melanoma metabolism to overcome resistance to treatment." Cancer Research 80, no. 19_Supplement (October 1, 2020): IA10. http://dx.doi.org/10.1158/1538-7445.mel2019-ia10.
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Abstract Despite adequate oxygen levels, cancer cells undergo anaerobic glycolysis converting glucose to lactate (the Warburg effect). It is now thought that the advantage of this for the cancer cell is that it provides the carbon and nitrogen precursors critical for macromolecule synthesis (amino acids, nucleotides, fatty acids) while still providing an adequate supply of ATP needed for growth. Understanding this metabolic landscape may provide strategies to overcome mechanisms of resistance to therapy in melanoma. AMP-activated protein kinase (AMPK) has been shown to inactivate BRAF by phosphorylating Ser 729, and in preclinical models, this can be used to enhance inhibitors of BRAFV600E. In the high ATP environment of a melanoma cell, AMPK is typically low but inducers of AMPK, such as biguanides, increase AMPK. The biguanide metformin does not enter melanoma cells efficiently due to the lack of organic cation transporter (OCT) expression on melanoma cells. However, phenformin does not require OCT for uptake. We are conducting a phase I trial in BRAF V600E-mutated melanoma patients using dabrafenib/trametinib and escalating doses of phenformin. One of the pharmacodynamic effects of phenformin is weight loss, which we are measuring. Interestingly, obesity has been associated with improved outcome in male melanoma patients treated with anti-PD1 antibodies. In contrast, our data in melanoma patients treated with anti-PD1 antibody immunotherapy do not show an association between outcome and obesity. Another consequence of anaerobic glycolysis is generation and excretion of large amounts of lactate. There is evidence that lactate can inhibit T-cell function, and we will discuss strategies to block lactate transport to enhance immunotherapy. Citation Format: Allison Betoff, Jonathan Zippin, Taha Merghoub, Paul B. Chapman, Jedd Wolchok. Targeting melanoma metabolism to overcome resistance to treatment [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA10.
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Zhai, Zili, Prasanna K. Vaddi, Jenny Mae Samson, Tomoya Takegami, and Mayumi Fujita. "NLRP1 Functions Downstream of the MAPK/ERK Signaling via ATF4 and Contributes to Acquired Targeted Therapy Resistance in Human Metastatic Melanoma." Pharmaceuticals 14, no. 1 (December 30, 2020): 23. http://dx.doi.org/10.3390/ph14010023.
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The BRAF V600E mutation leads to constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and its downstream effector responses. Uncovering the hidden downstream effectors can aid in understanding melanoma biology and improve targeted therapy efficacy. The inflammasome sensor, NACHT, LRR, and PYD domains-containing protein 1 (NLRP1), is responsible for IL-1β maturation and itself is a melanoma tumor promoter. Here, we report that NLRP1 is a downstream effector of MAPK/ERK signaling through the activating transcription factor 4 (ATF4), creating regulation in metastatic melanoma cells. We confirmed that the NLRP1 gene is a target of ATF4. Interestingly, ATF4/NLRP1 regulation by the MAPK/ERK pathway uses distinct mechanisms in melanoma cells before and after the acquired resistance to targeted therapy. In parental cells, ATF4/NLRP1 is regulated by the MAPK/ERK pathway through the ribosomal S6 kinase 2 (RSK2). However, vemurafenib (VEM) and trametinib (TRA)-resistant cells lose the signaling via RSK2 and activate the cAMP/protein kinase A (PKA) pathway to redirect ATF4/NLRP1. Therefore, NLRP1 expression and IL-1β secretion were downregulated in response to VEM and TRA in parental cells but enhanced in drug-resistant cells. Lastly, silencing NLRP1 in drug-resistant cells reduced their cell growth and inhibited colony formation. In summary, we demonstrated that NLRP1 functions downstream of the MAPK/ERK signaling via ATF4 and is a player of targeted therapy resistance in melanoma. Targeting NLRP1 may improve the therapeutic efficacy of targeted therapy in melanoma.
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Madhusudanannair, Vinu, Filip Janku, Gerald Steven Falchook, David S. Hong, Jennifer J. Wheler, Aung Naing, Siqing Fu, et al. "NRAS mutations in patients with advanced cancers treated with target-based therapies in early-phase clinical trials." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 3106. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.3106.
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3106 Background: NRAS mutations in cancers increase MAPK signaling. It is plausible that NRAS mutations may be associated with sensitivity to drugs targeting the MAPK pathway. Methods: Tumors from 689 patients with advanced cancers referred to the Clinical Center for Targeted Therapy (phase I program) were screened in a CLIA-certified laboratory for NRAS mutations and if feasible, for PIK3CA, KRAS, BRAF mutations and PTEN aberrations. Whenever possible, patients with NRAS mutations were treated with agents targeting the RAF-MEK pathway. Results: Of the 689 patients, 58 (8%) had NRAS mutations. NRAS mutations were most prevalent in melanoma (26/170, 25%), thyroid (5/26, 19%), endometrial (2/27, 7%), non-small cell lung (1/31, 3%), ovarian (1/60, 2%) and colorectal cancers (1/74, 1%). NRAS mutations were not seen in any of the tested head and neck squamous cell cancers (n = 44); sarcomas (n = 41) and breast cancers (n = 25). None (0/62, 0%) of the patients tested for KRAS had simultaneous NRAS and KRAS mutations, and only 2/42 (5%) tested for BRAF had simultaneous NRAS and BRAF mutations. Of 58 patients with NRAS mutations, 14 (24%) were enrolled in trials that included MEK axis inhibitors. Of these 14 patients, 13 had melanoma and 1 had ovarian cancer and 4/14 (29%) demonstrated tumor shrinkage >10% from baseline. In comparison, only 22/187 (12%) patients with wild-type/unknown NRAS, KRAS and BRAF treated on the same trials demonstrated tumor shrinkage >10% (p=0.086). Conclusions: NRAS mutations are diagnosed in variety of advanced cancers. Patients with NRAS mutations demonstrated a trend to better antitumor activity with MEK axis inhibitors compared to patients without NRAS, KRAS or BRAF mutations. Further studies are warranted to delineate the role of NRAS mutations in patients treated with MEK axis inhibitors.
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Wagenseller, Aubrey G., Amber L. Shada, Kevin D'Auria, Cheryl F. Murphy, Dandan Sun, Kerrington R. Molhoek, Jason A. Papin, Anindya Dutta, and Craig L. Slingluff. "MicroRNAs induced in melanoma treated with combination targeted therapy of temsirolimus and bevacizumab." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 8597. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8597.
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8597 Background: Targeted therapies directed at commonly overexpressed pathways in melanoma have clinical activity in numerous trials. Little is known about how these therapies influence microRNA expression, particularly with combination regimens. A better understanding of how microRNAs are altered with treatment may contribute to understanding mechanisms of therapeutic effects as well as mechanisms of tumor escape from therapy. Methods: Using microRNA arrays, we analyzed microRNA expression levels in melanoma samples from a Cancer Therapy Evaluation Program-sponsored phase II trial of combination temsirolimus and bevacizumab in stage III or IV melanoma, which elicited clinical benefit in a subset of patients. Seventeen patients were treated with temsirolimus for one week, then combination of both temsirolimus and bevacizumab. Metastatic melanoma biopsies were evaluated days 1, 2, and 23. Tumor samples were evaluated from 12 patients. Results: microRNA expression remained unchanged with temsirolimus alone; however, expression of 15 microRNAs was significantly upregulated (1.4 to 2.5-fold) with combination treatment, compared to pre-treatment levels. Interestingly, twelve of these fifteen microRNAs have been reported to possess tumor suppressor capabilities in various cancer types, including melanoma. We identified 15 putative oncogenes and B7-H3, IGF-1, and IGF-1R as potential targets of the 12 tumor suppressor microRNAs, based on published experimental evidence. For 18 of 25 pairings of microRNA and target-mRNA, changes in gene expression from pretreatment to post-combination treatment samples were inversely correlated with changes in microRNA expression, suggesting a functional effect of the microRNA changes induced by combination therapy. Clustering analysis based on selected microRNAs revealed signatures characteristic of clinical response to combination treatment and of tumor BRAF mutational status. Conclusions: We have identified microRNAs that may be involved in the mechanism of action of combination temsirolimus and bevacizumab in metastatic melanoma, possibly through inhibition of oncogenic pathways.
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Vosganian, Gregory S., Rinke Bos, and Linda Sherman. "Immunologic Effects of An Oral BRAF Inhibitor in a BRAF Wild-Type Murine Model." Blood 118, no. 21 (November 18, 2011): 4935. http://dx.doi.org/10.1182/blood.v118.21.4935.4935.
Full textAbstract:
Abstract Abstract 4935 Introduction: Metastatic melanoma represents a clinical challenge as aggressive therapy often results in unacceptable toxicity and less intensive therapy results in suboptimal clinical outcomes. PLX-4032 is an orally available small molecule which targets constitutively activated BRAFV600E in melanoma cells. BRAF is an important regulator of cell growth, proliferation and migration. We examined the effect of PLX-4032 on the immune system in two BRAF wild type murine systems: the first to determine the effect of PLX-4032 on cytokine production and the second to determine any functional immune effect of PLX-4032 in an insulinoma model. Methods: Effect of PLX-4032 on cytokine production: B10.D2 BRAF WT mice were injected with CD8 lymphocytes expressing a TCR specific for HA518-526 peptide (clone 1) and CD4 lymphocytes expressing a TCR specific for HA110-119 peptide (SFE) on Day 0 and concurrently simulated with appropriate peptide, incomplete Freund's adjuvant, and poly IC. Mice received PLX-4032 200mg/kg or placebo daily for 5 days. On day 6, splenic lymphocytes were harvested and flow cytometry performed to determine CD4 and CD8 IL2, IFN gamma, and TNF alpha production. Effect of PLX-4032 on functional immune response: B10.D2 BRAF WT rat insulin promoter (RIP)-Tag2-hemagglutinin mice bearing insulinoma were injected with clone 1 and SFE lymphocytes on Day 0 and received concurrent stimulation as above. Mice received PLX-4032 200mg/kg or placebo daily for 30 days and serum glucose levels were monitored weekly. Results: Effect of PLX-4032 on cytokine production: We noted no significant difference in the absolute number of splenic lymphocytes recovered in the two groups. There was no significant difference in the percent of CD8+ clone 1 cells producing TNF alpha, IL2 or IFN gamma. There was similarly no significant difference in the percent of CD4+/SFE lymphocytes recovered between the treatment and control groups, nor was there a significant difference in the percent of cells producing IFN gamma. Effect of PLX-4032 on functional immune response: Treatment with PLX-4032 resulted in no significant inhibition of the immune response of transferred lymphocytes against insulinoma. Mice in both groups developed significantly elevated serum glucose levels at the same time and remained diabetic for a similar duration. Discussion: Our data demonstrate that PLX-4032 does not appear to exert a quantitative or functional effect on the immune system in BRAF WT mice. Melanoma therapies often include medications which augment patient immune function or specifically target immune regulation; these data suggest that PLX-4032 does not inhibit normal immune function and therefore may have a role in combination with immunologically directed therapy, possibly resulting in synergistic anti-tumor effect by targeting multiple pathways involved in tumor survival. Disclosures: No relevant conflicts of interest to declare.