GS-626510 / Gilead - LARVOL DELTA

The synergistic interaction of the BET antagonist GS-626510 with the PI3Kδ inhibitor idelalisib in diffuse large B-cell lymphoma involves the blockade of the tumor-macrophage crosstalk (EACR 2022) - "In vivo, when compared to idelalisib and GS-626510 single agents, the combo treatment arm underwent a 2-3 fold increase in relative tumor growth inhibition, reaching 85% after two weeks of daily dosing of the animals, with no detectable toxicity. Conclusion The combination of idelalisib and GS-626510 is able to disrupt GCB-DLBCL crosstalk with M2-macrophages, thereby modulating the secretion of several inflammatory cytokines involved in the regulation of tumor B cell apoptotic threshold."

IO biomarker • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • BCL2 • BCL2L1 • CD20 • IL10 • IL1RN • MCL1 • MYC • PIK3CD • PPBP

Integrated mutational landscape analysis of uterine leiomyosarcomas. (PubMed, Proc Natl Acad Sci U S A) - "Finally, we found olaparib (PARPi; P = 0.002), GS-626510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and suggest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs."

Journal • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor • Uterine Corpus Leiomyosarcoma • ALK • ATRX • DAXX • MAP2K4 • MSI • MYC • PARP1 • PIK3CA • PTEN • RB1 • TP53

Derangements in HUWE1/c-MYC pathway confer sensitivity to the BET bromodomain inhibitor GS-626510 in uterine cervical carcinoma. (PubMed, Gynecol Oncol) - "Downregulation/inactivation of HUWE1 may increase c-MYC expression and proliferation in primary-CC-cell-lines. GS-626510 may represent a novel, potentially highly effective therapeutic agent against CC overexpressing c-MYC and/or harboring HUWE1 mutations. Clinical studies with BET inhibitor in CC-patients harboring radiation/chemotherapy-resistant disease are warranted."

Journal • Cervical Cancer • Gynecologic Cancers • Oncology • Solid Tumor • HUWE1 • MYC

[VIRTUAL] Derangements in HUWE1/c-MYC pathway confer sensitivity to the BET bromodomain inhibitor GS-626510 in uterine cervical carcinoma (AACR-II 2020) - "Downregulation/inactivation of HUWE1 may increase c-MYC expression and proliferation in primary CC cell lines. GS-626510 may represent a novel, potentially highly effective therapeutic agent against CC overexpressing c-MYC and/or harboring HUWE1 mutations. Clinical studies with BET inhibitor in CC-patients harboring radiation/chemotherapy-resistant disease are warranted."

Cervical Cancer • Gynecologic Cancers • Oncology • Solid Tumor • HUWE1 • MYC

Inhibition of BET bromodomain proteins with GS-5829 and GS-626510 in Uterine Serous Carcinoma, a biologically aggressive variant of Endometrial Cancer. (PubMed, Clin Cancer Res) - "GS-5829 and GS-626510 may represent novel, highly effective therapeutics agents against recurrent/chemotherapy resistant USC overexpressing c-Myc. Clinical studies with GS-5829 in USC-patients harboring chemotherapy-resistant disease are warranted."

Journal

Newly added product (Clinical Cancer Research) - Preclinical, Endometrial Cancer

Pipeline update

Whole exome sequencing (WES) of primary, metastatic and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors (SGO 2019) - "Finally, to search for new therapeutic targets we evaluated the in vitro and in vivo activity of BET inhibitor (i.e., JQ-1 and GS-626510) on primary tumors and xenografts harboring gain-of-function mutations in c-MYC. Our findings suggest early transcoelomic spreading capability may represent an intrinsic feature of ovarian cancer posing a formidable challenge for early ovarian cancer detection. BET inhibitors may represent a novel class of active drugs in patients with recurrent/chemotherapy-resistant ovarian tumors."

BRCA Biomarker

Whole exome sequencing (WES) of primary, metastatic and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors (SGO 2019) - "Finally, to search for new therapeutic targets we evaluated the in vitro and in vivo activity of BET inhibitor (i.e., JQ-1 and GS-626510) on primary tumors and xenografts harboring gain-of-function mutations in c-MYC. Our findings suggest early transcoelomic spreading capability may represent an intrinsic feature of ovarian cancer posing a formidable challenge for early ovarian cancer detection. BET inhibitors may represent a novel class of active drugs in patients with recurrent/chemotherapy-resistant ovarian tumors."

BRCA Biomarker

Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors. (PubMed, Proc Natl Acad Sci U S A) - "Among the 17 patients with matched tumors, four patients gained PIK3CA amplifications and two patients gained c-MYC amplifications in the recurrent tumors, with no loss of amplification or gain of deletions. Primary cell lines and xenografts derived from chemotherapy-resistant tumors demonstrated sensitivity to JQ1 and GS-626510 (P = 0.01), suggesting that oral BET inhibitors represent a class of personalized therapeutics in patients harboring recurrent/chemotherapy-resistant disease."

BRCA Biomarker • Journal