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Littérature scientifique sur le sujet « APR-246 »

Auteur : Grafiati
Publié le 1 avril 2023

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Articles de revues sur le sujet "APR-246"

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Jonsson-Videsater, Kerstin, Dina Ali, Hareth Nahi, Sofia Bengtzen, Stefan Deneberg, Christer Paul et Soren Lehmann. « In Vitro and Ex Vivo Studies On Cell Lines and Primary Human Leukemia Cells of the Effects of APR-246 Alone and in Combination with Conventional Chemotherapeutic Drugs. » Blood 114, no 22 (20 novembre 2009) : 2751. http://dx.doi.org/10.1182/blood.v114.22.2751.2751.

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Abstract Abstract 2751 Poster Board II-727 Introduction: Mutations of TP53 are associated with an extremely poor prognosis in hematopoietic malignancies and is found in 10 to 15% of patients with AML. APR-246 is a methylated form of the small molecule PRIMA-1. It primarily targets mutated p53 protein, but has cytotoxic and apoptosis inducing effects on primary leukemia cells from AML and CLL patients irrespectively of p53 status even though cells with mutated p53 have been shown to be more sensitive. In May 2009, a first-in-man trial has been initiated evaluating the effect of APR-246 in hematologic malignancies. Patients and Methods: Leukemic blast cells from 32 untreated patients with AML were isolated and analyzed. Sixteeen selected patients had normal karyotype and 16 selected patients had complex karyotype. All patient DNA were sequenced at exon 5-8 of TP53 gene. Cells were exposed to APR-246 (2.5μM and 5μM), Ara-C (0.5μM), daunorubicin (0,05μM) and fludarabin (1μM) alone and in combinations. Different timing schedules of the exposure were also used. Cell viability was assayed by bioluminescence measuring ATP. Expression of p53, Bax, Bcl-2 and active caspase –3 and induction of reactive oxygen species (DCF-fluorescence) was analyzed by flow cytometry. We also analyzed two leukemia cell lines, KBM3 and NB4, with and without p53mutation respectively, in order to study the combination effect with chemotherapeutic drugs and the role of preincubation with either of the drug. The Combination Index (CI) was calculated according to the additive model where a CI of less than 0.8 indicates synergy (Möllgård et al CCP, 2008). We also performed global gene expression analysis with Affymetrix platform 1.0 after 18h of APR-246 treatment at 15μM and 25μM in vitro. Results: APR-246 induced dose dependent cytotoxic effects in primary AML samples with a IC50 value of 5.0 μM after 4 days of incubation. A statistically significant increase in the expression of active caspase-3 after 48h treatment with APR-246 (p<0.001) and a tendency to p53 up-regulation (p=0.056) could be detected in patient cells with both normal and complex karyotype. Patients that up-regulated p53 after APR-246 exposure were more sensitive to APR-246 (p<0.05) and had a significantly lower level of Bax (p<0.05) before APR-246 treatment. The seven patients with TP53 mutation had significant lower sensitivity to daunorubicin and fludarabin (p<0.01) in vitro but not to APR-246, indicating a possible treatment alternative in multidrug resistant cells. In primary AML cells, the combination of APR-246 and daunorubicin was the most effective drug combination and gave strong synergy at simultaneous incubation. The TP53 mutated KBM3 cell line was significantly more sensitive to APR-246 (p<0.01) than wt TP53 NB4 cell line with IC50 of 15μM and 45μM respectively. Simultaneous exposure of APR-246 and conventional chemothperapeutic drugs showed synergy in drug combinations tested in both the mutated and the wild type cell line. Pre-incubation with APR-246 gave significantly stronger synergism with all tested drugs combined with 15μM APR-246 (CI for DNR 0.76, for Ara-C 0.65 and for fludarabin 0.60). Pre-incubation with conventional chemotherapeutic drugs showed significantly less synergy. Flow cytometry demonstrated a 2-fold increase in reactive oxygene species (ROS) after 24h and a 15-fold increase after 48h of APR-246 treatment in the TP53 mutated cell line. Global gene expression analysis showed that 50 % of the genes that were upregulated more than a 2.0 fold by APR-246 were associated to the redox status of the cells. Genes that were significantly upregulated were SLC7A11 and oxygenase 1, indicating that APR-246 may exert some of its cytotxic effects by incuding oxidative stress. Conclusions: We conclude that APR-246 exhibits a concentration and time dependent cytotoxic effects in wt and p53 mutated cell lines and primary AML cells ex vivo. APR-246 shows strong synergism together with conventional chemotherapeutic drugs, especially with pre-incubation with APR-246. The anti-leukemic effects are associated with an increase in ROS. A first-in-man trial with APR-246 in haematological malignancies has been initiated and an update of the trial will be given at the meeting. Disclosures: Paul: Aprea AB: Consultancy, Research Funding. Lehmann:Aprea AB: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Ceder, Anna Sophia, Sofi E. Eriksson, Emarndeena Haji Cheteh, Vladimir J. N. Bykov, Lars Abrahmsen et Klas G. Wiman. « Impact of combined MRP1 inhibition and mutant p53-targeting compound APR-246. » Journal of Clinical Oncology 37, no 15_suppl (20 mai 2019) : e14712-e14712. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14712.

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e14712 Background: The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. Mutant p53 protein is often expressed at high levels and accompanied with gain-of-function activities that promote tumor development and resistance towards conventional treatment. APR-246 is a mutant p53-reactivating small molecule undergoing a Phase III clinical study in myelodysplastic syndrome (MDS), and several phase II studies. APR-246 is non-enzymatically converted to its active product methylene quinuclidinone (MQ) which binds to cysteine residues in p53. This stimulates proper folding of p53's DNA-binding core domain, leading to cell death. APR-246 also exhibits pro-oxidant activity as the electrophile MQ binds and inactivates important antioxidants such as glutathione and thioredoxin reductase, which both are essential for cellular defense against oxidative and electrophilic stress. Methods: All results are in vitro experiments by LC-MS as well as experiments in cultured cells, including 14C-APR-246/MQ detection, cell viability measurements, LC-MS analysis, enzyme recycling measurements and Western blotting. Results: We have utilized 14C-labelled APR-246 to investigate the effect of APR-246 and its active moiety MQ in tumor cell cultures upon inhibition of efflux transporter multidrug resistance protein 1 (MRP1) or cystine-glutamate transporter (xCT). Transient downregulation or small molecule inhibitors (MK-571, reversan, sulfasalazin) targeting MRP1 or xCT increased drug content and shifted intra- and extracellular thiol status. Missense mutant TP53-carrying cells exhibited higher sensitivity to APR-246 and combination therapies. MRP1 inhibition showed strong synergy with APR-246 and increased intracellular levels of MQ conjugated to glutathione (GS-MQ). We found that GS-MQ conjugate formation is reversible, and suggest that the intrinsic reversibility of MQ adduct formation is an important aspect of the mechanism of action of APR-246. This reversibility may also in part account for the benign safety profile reported from clinical studies with APR-246. Conclusions: Sensitivity to APR-246 is affected by MRP1 efflux activity and the redox status, reflected in ratios of cysteine/cystine and reduced/oxidized glutathione (GSH/GSSG).
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Müller, Michael, Lisa Rösch, Sara Najafi, Charlotte Gatzweiler, Johannes Ridinger, Xenia F. Gerloff, David T. W. Jones et al. « Combining APR-246 and HDAC-Inhibitors : A Novel Targeted Treatment Option for Neuroblastoma ». Cancers 13, no 17 (5 septembre 2021) : 4476. http://dx.doi.org/10.3390/cancers13174476.

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APR-246 (Eprenetapopt/PRIMA-1Met) is a very potent anti-cancer drug in clinical trials and was initially developed as a p53 refolding agent. As an alternative mode of action, the elevation of reactive oxygen species (ROS) has been proposed. Through an in silico analysis, we investigated the responses of approximately 800 cancer cell lines (50 entities; Cancer Therapeutics Response Portal, CTRP) to APR-246 treatment. In particular, neuroblastoma, lymphoma and acute lymphocytic leukemia cells were highly responsive. With gene expression data from the Cancer Cell Line Encyclopedia (CCLE; n = 883) and patient samples (n = 1643) from the INFORM registry study, we confirmed that these entities express low levels of SLC7A11, a previously described predictive biomarker for APR-246 responsiveness. Combining the CTRP drug response data with the respective CCLE gene expression profiles, we defined a novel gene signature, predicting the effectiveness of APR-246 treatment with a sensitivity of 90% and a specificity of 94%. We confirmed the predicted APR-246 sensitivity in 8/10 cell lines and in ex vivo cultures of patient samples. Moreover, the combination of ROS detoxification-impeding APR-246 with approved HDAC-inhibitors, known to elevate ROS, substantially increased APR-246 sensitivity in cell cultures and in vivo in two zebrafish neuroblastoma xenograft models. These data provide evidence that APR-246, in combination with HDAC-inhibitors, displays a novel potent targeted treatment option for neuroblastoma patients.
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Hong, Yuheng, Tianyuan Ren, Xiaoxuan Wang, Kai Fu, Xianhuo Wang et Huilai Zhang. « APR-246 Reveals a Therapeutic Potential Via Triggering Different Cell Death Mechanisms in Diffuse Large B Cell Lymphoma ». Blood 138, Supplement 1 (5 novembre 2021) : 3521. http://dx.doi.org/10.1182/blood-2021-150582.

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Abstract Background: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy and is characterized by its pronounced genetic and clinical heterogeneity. Although the first-line therapy (R-CHOP) improves the curability of patients with DLBCL, nearly 40% remainder ultimately undergo relapsed or refractory disease. Emerging evidence has shown that TP53 mutations correlate with the recurrence and progression of DLBCL. APR-246, also known as PRIMA-1MET, can reactivate the trans-activation of TP53 mutants by facilitating their DNA binding to target genes, making it a promising therapeutic compound for mutated TP53 carcinomas. Although APR-246 in combination with other chemicals has been applied in clinical trials for non-Hodgkin lymphoma (NHL), the efficacy and the underlying molecular mechanisms of APR-246 on DLBCL remain unclear. The arms are to investigate the TP53 mutations and the correlation of mutated TP53 with the prognosis. Furthermore, we evaluated the effect of APR-246 on DLBCL in vitro and in vivo. Methods: Multiple datasets, including the Gene Expression Omnibus (GEO) and cBioPortal, were searched for available data for DLBCL. For evaluation of APR-246 effect on DLBCL in vitro, ten DLBCL cell lines harbouring different and representative molecular properties, especially distinct TP53 mutation status, were tested. To validate the therapeutic effect of APR-246 in vivo, NSG mice were injected subcutaneously with the DLBCL cells with TP53 mutations to establish a xenograft animal model, and then these mice received the APR-246 administration. The cell viability of DLBCL was measured post addition of APR-246. Pharmaceutical inhibition of different cell death pathways was applied to elucidate the mechanisms by which APR-246 functions. Results: Total 2204 patients with DLBCL were evaluated, of which nearly 15% contained TP53 mutations. The missense mutation of TP53 was up to 76% and mutations occurring in the DNA binding domain (DBD) was about 90%. Patients with TP53 mutations had poor OS (p=0.0118). Further, we found that patients with TP53 mutations in GCB and UNC subtypes exhibited inferior OS (p=0.043; p=0.049, respectively), but no in ABC subtype. Notably, TP53 single mutations located in the DBD (exon 5-8) led to an unfavorable survival (p=0.0263), while patients carrying TP53 multiple mutations and single mutations in other domains exhibited no difference in survival time than those with wild-type TP53. APR-246 induced the cell death in a dose dependent manner for all DLBCL cell lines. DLBCL cells with TP53 missense mutations in the DBD were the most sensitive to APR-246 than those with intact or other types of mutated TP53. APR-246 mediated the cell death via p53-dependent ferritinophagy for DLBCL cells with TP53 missense mutations in the DBD. In addition, APR-246 also induced the ferroptosis for other DLBCL cells harbouring wild type TP53 and other forms of TP53 mutations. Conclusions: Nearly 15% of patients with DLBCL harbouring TP53 mutations had inferior prognosis than those with wild-type TP53. Patients with TP53 single mutations occurred in the DBD (exon 5-8) showed poorer prognosis than those with TP53 multiple mutations and single mutations in other domains. APR-246 induced the cell death of DLBCL through different mechanisms, depend on different forms of TP53 mutations, which provided an evidence for clinical application of APR-246 in the treatment of DLBCL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Synnott, Naoise C., Alyson M. Murray, Norma O'Donovan, Michael J. Duffy et John Crown. « Combined treatment using the anti-p53 drug, APR-246 and eribulin : Synergistic growth inhibition in p53-mutated breast cancer cells. » Journal of Clinical Oncology 35, no 15_suppl (20 mai 2017) : e14098-e14098. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e14098.

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e14098 Background: TP53 is the most frequently mutated gene in triple-negative breast cancer, being present in approximately 80% of cases. APR-246 is a novel anticancer drug that acts by reactivating the mutant p53 protein, thereby converting it to a form with wild-type properties. Previously, we showed that APR-246 had antiproliferative, anti-migratory and pro-apoptotic activities in a panel of 23 breast cancer cell lines, including triple-negative (TN) cell lines. The aim of this study was to investigate if combined treatment with APR-246 and different cytotoxic agents resulted in enhanced growth inhibition. Methods: Cell viability was determined using the MTT assay. Combination index (CI) values were calculated using Calcusyn software, based on the Chou-Talalay method. Apoptosis was detected using Annexin V-FITC Apoptosis Detection Kit followed by FACs analysis. Results: Highly synergistic cell growth inhibition was found when APR-246 was combined with eribulin (Eisai Ltd.) in 6 different p53-mutated cell lines (mean CI values range from 0.38 to 0.77). In contrast, enhanced growth inhibition was not found using this combination in the 3 p53-WT cell lines investigated (mean CI values ranged from 1.13 to 2.9). Overall, p53 mutated cell lines had a significantly lower CI values than p53 wild-type cells (p = 0.008). In all the 4 p53-mutated cell lines investigated, a significant increase in apoptosis was also seen when APR-246 was combined with eribulin. This enhanced apoptosis appeared to result from increased mRNA expression of the pro-apoptotic factors PUMA and NOXA by the drug combination compared to either compound alone. In contrast to our findings with eribulin, combined treatment with APR-246 plus docetaxel, doxorubicin, cisplatin or carboplatin was cell line-dependent. Thus, docetaxel plus APR-246 was synergistic in 1/6 cell lines, while doxorubicin, cisplatin or carboplatin plus APR-246 was synergistic in 3/6 cell lines. Conclusions: Clinical trials investigating the combination of APR-246 and eribulin should be considered in patients with a p53 mutation such as triple-negative breast cancer.
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Xin, Qian, Qinghong Ji, Ying Zhang, Weihong Ma, Baoqing Tian, Yanli Liu, Yunsong Chen et al. « Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer ». Oxidative Medicine and Cellular Longevity 2022 (20 juin 2022) : 1–17. http://dx.doi.org/10.1155/2022/1112987.

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Lung cancer has become a global health issue in recent decades. Approximately 80-85% of cases are non-small-cell lung cancer (NSCLC). Despite the high rate of resistance, cisplatin-base chemotherapy is still the main treatment for NSCLC patients. Thus, overcoming cisplatin resistance is urgently needed in NSCLC therapy. In this study, we identify NADPH metabolism and reactive oxygen species (ROS) levels as the main causes accounting for cisplatin resistance. Based on a small panel consisting of common chemotherapy drugs or compounds, APR-246 is proved to be an effective compound targeting cisplatin-resistant NSCLC cells. APR-246 specially inhibits proliferation and colony formation of cisplatin-resistant cells. In details, APR-246 can significantly cause G0/G1 accumulation and S phase arrest of cisplatin resistant cells and gives rise to severe mitochondria dysfunction as well as elevated apoptosis. Further study proves that it is the aberrant ROS levels as well as NRF2/SLC7A11/GSH axis dysfunction accounting for the specific antitumor effects of APR-246. Scavenging ROS with N-acetylcysteine (NAC) disrupts the inhibitory effect of APR-246 on cisplatin-resistant cells. Mechanistically, NRF2 is specifically degraded by the proteasome following its own ubiquitylation in APR-246-treated cisplatin-resistant cells, which in turn decreases NRF2/SLC7A11/GSH axis activity. Our study provides new insights into the biology driving cisplatin resistance of lung cancer and highlights APR-246 as a potential therapeutic reagent for overcoming cisplatin resistance.
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Mohell, Nina, Charlotta Liljebris, Jessica Alfredsson, Ylva Lindman, Maria Uustalu, Thomas Uhlin, Mats R. H. Linderholm et Klas G. Wiman. « Preclinical Efficacy and Toxicology Studies of APR-246, a Novel Anticancer Compound Currently In Clinical Trials for Refractory Hematological Malignancies and Prostate Cancer ». Blood 116, no 21 (19 novembre 2010) : 1806. http://dx.doi.org/10.1182/blood.v116.21.1806.1806.

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Abstract Abstract 1806 The tumor suppressor protein p53 is a transcription factor involved in cell cycle arrest, senescence and apoptosis. The p53 gene is frequently mutated in cancer, and cancer cells carrying defects in p53 are generally more resistant to conventional chemotherapy. Thus, restoration of wild type function of p53 is a promising novel strategy for cancer therapy. APR-246 belongs to a new class of small molecules (quinuclidinones) that reactivates non-functional p53 by promoting its correct folding and triggering apoptosis (Lambert et al. Cancer Cell 15, 2009). The lead compound of APR-246, PRIMA-1 (p53 Reactivation and Induction of Massive Apoptosis) was identified by a cellular screen of a NCI (National Cancer Institute) library, and an optimization program led to the discovery of the analog APR-246 (PRIMA-1MET). In various in vitro,ex vivo andin vivo cancer models, APR-246 has shown good antitumor activity. It reduces cell viability and/or induces apoptosis in a large number of human cancer cell lines with different p53 status, including leukemia, lymphoma and myeloma cell lines (Mohell et al. Blood 114, 2009). Ex vivo efficacy of APR-246 alone and in combination with conventional chemotherapeutic drugs has been shown in primary cells from patients with acute myeloid leukemia (AML) (Jonsson-Videsater et al. Blood 114, 2009). Ex vivo efficacy of APR-246 has also been shown in primary cells from patients with chronic lymphocytic leukemia (CLL). APR-246 was 4–8 fold more potent in killing malignant than normal lymphocytes, whereas common cytostatics often have negative ratio (Mohell et al. Blood 114, 2009). In vivo efficacy of APR-246/PRIMA-1 has been demonstrated in xenograft studies using many solid tumor cell lines (Mohell et al. Blood 114, 2009). Here we present results from studies with APR-246 using in vivo systemic and metastasic xenograft model with the human AML primary cell line AML-PS. This model was established by Giovazzi et al. (Int. J. Cancer 61, 1995) and is considered as a predictive in vivo model for human AML. In addition, some key results from preclinical safety and toxicology studies are reported. Briefly, SCID (severe combined immunodeficiency) mice were inoculated i.v. with 5×106 human AML-PS primary cells. Three days after inoculation treatment with i.v. injections of APR-246 (200 and 300 mg/kg), twice daily for 10 days, was initiated. Mice were monitored daily for health status and mortality. Blood samples were collected for determination of the percentage of circulating human leukemia cells by FACS analysis. Human leukemic cells were detected using a fluorescent antibody against the major histocompatibility complex (HLA). In parallel, pharmacokinetic experiments to measure the concentration of APR-246 in the blood were performed. We found that APR-246 had a statistically significant antitumor effect by decreasing the percentage of circulating human AML-PS cells and increasing the survival time of the mice (P=0.0024, n=10). A good correlation between increase in survival time and decrease in circulating tumor cells in the blood was observed. Further in vivo efficacy studies using various treatment schedules and combinations with conventional cytostatics are ongoing. APR-246 was also investigated in pivotal toxicology studies using single and repeat-dose regimen. In dogs, APR-246 was well tolerated when administered as 2 h infusion with NOAEL (no observed adverse effect level) of 200 mg/kg/day (4000 mg/m2/day). In both dogs and mice, Cmax levels less than 100 μg/ml did not induce any toxicity, regardless of the administration protocol. No systemic target organ toxicity was observed in mice or dogs, including blood and bone-marrow parameters. In conclusion, APR-246 has in various efficacy models demonstrated significant antitumor activity and a unique pharmacological profile. In preclinical safety/toxicity studies no toxicity at predicted therapeutic plasma concentrations was observed. Thus, APR-246 appears to be a promising novel anticancer compound to treat patients resistant to common chemotherapy. Currently, APR-246 is investigated in a dose escalating Phase I/IIa First-in-Man study for refractory hematological malignancies and prostate cancer. The Phase II Proof of Concept study is planned to start in 2011. Disclosures: Mohell: Aprea AB: Employment. Liljebris:Aprea AB: Employment. Alfredsson:Aprea AB: Employment. Lindman:Aprea AB: Employment. Uustalu:Aprea AB: Employment. Uhlin:Aprea AB: Employment. Linderholm:Aprea AB: Consultancy. Wiman:Aprea AB: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
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Venkatesh, Divya, Judith Michels, Cailian Liu, Sadna Budhu, Mariam M. George, Lars Abrahmsen, Roberta Zappasodi, Jedd D. Wolchok et Taha Merghoub. « Abstract 1291 : APR-246 enhances tumor immunogenicity even in the absence of p53 ». Cancer Research 82, no 12_Supplement (15 juin 2022) : 1291. http://dx.doi.org/10.1158/1538-7445.am2022-1291.

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Abstract Despite the significant success of immunotherapy, more than 40% of cancer patients remain unresponsive or exhibit an insufficient response. Well-designed combinations of targeted therapy and immunotherapy have the potential to increase effectiveness of cancer treatment and overcome the absence of response to either therapy alone. Since targeted therapies that enhance tumor antigenicity can enhance the effectiveness of immune based therapies, we have built a compendium of in vitro and in vivo assays to evaluate the effect of multiple immunogenic drugs. In these assays, we use the preclinical melanoma cell line B16-F10 model as it is highly metastatic and responds poorly to immunotherapy alone. The tumor suppressor p53 is a key target both in terms of targeted therapy owing to its role in halting tumor progression as well as in combination with immunotherapy, since p53 has varied roles in immune modulation. APR-246 can activate p53 and elicit some p53-independent effects in various tumor models predominantly through the induction of endoplasmic reticulum stress and oxidative stress. Since these cellular stressors (including p53) have been shown to be capable of rendering tumor cells immunogenic, we hypothesized that APR-246 may also increase the antigenicity of tumor cells. Indeed, we observed that treatment of B16 cells with APR-246 increases their MHC expression. Additionally, in our in vitro co-culture assays, cells treated with APR-246 were able to activate antigen-specific cytotoxic T cells either directly or via CD11c+ cells. We also observed that mice immunized with APR-246-treated B16 cells and then implanted with healthy untreated melanoma cells, were able to confer prolonged tumor free survival. Taken together, we believe that APR-246 has the potential to make for a strong combination with immunomodulatory therapies owing to its immunogenic potential. Based on these observations, we rationally designed a combination treatment regimen that would further enhance the immunogenic effects elicited by APR-246 on tumor cells. The triple combination of APR-246 with the TLR4 agonist, Monophosphoryl lipid A (MPL) and the anti-CD40 antibody significantly reduced the growth of B16 tumor in C57BL/6J mice. Strikingly, using CRISPR generated B16 p53 KO cells, we have discovered that these effects of APR-246 exist even in the absence of p53, albeit slightly reduced. Therefore, our results indicate that combination of APR-246 with immunomodulatory agents may be effective in treating cancers irrespective of their genetic status of p53. Our finding suggests that drugs with immunogenic potential, in addition to their original therapeutic indication, such as APR-246 are good candidates for the improvement of various clinically relevant immune modulatory therapies. Note: D.V. and J.M. contributed equally to this work. Citation Format: Divya Venkatesh, Judith Michels, Cailian Liu, Sadna Budhu, Mariam M. George, Lars Abrahmsen, Roberta Zappasodi, Jedd D. Wolchok, Taha Merghoub. APR-246 enhances tumor immunogenicity even in the absence of p53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1291.
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Nagourney, Adam J., Joshua B. Gipoor, Steven S. Evans, Paulo D’Amora, Max S. Duesberg, Paula J. Bernard, Federico Francisco et Robert A. Nagourney. « Therapeutic Targeting of P53 : A Comparative Analysis of APR-246 and COTI-2 in Human Tumor Primary Culture 3-D Explants ». Genes 14, no 3 (19 mars 2023) : 747. http://dx.doi.org/10.3390/genes14030747.

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Background: TP53 is the most commonly mutated gene in human cancer with loss of function mutations largely concentrated in “hotspots” affecting DNA binding. APR-246 and COTI-2 are small molecules under investigation in P53 mutated cancers. APR binds to P53 cysteine residues, altering conformation, while COTI-2 showed activity in P53 mutant tumors by a computational platform. We compared APR-246 and COTI-2 activity in human tumor explants from 247 surgical specimens. Methods: Ex vivo analyses of programmed cell death measured drug-induced cell death by delayed-loss-of-membrane integrity and ATP content. The LC50s were compared by Z-Score. Synergy was conducted by the method of Chou and Talalay, and correlations were performed by Pearson moment. Results: APR-246 and COTI-2 activity favored hematologic neoplasms, but solid tumor activity varied by diagnosis. COTI-2 and APR-246 activity did not correlate (R = 0.1028) (NS). COTI-2 activity correlated with nitrogen mustard, cisplatin and gemcitabine, doxorubicin and selumetinib, with a trend for APR-246 with doxorubicin. For ovarian cancer, COTI-2 showed synergy with cisplatin at 25%. Conclusions: COTI-2 and APR-246 activity differ by diagnosis. A lack of correlation supports distinct modes of action. Cisplatin synergy is consistent with P53’s role in DNA damage. Different mechanisms of action may underlie disease specificity and offer better disease targeting.
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Macha, Shawn J., Balakrishna Koneru, Trevor Burrow, Charles Zhu, Dzmitry Savitski, Jonas Nance, Kristyn McCoy, Cody Eslinger et C. Patrick Reynolds. « Abstract 6228 : APR-246, which restores p53 function, is highly active against alternative lengthening of telomere (ALT) cell lines and PDXs ». Cancer Research 82, no 12_Supplement (15 juin 2022) : 6228. http://dx.doi.org/10.1158/1538-7445.am2022-6228.

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Abstract Introduction: Most cancers proliferate by activating telomerase (TA+) while 10% of cancers utilize alternate lengthening of telomeres (ALT). ALT has been associated with resistance to DNA damaging agents, p53 loss-of-function (p53LOF), ATRX mutations, and very poor survival. ATM kinase, which activates functional p53, is constitutively activated in ALT cancers (Science Translational Medicine 18:eabd5750, 2021). We hypothesized that the constitutive activation of ATM kinase in ALT cancers would confer high sensitivity to pharmacological reactivation of p53 function. Methods: We used patient-derived ALT (telomeric DNA C-circle positive) and TA+ neuroblastoma, sarcoma, colorectal, and breast cancer cell lines and xenografts treated with the clinical-stage p53 reactivator eprenetapopt (APR-246) and irinotecan. In vitro cytotoxicity was assayed by DIMSCAN digital imaging microscopy, ATM activation by immunofluorescence microscopy, and protein expression by western blotting. Results: ALT p53LOF cell lines were significantly (p&lt;0.05) less sensitive to DNA-damaging agents relative to TA+ p53LOF comparators. Constitutive phosphorylation (activation) of ATM kinase and the DNA damage marker 53BP1 were observed at telomeres in ALT but not TA+ cell lines. APR-246 induced p53 targets p21 and NOXA and was significantly more cytotoxic (p&lt;0.001) for ALT relative to TA+ cell lines, regardless of TP53 status. Overexpression of p53 in a TP53-null ALT cell line increased sensitivity (p&lt;0.0001) to APR-246. Knockdown of p53 or ATM kinase in ALT TP53 mutated and wild-type cell lines antagonized (p&lt;0.0001) APR-246 activity. Induction of telomere dysfunction in a TA+ p53LOF neuroblastoma cell line using dominant-negative TRF2 (a shelterin protein that blocks ATM activation at telomeres) activated ATM and sensitized cells to APR-246 (p&lt;0.01). APR-246 enhanced the cytotoxicity of irinotecan (as SN38) in ALT cell lines in vitro to a higher degree than in TA+ p53LOF cell lines (p&lt;0.05). Single-agent APR-246 significantly (p&lt;0.0001) increased event-free survival (EFS) of mice with ALT xenografts relative to controls. APR-246 enhanced (p&lt;0.0001) the activity of irinotecan in 3 neuroblastoma, 2 rhabdomyosarcoma, 1 colorectal, and 1 triple-negative breast ALT xenograft models with most mice (47/56) achieving complete responses and an EFS of &gt;100 days (45/56) compared to no complete responses (median EFS ~ 34 days) in mice treated with only irinotecan (p&lt;0.0001). APR-246 + irinotecan had no significant effect relative to irinotecan alone (p=0.08) on EFS of mice with TA+ p53LOF xenografts (median EFS ~ 40 days). Conclusion: ALT cancers of a variety of histologies are highly resistant to DNA damaging agents, have p53LOF, and constitutive activation of ATM kinase, which confers high sensitivity to p53 reactivation by APR-246. APR-246 warrants clinical testing in patients with ALT cancers. Citation Format: Shawn J. Macha, Balakrishna Koneru, Trevor Burrow, Charles Zhu, Dzmitry Savitski, Jonas Nance, Kristyn McCoy, Cody Eslinger, C Patrick Reynolds. APR-246, which restores p53 function, is highly active against alternative lengthening of telomere (ALT) cell lines and PDXs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6228.
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Actes de conférences sur le sujet "APR-246"

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Hernandez, Ana, Codi Mai, Shady Tantawy, Mary Ayres, Zahid Siddik et Varsha Gandhi. « APR-246 induces ferroptosis and overcomes cisplatin resistance in ovarian cancer ». Dans The MD Anderson Summer Experience 2022. The University of MD Anderson Cancer Center, 2022. http://dx.doi.org/10.52519/00007.

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Venkatesh, Divya, Judith Michels, Cailin Lu, Sadna Budhu, Mariam George, Ouathek Ouerfelli, Lars Abrahmsen, Roberta Zappasodi, Jedd Wolchok et Taha Merghoub. « 903 APR-246 induces an increase in tumor immunogenicity in a p53 independent manner ». Dans SITC 37th Annual Meeting (SITC 2022) Abstracts. BMJ Publishing Group Ltd, 2022. http://dx.doi.org/10.1136/jitc-2022-sitc2022.0903.

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Fransson, Åsa, Daria Glaessgen, Jessica Alfredsson, Klas G. Wiman, Svetlana Bajalica Lagercrantz et Nina Mohell. « Abstract 1639 : Strong synergy with APR-246 and DNA-damaging drugs in primary ovarian cancer cells ». Dans Proceedings : AACR 106th Annual Meeting 2015 ; April 18-22, 2015 ; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-1639.

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Mohell, Nina, Åsa Fransson, Jessica Alfredsson, Mikael von Euler, Ulf Björklund et Lars Abrahmsen. « Abstract 2523 : Strong synergistic effects with APR-246 and cisplatin in p53-mutant lung cancer cells ». Dans Proceedings : AACR 106th Annual Meeting 2015 ; April 18-22, 2015 ; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-2523.

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Ghosh, Arnab, Judith Michel, Lauren Dong, Nathan Suek, Hong Zhong, Sadna Budhu, Olivier de Henau, Jedd Wolchok et Taha Merghoub. « Abstract 4843 : TP53-stabilization with APR-246 enhances antitumor effects of immune checkpoint blockade in preclinical models ». Dans Proceedings : AACR Annual Meeting 2019 ; March 29-April 3, 2019 ; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-4843.

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Ghosh, Arnab, Judith Michel, Lauren Dong, Nathan Suek, Hong Zhong, Sadna Budhu, Olivier de Henau, Jedd Wolchok et Taha Merghoub. « Abstract 4843 : TP53-stabilization with APR-246 enhances antitumor effects of immune checkpoint blockade in preclinical models ». Dans Proceedings : AACR Annual Meeting 2019 ; March 29-April 3, 2019 ; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-4843.

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Mohell, Nina, Jessica Alfredsson, Åsa Fransson, Vladimir Bykov, Mikael von Euler, Klas Wiman et Ulf Björklund. « Abstract 1801 : APR-246, a clinical-stage mutant p53-reactivating compound, resensitizes ovarian cancer cells to platinum compounds and doxorubicin ». Dans Proceedings : AACR Annual Meeting 2014 ; April 5-9, 2014 ; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-1801.

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Mohell, Nina, Åsa Fransson, Jessica Alfredsson, Mikael von Euler, Ulf Björklund et Lars Abrahmsen. « Abstract 270 : Synergistic effect with APR-246 and standard chemotherapy in small cell lung cancer cells carrying smoking-associated TP53 mutations ». Dans Proceedings : AACR 107th Annual Meeting 2016 ; April 16-20, 2016 ; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-270.

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Mohell, Nina, Jessica Alfredsson, Maria Uustalu, Åsa Fransson, Vladimir J. N. Bykov, Klas G. Wiman et Ulf Björklund. « Abstract 3448 : Strong synergistic effects with cisplatin and APR-246, a novel compound reactivating mutant p53, in ovarian cancer cell lines and primary cells from patients. » Dans Proceedings : AACR 104th Annual Meeting 2013 ; Apr 6-10, 2013 ; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-3448.

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Sallman, David A., Amy DeZern, Kendra Sweet, David P. Steensma, Thomas Cluzeau, Mikkael Sekeres, Guillermo Garcia-Manero et al. « Abstract CT068 : Phase Ib/II combination study of APR-246 and azacitidine (AZA) in patients withTP53mutant myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) ». Dans Proceedings : AACR Annual Meeting 2018 ; April 14-18, 2018 ; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-ct068.

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