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Journal articles on the topic 'ROR1/2'

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Published: 4 June 2021
Last updated: 14 February 2022

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1

Balaian, Larissa, Anil Sadarangani, George F. Widhopf, et al. "A Highly Selective Anti-ROR1 Monoclonal Antibody Inhibits Human Acute Myeloid Leukemia CD34+ Cell Survival and Self-Renewal." Blood 120, no. 21 (2012): 2560. http://dx.doi.org/10.1182/blood.v120.21.2560.2560.

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Abstract Abstract 2560 The mammalian orphan receptor tyrosine kinase-1 (ROR1) is expressed in a wide-variety of tissues during early embryonic development. By the late stages of embryogenesis the expression of this developmentally important protein is greatly diminished. Although not expressed in the tissues of post-partum animals, the ROR1 protein is expressed on neoplastic cells in chronic lymphocytic leukemia (CLL), some B-cell malignancies, and a variety of different carcinomas. We examined for expression of ROR1 in primary acute myeloid leukemia (AML) cells harvested from marrow aspirates
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2

Kipps, Thomas, Laura Z. Rassenti, George F. Widhopf II, and Thomas J. Kipps. "Wnt5a Induces ROR1 Dependent Tyrosine Phosphorylation of DOCK2, and Enhanced Activation of ERK to Promote Proliferation of CLL Cells." Blood 132, Supplement 1 (2018): 4404. http://dx.doi.org/10.1182/blood-2018-99-117175.

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Abstract ROR1 (receptor tyrosine kinase-like orphan receptor 1) is a conserved, oncoembryonic surface antigen expressed in chronic lymphocytic leukemia (CLL) B cells, but not on most normal post-partem tissues. Patients with high-level leukemia-cell expression of ROR1 have been found to have a shorter median time from diagnosis to therapy and shorter median survival than patients with CLL cells that express low-to-negligible amounts of ROR1 (Cui B. et al., Blood, 128:2931, 2016). In prior studies we found that Wnt5a could induce ROR1 to recruit DOCK2 at proline 808 and activate Rac1/2, leading
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3

Milleck, Julia, Karl-Anton Kreuzer, Mario Assenmacher, Jürgen Schmitz, and Peter S. Jähn. "Characterization of Peripheral B Cells Expressing CLL-Associated Receptor Tyrosine Kinase ROR1 in Healthy Donors." Blood 120, no. 21 (2012): 1787. http://dx.doi.org/10.1182/blood.v120.21.1787.1787.

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Abstract Abstract 1787 Recent studies have described an extensive expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1) on the surface of malignant B cells in patients suffering from chronic lymphoid leukemia (CLL). ROR1 expression has also been detected in ovarian cancer, renal cancer, melanoma, and lung adenocarcinoma, suggesting a general role of ROR1 in cancer genesis and/or maintenance. However, low levels of ROR1 mRNA or protein expression have also been found on undifferentiated embryonic stem cells, adipose tissue and on early stage of B-cells in bone marrow, but not
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4

Hasan, Md Kamrul, Jian Yu, George F. Widhopf, et al. "Wnt5a induces ROR1 to recruit DOCK2 to activate Rac1/2 in chronic lymphocytic leukemia." Blood 132, no. 2 (2018): 170–78. http://dx.doi.org/10.1182/blood-2017-12-819383.

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5

Daneshmanesh, Amir Hossein, Mohammad Hojjat-Farsangi, Asa Sandin, et al. "Monoclonal Antibody Against ROR1 in Chronic Lymphocytic Leukemia Cells Induced Apoptosis Via PI3-Kinase/AKT/CREB Pathway." Blood 120, no. 21 (2012): 1769. http://dx.doi.org/10.1182/blood.v120.21.1769.1769.

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Abstract Abstract 1769 Background: Phosphoinositide 3-kinase (PI3K)/AKT cascade regulates cell survival, proliferation and differentiation in a variety of cells. In CLL cells PI3K pathway is constitutively activated leading to AKT activation and phosphorylation of cAMP response element-binding protein (CREB). CREB is a transcription factor overexpressed and constitutively phosphorylated in a variety of cancers and seems to have a role in tumor pathobiology. There is a great need to develop novel strategies for targeted therapy in CLL. Monoclonal antibodies (mAbs) specifically targeting leukemi
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6

Karvonen, Hanna, David Chiron, Wilhelmiina Niininen, et al. "Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma." Blood Advances 1, no. 24 (2017): 2257–68. http://dx.doi.org/10.1182/bloodadvances.2017010215.

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Key Points Targeting ROR1 downregulates NF-κB p65 expression and sensitizes MCL cells to BCR- or Bcl-2–targeted drugs. Inhibition of BCR signaling by BTK-specific inhibitors such as ibrutinib impairs ROR1 levels and consecutively ROR1-targeted therapies.
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7

Ghaderi, Amineh, Amir Hossein Daneshmanesh, Ali Moshfegh, et al. "ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells." Biomedicines 8, no. 6 (2020): 170. http://dx.doi.org/10.3390/biomedicines8060170.

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The receptor tyrosine kinase ROR1 is absent in most normal adult tissues, but overexpressed in several malignancies. In this study, we explored clinical and functional inhibitory aspects of ROR1 in diffuse large B-cell lymphoma (DLBCL). ROR1 expression in tumor cells was more often observed in primary refractory DLBCL, Richter’s syndrome and transformed follicular lymphoma than in relapsed and non-relapsed DLBCL patients (p < 0.001). A survival effect of ROR1 expression was preliminarily observed in relapsed/refractory patients independent of gender and stage but not of age, cell of origin
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8

Yu, Jian, Bing Cui, George F. Widhopf, et al. "Preclinical Development Of ROR1 Peptide Based Vaccine With Activity Against Chronic Lymphocytic Leukemia In ROR1 Transgenic Mice." Blood 122, no. 21 (2013): 4174. http://dx.doi.org/10.1182/blood.v122.21.4174.4174.

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Abstract Receptor tyrosine kinase-like orphan receptor (ROR1) is expressed on chronic lymphocytic leukemia (CLL) and other cancers, but not on normal post-partum tissues, except for a small subset of precursor B cells known as hematogones. Because of its restricted expression on cancer cells, ROR1 is an attractive target for developing novel anti-cancer therapies. In this study, we designed several different peptides, corresponding to distinct epitopes in the extracellular domain of ROR1. Each peptides was conjugated with keyhole-limpet hemocyanin (KLH) to generate a peptide-KLH vaccine, which
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9

Diamanti, Paraskevi, Bethan Kathleen Bailey, Obinna Ebere Iheanacho, Amit C. Nathwani, and Allison Blair. "Evaluating ROR1 As a Target in Childhood Leukemia." Blood 134, Supplement_1 (2019): 2635. http://dx.doi.org/10.1182/blood-2019-126734.

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Disease relapse in childhood acute lymphoblastic leukemia (ALL) patients may occur due to persistence of resistant cells with leukemia propagating ability (LPC). Immunotherapeutic approaches, such as bi-specific T cell engagers (BiTEs) and chimeric antigen receptor (CAR) T cells against CD19, have been shown to successfully treat relapsed ALL. However, such therapies cannot target LPC that lack or have lost expression of CD19. Receptor tyrosine kinase like orphan 1 receptor (ROR1) is a surface antigen, overexpressed in hematological malignancies, including chronic lymphocytic leukemia (CLL) an
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10

Mellstedt, Håkan, Amineh Ghaderi, Johanna Aschan, et al. "ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Mantle Cell Lymphoma (MCL) Cells." Blood 134, Supplement_1 (2019): 5312. http://dx.doi.org/10.1182/blood-2019-129773.

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Background: ROR1 - a receptor tyrosine kinase (RTK) - is essential for normal embryonic development, but is absent on most normal adult tissues. ROR1 is of importance of cell proliferation, differentiation, survival and metabolism. However, ROR1 is overexpressed in several types of cancer (onco-fetal RTK). MCL is an aggressive and incurable non-Hodgkin lymphoma characterized by translocation (11;14) (q13;q32) and cyclin D overexpression. ROR1 has been described to be highly expressed in MCL cells. We have previously presented results on a small molecule ROR1 inhibitor in CLL (KAN0439834) (Leuk
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11

CUi, Bing, George F. Widhopf, Jian Yu, et al. "Targeting of Chronic Lymphocytic Leukemia B Cells with a Novel Monoclonal Antibody to ROR1." Blood 118, no. 21 (2011): 984. http://dx.doi.org/10.1182/blood.v118.21.984.984.

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Abstract Abstract 984 ROR1 is an orphan receptor tyrosine kinase that is expressed on leukemia cells of patients with chronic lymphocytic leukemia (CLL), but not on most adult tissues of healthy adults, including CD5+ B cells. To generate anti-ROR1 antibodies, we immunized mice using different strategies employing vaccines comprised of recombinant ROR1 protein, polynucleotide-ROR1 vaccines and CD154 genetic adjuvants, or replication-defective adenovirus vectors encoding ROR1 and CD154. We extirpated the spleens of animals that developed high-titer serum anti-ROR1 antibodies and used these to g
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12

Karachaliou, Niki, Ana Drozdowskyj, Carlota Costa, et al. "ROR1 mRNA expression in EGFR-mutant non-small-cell lung cancer (NSCLC) patients (p) with the T790M mutation: A potential therapeutic target." Journal of Clinical Oncology 31, no. 15_suppl (2013): 11027. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.11027.

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11027 Background: Progression-free survival (PFS) is short in NSCLC driven by EGFR mutations treated with erlotinib alone, due to crosstalk with other signaling pathways that can cause secondary dependency. ROR1 knockdown inhibited the growth of NCI-H1975 cells (with EGFR L858R and T790M mutations). A pro-survival function for ROR1/MEK/ERK signaling has been demonstrated, with cooperation with AKT. In a subset of 95 p in the EURTAC trial (clinicaltrials.gov NCT00446225), 65% had pre-treatment T790M mutations. We have assessed ROR1 expression in 45 of these 95 p. Methods: The T790M mutation was
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13

Hojjat-Farsangi, Mohammad, Amineh Ghaderi, AmirHossein Daneshmanesh, et al. "Diffuse Large B Cell Lymphoma (DLBCL) Expresses ROR1 and a ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Tumor Cells." Blood 134, Supplement_1 (2019): 2565. http://dx.doi.org/10.1182/blood-2019-126801.

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Background: Receptor tyrosine kinase (RTK) (ROR1) is normally expressed during embryogenesis but absent in most normal tissues. However, ROR1 is overexpressed in several cancers (onco-fetal RTK) and of importance for various tumor cell functions such as proliferation and survival. In patients with diffuse large B-cell lymphomas (DLBCL) there is a great medical need to develop new treatment alternatives for those not responding to primary treatment as well as for patients with relapse as effective treatments are warranted. Inhibition of ROR1 by a small molecule ROR1 inhibitor (KAN0439834) abrog
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14

Yu, Jian, Liguang Chen, Yun Chen та ін. "Wnt5a Induces Association of ROR1 with 14-3-3ζ to Enhance Chemotaxis and Proliferation in Chronic Lymphocytic Leukemia". Blood 128, № 22 (2016): 349. http://dx.doi.org/10.1182/blood.v128.22.349.349.

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Abstract Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic antigen that is expressed on CLL cells, but not on normal postpartum tissues. We found that ROR1 was a receptor for Wnt5a, which could activate Rho GTPases (e.g. RhoA and Rac1) in CLL cells by inducing the recruitment to ROR1 of guanine exchange factors (GEFs), notably ARHGEF2. How ARHGEF2 can complex with ROR1 was not known. We performed mass spectrometry-based proteomics to interrogate immune-precipitates of Wnt5a-activated ROR1 and identified 14-3-3ζ, a highly conserved, cytoplasmic-protein member of the tet
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15

Cui, Bing, George F. Widhopf, Charles E. Prussak, et al. "Cirmtuzumab Vedotin (UC-961ADC3), An Anti-ROR1-Monomethyl Auristatin E Antibody-Drug Conjugate, Is a Potential Treatment For ROR1-Positive Leukemia and Solid Tumors." Blood 122, no. 21 (2013): 1637. http://dx.doi.org/10.1182/blood.v122.21.1637.1637.

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Abstract ROR1 is an onco-embryonic antigen that is expressed on the neoplastic cells of patients with chronic lymphocytic leukemia (CLL), other B-cell lymphomas, acute leukemias, or many different solid-tumors, but not on non-neoplastic post-partum tissues, except for the uncommon precursor B cells known as hematogones. Because of its restricted expression on human malignancies, we have generated a series of monoclonal antibodies (mAb) against the extracellular domain of human ROR1 and are advancing our lead candidate mAb UC-961 (cirmtuzumab) into human clinical trials. Along with the anti-leu
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16

Gohil, Satyen Harish, Marco Della Peruta, Solange R. Paredes-Moscosso, et al. "Novel Humanised ROR1 Chimeric Antigen Receptors for the Treatment of Haematological Malignancies." Blood 128, no. 22 (2016): 3361. http://dx.doi.org/10.1182/blood.v128.22.3361.3361.

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Abstract Introduction: Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1) is a surface antigen expressed on a range of haematological and solid malignancies including Chronic Lymphocytic Leukaemia (CLL). Although expressed during embryogenesis, its virtual absence on normal adult tissues makes it an attractive target for immunotherapy, especially with Chimeric Antigen Receptor modified T-cells (CAR T-cells). We have generated novel fully humanised ROR1CAR constructs for the treatment of CLL and other ROR1 positive malignancies. Results: Following a rat immunisation programme 38 oligloclona
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17

Hu, Eileen Y., Priscilla Do, Swagata Goswami, et al. "The ROR1 antibody-drug conjugate huXBR1-402-G5-PNU effectively targets ROR1+ leukemia." Blood Advances 5, no. 16 (2021): 3152–62. http://dx.doi.org/10.1182/bloodadvances.2020003276.

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Abstract Antibody-drug conjugates directed against tumor-specific targets have allowed targeted delivery of highly potent chemotherapy to malignant cells while sparing normal cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein with limited expression on normal adult tissues and is overexpressed on the surface of malignant cells in mantle cell lymphoma, acute lymphocytic leukemia with t(1;19)(q23;p13) translocation, and chronic lymphocytic leukemia. This differential expression makes ROR1 an attractive target for antibody-drug conjugate therapy, especially in m
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18

Hojjat-Farsangi, Mohammad, Ali Moshfegh, Amir Hossein Daneshmanesh, et al. "First-in-Class ROR1 Small Molecule Inhibitor (KAN0439834) Downregulated Wnt-Canonical and Non-Canonical Signaling Pathways and Induced Apoptosis of CLL Cells." Blood 126, no. 23 (2015): 2912. http://dx.doi.org/10.1182/blood.v126.23.2912.2912.

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Abstract Background: The receptor tyrosine kinase (RTK) ROR1 is detected during embryogenesis but downregulated in adult normal tissues. However, it is expressed in several solid tumors and hematological malignancies. Targeting ROR1 with specific siRNAs in chronic lymphocytic leukemia (CLL) induced apoptosis of the leukemic cells. Moreover, ROR1 specific monoclonal antibodies (mAbs) dephosphorylated ROR1 followed by apoptosis of the CLL cells. Furthermore, ROR1 tyrosine kinase inhibitors (ROR1-TKI) (small molecule inhibitors) have been shown to dephosphorylate ROR1, downregulate the activated
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19

Heidenreich, Falk, Elke Ruecker-Braun, Juliane S. Stickel, et al. "ROR1 Specific T Cell Clones from Healthy Individuals Show Common T Cell Receptor Motifs." Blood 128, no. 22 (2016): 3364. http://dx.doi.org/10.1182/blood.v128.22.3364.3364.

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Abstract Background Immunotherapy for CLL with new antibodies or T-cells with modified TCR relies on attractive targets. ROR1 is such a promising target since it is highly overexpressed in CLL. Chimeric antigen receptor engineered T cells and antibodies directed against the extracellular part of ROR1 have already been developed and tested in vitro or in animal models, but still there is no MHC-class I presented peptide serving as target structure for CD8+ T cells (with or without a genetically modified T cell receptor) available. Aim The aim of this study was (1) to identify an immunogenic MHC
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20

Rabbani, Hodjattallah, Amir Hossein Daneshmanesh, Abdul Salam Khan, et al. "Ror1 Targeting Monoclonal Antibodies Induced Apoptosis of Chronic Lymphocytic Leukemia Cells– A Potential Novel Therapeutic Approach." Blood 116, no. 21 (2010): 916. http://dx.doi.org/10.1182/blood.v116.21.916.916.

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Abstract Abstract 916 Methods: A peptide-based mouse monoclonal antibody generation method was used for producing MAbs against the three extracellular domains of Ror1. Twenty CLL patients (10 with progressive and 10 with non-progressive disease) were enrolled in this study. Flow cytometry was used for surface staining of Ror1. Annexin V and propidium iodide (flow cytometry) as well as PARP cleavage (Western blot) was used for detection of apoptosis. Results: Six monoclonal antibodies of different isotypes (IgG, IgM) were produced against Ror1. The frequency of Ror1 positive cells were in the r
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21

Qi, Junpeng, Xiuling Li, Haiyong Peng, et al. "Potent and selective antitumor activity of a T cell-engaging bispecific antibody targeting a membrane-proximal epitope of ROR1." Proceedings of the National Academy of Sciences 115, no. 24 (2018): E5467—E5476. http://dx.doi.org/10.1073/pnas.1719905115.

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T cell-engaging bispecific antibodies (biAbs) present a promising strategy for cancer immunotherapy, and numerous bispecific formats have been developed for retargeting cytolytic T cells toward tumor cells. To explore the therapeutic utility of T cell-engaging biAbs targeting the receptor tyrosine kinase ROR1, which is expressed by tumor cells of various hematologic and solid malignancies, we used a bispecific ROR1 × CD3 scFv-Fc format based on a heterodimeric and aglycosylated Fc domain designed for extended circulatory t1/2 and diminished systemic T cell activation. A diverse panel of ROR1-t
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22

Specht, Jennifer M., Sylvia Lee, Cameron Turtle, et al. "Phase I study of immunotherapy for advanced ROR1+ malignancies with autologous ROR1-specific chimeric antigen receptor-modified (CAR)-T cells." Journal of Clinical Oncology 36, no. 5_suppl (2018): TPS79. http://dx.doi.org/10.1200/jco.2018.36.5_suppl.tps79.

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TPS79 Background: CAR-T cells have demonstrated marked tumor regression in patients (pts) with hematologic malignancies. ROR1, a tyrosine kinase orphan receptor, is expressed in triple negative breast cancers (TNBC) and non-small cell lung cancers (NSCLC) and is a novel candidate for CAR-T cell therapy. ROR1-specific CAR-T cells are engineered with lentiviral vector encoding ROR1 scFv/4-1BB/CD3ζ and a truncated EGFR molecule to permit elimination of ROR1 CAR-T cells in case of toxicity. Methods: NCT02706362 is a phase I study evaluating the safety and anti-tumor activity of adoptively transfer
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23

Cui, Bing, Liguang Chen, Laura Z. Rassenti, et al. "High-Level Expression of ROR1 Associates with Early Disease Progression in Patients with Chronic Lymphocytic Leukemia." Blood 126, no. 23 (2015): 1713. http://dx.doi.org/10.1182/blood.v126.23.1713.1713.

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Abstract ROR1 is a type-1 tyrosine kinase-like orphan-receptor that ordinarily is expressed during embryogenesis, but that also is found on leukemia cells of patients (pts) with chronic lymphocytic leukemia (CLL). In prior studies we found ROR1 served as a receptor for Wnt5a, which could promote survival/growth of CLL cells. We found Wnt5a in the plasma is significantly higher in pts with CLL (3.2±1.6 ng/ml (mean ±S.D.), N = 36) than in healthy adults (0.14±0.16 ng/ml, N=14, p<0.01) and also may be elaborated by accessory cells in the CLL microenvironment. On the other hand, reducing expres
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24

Sanchez-Lopez, Elsa, Emanuela M. Ghia, Laura Antonucci, et al. "Activation of NF-Kappa B-p62-NRF2 Signaling Supports the Survival of CLL Cells That Express High Levels of ROR1." Blood 132, Supplement 1 (2018): 3122. http://dx.doi.org/10.1182/blood-2018-99-115564.

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Abstract Recent studies have linked the autophagy adaptor p62/SQSTM1 to tumorigenesis via NRF2 signaling. Increased accumulation p62 is associated with disease progression in many cancers, however its expression in CLL has yet to be investigated. Importantly, p62, encoded by the SQSTM1 gene, mRNA expression and protein accumulation is regulated by nuclear factor-kappa B (NF-κB), a key transcription factor for CLL survival. In addition, CLL cells express receptor tyrosine kinase-like orphan receptor 1 (ROR1), an oncoembryonic protein that also is expressed on cancer cells of numerous malignanci
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25

Liu, Yong, Guohui Wang, Xiangwu Yang, Pengzhou Li, Hao Ling, and Shaihong Zhu. "MicroRNA-27b-3p regulates function and metabolism in insulin resistance cells by inhibiting receptor tyrosine kinase-like orphan receptor 1." European Journal of Inflammation 16 (January 1, 2018): 205873921876205. http://dx.doi.org/10.1177/2058739218762058.

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Type 2 diabetes mellitus (T2DM) is associated with insulin resistance-induced lipid and glucose metabolism disorder. The study was aimed to explore the potential functional role of microRNA (miR)-27b-3p in T2DM, as well as underlying mechanisms. An insulin resistance cell model was induced in HepG2 cells and then expression of miR-27b-3p and receptor tyrosine kinase-like orphan receptor 1 (ROR1) was analyzed. The expression of miR-27b-3p was overexpressed or silenced, and the relationship between ROR1 and miR-27b-3p was investigated. Thereafter, the effects of miR-27b-3p on percentage of gluco
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26

Mian, Yousaf A., George F. Widhopf II, Thanh-Trang Vo, Katti Jessen, Laura Z. Rassenti, and Thomas J. Kipps. "Development of Cirmtuzumab Antibody-Drug Conjugates (ADCs) Targeting Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1)." Blood 132, Supplement 1 (2018): 1862. http://dx.doi.org/10.1182/blood-2018-99-119447.

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Abstract ROR1 is an onco-embryonic surface antigen expressed on chronic lymphocytic leukemia (CLL) and a variety of other cancers, but not on most normal adult tissues. We generated a humanized IgG1 monoclonal antibody (mAb) cirmtuzumab (formerly UC-961) that binds with high affinity to a specific extracellular epitope of human ROR1 and that can block Wnt5a-induced ROR1 signaling (Yu, J et al, J Clin Invest126:585, 2016; Yu, J et al, Leukemia31:1333, 2017). Preclinical studies found that cirmtuzumab did not react with normal post-partem cells and had a pharmacokinetic (PK) volume distribution
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27

Ghia, Emanuela M., Michael Y. Choi, George F. Widhopf II, Laura Z. Rassenti, and Thomas J. Kipps. "ROR1 Expression Is Associated with Oncogenic Dedifferentiation in Chronic Lymphocytic Leukemia." Blood 132, Supplement 1 (2018): 1853. http://dx.doi.org/10.1182/blood-2018-99-119711.

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Abstract An integrated analysis of transcriptomic signatures applied to almost 12,000 primary human tumors of 33 different cancer types from The Cancer Genome Atlas (TCGA) datasets defined a signature to quantify various degrees of stemness and assigned a stemness index to each tumor included in the analysis. Stemness indices were lowest in normal cells, increased in primary tumors, and were highest in metastatic disease, consistent with the notion that tumor progression generally involves oncogenic dedifferentiation. Higher values for stemness indices were associated with biological processes
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28

Stüber, Tanja, Razieh Monjezi, Lars Wallstabe та ін. "Inhibition of TGF-β-receptor signaling augments the antitumor function of ROR1-specific CAR T-cells against triple-negative breast cancer". Journal for ImmunoTherapy of Cancer 8, № 1 (2020): e000676. http://dx.doi.org/10.1136/jitc-2020-000676.

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BackgroundImmunotherapy with chimeric antigen receptor (CAR)-engineered T-cells is effective in some hematologic tumors. In solid tumors, however, sustained antitumor responses after CAR T-cell therapy remain to be demonstrated both in the pre-clinical and clinical setting. A perceived barrier to the efficacy of CAR T-cell therapy in solid tumors is the hostile tumor microenvironment where immunosuppressive soluble factors like transforming growth factor (TGF)-β are thought to inhibit the cellular immune response. Here, we analyzed whether CAR T-cells specific for the receptor tyrosine kinase-
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29

Vaisitti, Tiziana, Katti Jessen, Thanh-Trang Vo, et al. "Vls-101 Is a Novel Therapeutic Antibody-Drug Conjugate (ADC) Targeting Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) in Richter's Syndrome (RS)." Blood 134, Supplement_1 (2019): 2856. http://dx.doi.org/10.1182/blood-2019-126827.

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ROR1 is a transmembrane receptor with tightly controlled expression during development. It is present on multiple tumor types but not on normal adult tissues. Hematological malignancies are often ROR1-positive, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and diffuse large B cell lymphoma (DLBCL). Given its unique pattern of expression, ROR1 represents a tumor-specific therapeutic target. The anti-ROR1 antibody, UC-961, is ahumanized IgG1 monoclonal antibody (mAb) that binds with high affinity to a specific extracellular epitope of human ROR1 receptor and can block
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30

Zhang, Suping, Wenjin Cui, Robert Mattrey, and Thomas J. Kipps. "Efficient Gene Delivery to Chronic Lymphocytic Leukemia (CLL) Cells with Microbubbles Bearing ROR1 Antibody." Blood 118, no. 21 (2011): 2857. http://dx.doi.org/10.1182/blood.v118.21.2857.2857.

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Abstract Abstract 2857 Patients of chronic lymphocytic leukemia (CLL) typically develop progressive immune deficiency, which impairs their response to vaccines. Prior studies showed that infusions of autologous CLL cells transduced ex vivo with adenovirus encoding CD154 could elicit anti-leukemia immune responses. However, the need for high amounts of high-titer adenovirus complicates this approach and handicaps clinical development. A recently developed technology, known as microbubbles, could be activated using safe ultrasound (U/S) energy, potentially providing a new tool with which to affe
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31

Widhopf, George F., Bing Cui, Christina C. N. Wu, et al. "Targeting Of Chronic Lymphocytic Leukemia B Cells With a Humanized Monoclonal Antibody Specific For ROR1." Blood 122, no. 21 (2013): 2873. http://dx.doi.org/10.1182/blood.v122.21.2873.2873.

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Abstract ROR1 is an onco-embryonic antigen that is expressed on the neoplastic cells of patients with chronic lymphocytic leukemia (CLL), other B-cell lymphomas, acute leukemias, or many different solid-tumors, but not on non-neoplastic post-partum tissues, except for the uncommon precursor B cells known as hematogones. We generated over 70 hybridomas, each producing a monoclonal-antibody (mAb) specific for the extracellular domain of ROR1 and found only one (D10) that had anti-leukemia activity in a niche-dependent assay, despite having a relatively low ROR1-binding affinity (Kd 40 nM). We ge
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32

Chiang, Chi-Ling, Swagata Goswami, Frank W. Frissora, et al. "ROR1-targeted delivery of miR-29b induces cell cycle arrest and therapeutic benefit in vivo in a CLL mouse model." Blood 134, no. 5 (2019): 432–44. http://dx.doi.org/10.1182/blood.2018882290.

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Abstract Chronic lymphocytic leukemia (CLL) occurs in 2 major forms: aggressive and indolent. Low miR-29b expression in aggressive CLL is associated with poor prognosis. Indiscriminate miR-29b overexpression in the B-lineage of mice causes aberrance, thus warranting the need for selective introduction of miR-29b into B-CLL cells for therapeutic benefit. The oncofetal antigen receptor tyrosine kinase orphan receptor 1 (ROR1) is expressed on malignant B-CLL cells, but not normal B cells, encouraging us with ROR1-targeted delivery for therapeutic miRs. Here, we describe targeted delivery of miR-2
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33

Hudecek, Michael, Maria-Teresa Lupo-Stanghellini, Paula Kosasih, et al. "Naïve CD4+ T Cells Modified to Express a ROR1-Specific CAR Mediate Anti-Tumor Activity and Provide Superior Help to CD8+ ROR1-CAR T Cells." Blood 118, no. 21 (2011): 643. http://dx.doi.org/10.1182/blood.v118.21.643.643.

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Abstract Abstract 643 The engineering of T cells modified to express single-chain antibody-derived chimeric antigen receptors (CARs) that recognize surface molecules expressed on malignant B cells independent from HLA is an area of intense research. The successful use of CAR-modified T cells to treat B-cell malignancies requires the definition of T cells or T-cell subsets that possess an intrinsic ability to confer potent and durable anti-tumor responses, and would ideally be directed against an antigen with selective expression on malignant, but not on normal B cells. Current efforts have foc
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34

Tolcher, Anthony W., Funda Meric-Bernstam, Meredith McKean, et al. "NBE-002: A novel anthracycline-based antibody-drug conjugate (ADC) targeting ROR1 for the treatment of advanced solid tumors—A phase 1/2 clinical trial." Journal of Clinical Oncology 39, no. 15_suppl (2021): TPS1108. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps1108.

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TPS1108 Background: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is highly expressed during embryonic development, but is minimally present or absent on post-partum healthy tissues. ROR1 is expressed in a variety of hematological and solid tumors and is associated with aggressive cancer phenotype and poor clinical outcomes. NBE-002 is an ADC targeting ROR1, obtained by site-specific, enzymatic conjugation of the anthracycline-derivative PNU-159682, modified with a non-cleavable linker to a humanized recombinant IgG1 monoclonal antibody, based on a novel anti-human ROR1 monoclonal
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35

Jiang, Vivian Changying, Yang Liu, Joseph McIntosh, et al. "Targeting ROR1 Using the Antibody Drug Conjugate Vls-101 in Aggressive Mantle Cell Lymphoma." Blood 136, Supplement 1 (2020): 33. http://dx.doi.org/10.1182/blood-2020-137660.

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ROR1 is a transmembrane receptor with tightly controlled expression during embryonic development. While it is expressed on multiple tumor types it is not expressed in normal adult tissues. ROR1-positive B cell non-Hodgkin's lymphomas (B-NHL) include mantle cell lymphoma (MCL), and diffuse large B cell lymphoma. Given its unique expression pattern, ROR1 represents a tumor-specific therapeutic target with little or no normal tissue toxicity. VLS-101, utilizes the UC-961 anti-ROR1 antibody which is conjugated to monomethyl auristatin E (MMAE) via a cleavable linker. VLS-101/ROR1 complex induce in
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36

Goydel, Rebecca S., Justus Weber, Haiyong Peng, et al. "Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications." Journal of Biological Chemistry 295, no. 18 (2020): 5995–6006. http://dx.doi.org/10.1074/jbc.ra120.012791.

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Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens restricted to cancer cells. A receptor tyrosine kinase, receptor tyrosine kinase-like orphan receptor 2 (ROR2), is normally expressed only during embryogenesis and is tightly down-regulated in postnatal healthy tissues. However, it is up-regulated in a diverse set of hematologic and solid malignancies, thus ROR2 represents a candidate antigen for antibody-based cancer therapy. Here we describe the affinity maturation and humanization of a rabbit mAb that binds human and mouse ROR2
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37

Choi, Michael Y., William G. Wierda, Hun Ju Lee, et al. "Phase 1/2 trial of cirmtuzumab and ibrutinib: Planned analysis of phase 1 CLL cohorts." Journal of Clinical Oncology 37, no. 15_suppl (2019): 7527. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.7527.

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7527 Background: Cirmtuzumab (C) is a humanized mAb that binds ROR1 and blocks Wnt5a from binding and activating ROR1 on CLL and mantle cell lymphoma (MCL); C does not bind normal adult tissues. A phase 1 trial of C showed excellent safety and inhibition of Wnt5a-ROR1 signaling. Ibrutinib (Ibr) does not inhibit the ROR1 pathway, and C+Ibr exert synergistic effects in CLL and MCL. The current clinical trial combines C+Ibr for patients (pts) with CLL and MCL. A planned analysis of the phase 1 CLL portion is presented. Methods: Eligible pts had CLL needing treatment according to iwCLL guidelines.
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38

Mestermann, K., M. Eichler, M. Machwirth, et al. "P09.08 Clinical-grade manufacturing of ROR1 CAR T cells using a novel virus-free protocol." Journal for ImmunoTherapy of Cancer 8, Suppl 2 (2020): A55.2—A56. http://dx.doi.org/10.1136/jitc-2020-itoc7.108.

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BackgroundImmunotherapy with T cells that were modified by gene-transfer to express a ROR1-specific chimeric antigen receptor (ROR1 CAR-T) has therapeutic potential in ROR1+ malignancies in hematology and oncology. The ROR1 tumor antigen has a favorable expression profile with absence in vital normal human tissues. In this study, we sought to establish and validate clinical-grade manufacturing of ROR1 CAR-T to enable a Phase I/IIa clinical trial. In particular, we sought to integrate virus-free gene-transfer based on Sleeping Beauty transposition into this manufacturing protocol to permit scal
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39

Schultheiss, H., C. Dechert, K. H. Kogel, and R. Hückelhoven. "Knock-down of the small G-protein RACB enhances penetration-resistance of barley against the powdery mildew fungus." Plant Protection Science 38, SI 2 - 6th Conf EFPP 2002 (2017): 477–79. http://dx.doi.org/10.17221/10528-pps.

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Small G-proteins (RAC and RHO) are known to be involved in regulation of superoxide (O<sub>2</sub><sup>•–</sup>) production and the assembly of actin fibres. These processes are known to be crucial for accessibility and inaccessibility of barley cells to the biotrophic fungus Blumeria graminis f.sp. hordei (Bgh). Using a candidate RT-PCR approach six Rac-related cDNA-clones were isolated from barley. The transient knock-down of RacB led to a remarkably lower penetration efficiency of Bgh into susceptible barley lines (Mlo/Ror1). Surprisingly the inhibition of RacB expre
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40

Broome, H. Elizabeth, Laura Z. Rassenti, Michael Y. Choi, and Thomas J. Kipps. "Low Expression of ROR1 on Chronic Lymphocytic Leukemia Is Associated with Other Atypical Findings." Blood 118, no. 21 (2011): 4588. http://dx.doi.org/10.1182/blood.v118.21.4588.4588.

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Abstract Abstract 4588 ROR1 is a developmental embryonic surface antigen that also is expressed on chronic lymphocytic leukemia (CLL) cells, but not on most tissues or cells of healthy adults, including secondary lymphoid tissues or normal CD5 B cells. Studies involving relatively small numbers of patients have identified expression of ROR1 on the neoplastic cells of nearly all patients examined. However, it is not established whether there are cases of bona fide CLL that lack expression of this antigen or whether cases of putative CLL that lack expression of ROR1 actually represent a disease
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41

Hellqvist, Eva, Christina C. N. Wu, George F. Widhopf, et al. "Selective Clearance of Chronic Lymphocytic Leukemia Cells in Vivo Following Treatment with UC99961, an Anti-ROR1 Monoclonal Antibody." Blood 120, no. 21 (2012): 3886. http://dx.doi.org/10.1182/blood.v120.21.3886.3886.

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Abstract Abstract 3886 ROR1 is a receptor-tyrosine kinase like protein expressed on the surface of chronic lymphocytic leukemia (CLL) B cells, but not on normal mature B cells, suggesting that it may be a promising therapeutic target. We have generated a chimeric monoclonal antibody (mAb), UC99961, which binds to an intradomain epitope of human ROR1 (hROR1). UC99961 binds the same epitope as the murine anti-hROR1 mAb, UC D10–001, which has direct cytotoxic effects on hROR1 positive CLL cells. In this study we investigated the in-vivo anti-leukemic activity and tolerability of UC99961 on ROR1+
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42

CHAUVET, Caroline, Brigitte BOIS-JOYEUX та Jean-Louis DANAN. "Retinoic acid receptor-related orphan receptor (ROR) α4 is the predominant isoform of the nuclear receptor RORα in the liver and is up-regulated by hypoxia in HepG2 human hepatoma cells". Biochemical Journal 364, № 2 (2002): 449–56. http://dx.doi.org/10.1042/bj20011558.

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The retinoic acid receptor-related orphan receptor α (RORα) is critically involved in many physiological functions in several organs. We find that the main RORα isoform in the mouse liver is the RORα4 isoform, in terms of both mRNA and protein levels, while the RORα1 isoform is less abundant. Because hypoxia is a major feature of liver physiology and pathology, we examined the effect of this stress on Rora gene expression and RORα transcriptional activity. HepG2 human hepatoma cells were cultured for 24h under normoxia (20% O2) or hypoxia (10, 2, and 0.1% O2) and the abundance of the Rora tran
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43

Choi, Michael Y., George F. Widhopf, Jian Yu, et al. "Immunotherapeutic Targeting of ROR1-Dependent, Non-Canonical Wnt5a-Signaling By Cirmtuzumab: A First-in-Human Phase I Trial for Patients with Intractable Chronic Lymphocytic Leukemia." Blood 128, no. 22 (2016): 3224. http://dx.doi.org/10.1182/blood.v128.22.3224.3224.

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Abstract Background: Cirmtuzumab is a first-in-class humanized mAb specific for ROR1, an oncoembryonic antigen found on CLL and cancer stem cells of various cancers, but not on normal post-partum tissues. Work has defined that ROR1 serves as a receptor for Wnt5a, which induces non-canonical Wnt-signaling that promotes planar-cell-polarity, migration, stem-cell renewal, and proliferation. Recent studies demonstrated that Wnt5a binds to ROR1 and induces activation of RhoA and Rac1, promoting leukemia-cell migration and proliferation, respectively. By binding a functional epitope in the extracell
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44

Mani, Rajeswaran, Yicheng Mao, Frank W. Frissora, et al. "Tumor Antigen ROR1 Targeted Delivery Of FTY720 Derivative OSU-2S Prolongs Survival In ROR1 Engineered Mouse Model Of Chronic Lymphocytic Leukemia." Blood 122, no. 21 (2013): 4168. http://dx.doi.org/10.1182/blood.v122.21.4168.4168.

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Abstract The discovery of predominantly inactive phosphatases in a variety of cancers and the potential for phosphatase targeted therapy as an alternative to kinase inhibitors especially in situations where the efficacy of the kinase inhibitors are compromised due to resistance mechanisms attributed to mutations and single nucleotide polymorphisms of the drug targets prompted us to evaluate potential activators of phosphatases in chronic lymphocytic leukemia (CLL) and other B cell malignancies. We have recently identified cytotoxic activity of OSU-2S, a novel non-immunosuppressive FTY720 deriv
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45

Choi, Michael, George F. Widhopf II, Jian Yu, et al. "Durable and Specific Inhibition of ROR1 Signaling Associates with Prolonged Progression Free Survival in Patients with Chronic Lymphocytic Leukemia Treated with Cirmtuzumab." Blood 130, Suppl_1 (2017): 829. http://dx.doi.org/10.1182/blood.v130.suppl_1.829.829.

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Abstract Small-molecule drugs that inhibit survival signals in leukemia cells have demonstrated high efficacy in the treatment of patients (pts) with chronic lymphocytic leukemia (CLL). Although not directly cytotoxic for leukemia cells, these drugs block key signaling pathways that govern leukemia-cell trafficking, proliferation, and survival. However, non-specific inhibition of enzymes involved in other signaling pathways in non-neoplastic cells may result in toxicity, which can limit the therapeutic index of such drugs, at least in some settings. Monoclonal antibodies (mAbs) also may be use
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46

Lee, Hun Ju, Michael Y. Choi, Tanya Siddiqi, et al. "Clinical activity of cirmtuzumab, an anti-ROR1 antibody, in combination with ibrutinib: Interim results of a phase Ib/II study in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL)." Journal of Clinical Oncology 38, no. 15_suppl (2020): 8036. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.8036.

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8036 Background: ROR1 is an onco-embryonic tyrosine kinase receptor that is re-expressed at high levels on many hematologic and solid cancers but not on normal adult tissues. ROR1 binds Wnt5a, resulting in increased tumor growth and survival, cancer cell stemness and epithelial mesenchymal transition. Cirmtuzumab (Cirm) is a humanized monoclonal antibody designed to inhibit the tumor promoting activity of ROR1. In this study, we examined the safety and efficacy of Cirm in combination with ibrutinib (Ibr) in MCL or CLL. Methods: As of Jan 29, 2020, 12 pts with relapsed refractory (RR) MCL were
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47

Okada, Kosuke, Takeki Fujimura, Takeshi Kikuchi, et al. "Effect of interleukin (IL)-35 on IL-17 expression and production by human CD4+ T cells." PeerJ 5 (February 15, 2017): e2999. http://dx.doi.org/10.7717/peerj.2999.

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Background Interleukin (IL)-17 produced by mainly T helper 17 (Th17) cells may play an important destructive role in chronic periodontitis (CP). Thus, anti-inflammatory cytokines, such as IL-35, might have a beneficial effect in periodontitis by inhibiting differentiation of Th17 cells. Th17 differentiation is regulated by the retinoic acid receptor-related orphan receptor (ROR) α (encoded by RORA) and RORγt (encoded by RORC). However, the role of IL-35 in periodontitis is not clear and the effect of IL-35 on the function of Th17 cells is still incompletely understood. Therefore, we investigat
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48

Ghia, Emanuela M., Laura Z. Rassenti, Michael Y. Choi, Elvin Chu, George F. Widhopf II, and Thomas J. Kipps. "High-Level ROR1 and BCL2, Cancer-Stemness, and BCL2 Mutations Associate with Venetoclax Resistance in Chronic Lymphocytic Leukemia." Blood 134, Supplement_1 (2019): 476. http://dx.doi.org/10.1182/blood-2019-131426.

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Venetoclax (Ven) is an inhibitor of BCL2 that is highly active in patients (pts) with chronic lymphocytic leukemia (CLL), effecting remissions without detectable minimal residual disease (MRD), particularly when used in combination with an anti-CD20 mAb (Seymour et al., N Engl J Med, 2018). However, pts can have persistent detectable MRD (i.e. ≥10-4 CLL cells by flow cytometry) after ≥1 year (yr) of Ven therapy (V-Rx); such pts are at risk for developing progressive disease (PD) even with continued V-Rx (Kater et al., J Clin Oncol, 2019). Evaluation of CLL cells from such pts may define biolog
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49

Choi, Michael Y., George F. Widhopf, Januario Castro, et al. "Cirmtuzumab (UC-961), a First-in-Class Anti-ROR1 Monoclonal Antibody: Planned Interim Analysis of Initial Phase 1 Cohorts." Blood 126, no. 23 (2015): 1736. http://dx.doi.org/10.1182/blood.v126.23.1736.1736.

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Abstract INTRODUCTION: Chronic lymphocytic leukemia (CLL) cells of nearly all patients (pts) express ROR1 (Receptor tyrosine kinase-like Orphan Receptor 1), an orphan-receptor tyrosine-kinase-like protein that is normally expressed during embryogenesis, but not by normal post-partum tissues. ROR1 is a receptor for Wnt5a, which can induce non-canonical Wnt signaling to enhance CLL-cell survival and/or proliferation. We have developed antibodies that bind to epitopes that span the extracellular portion of human ROR1, and selected one mAb that had the most potent activity in inhibiting such signa
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50

Choi, Michael Y., Emanuela M. Ghia, Tanya Siddiqi, et al. "Cirmtuzumab, a ROR1 Targeted Mab, Reverses Cancer Stemness, and Its Combination with Ibrutinib Is Safe and Effective: Planned Analysis of the Cirll Phase 1/2 Trial for CLL and MCL." Blood 134, Supplement_1 (2019): 1755. http://dx.doi.org/10.1182/blood-2019-131498.

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Cirmtuzumab (Cirm) is a novel humanized mAb specific for ROR1, which is expressed primarily during embryogenesis and in many cancers, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but generally not on normal post-partum tissues. A Phase I study involving patients (pts) with CLL showed Cirm was safe and effective in blocking ROR1-signaling and in reversing cancer-cell-stemness transcriptome signatures associated with aggressive malignancies (Choi et al., Cell Stem Cell, 2018; Malta et al., Cell, 2018). Cirm also was shown to block Wnt5a-ROR1 survival-signaling in
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