Cancer Res. Huntoon, C. J. et al. In a first-in-human, Phase I trial, researchers at The University of Texas MD Anderson Cancer Center discovered that ATR inhibitor RP-3500 was safe and well tolerated with promising clinical benefit. Epithelial ovarian cancer is comprised of several subtypes, the most common being high grade serous carcinoma (HGSC). PARP inhibitors are a targeted therapy that prevent cancer cells from reproducing. âThis is the first randomized study of ATR inhibitor therapy in any tumor type, and the first suggesting a benefit of adding an ATR inhibitor to standard chemotherapy in ovarian ⦠November 18, 2021. Cell cycle effects and chemo-and radiopotentiation by NU6027 were determined in MCF7 cells and the role of mismatch repair and p53 was determined in isogenically matched ovarian ⦠Repare Therapeuticsâ RP-3500 Shows Potential of ATR Inhibitors in Precision Oncology. HRD impairs normal DNA damage repair which results in loss or ⦠Taken together, our results established that ATR and Chk1 inhibitors differentially sensitize ovarian cancer cells to commonly used chemotherapy agents and that Chk1 phosphor-ylation ⦠Catherine J. Huntoon, Karen S. Flatten, Andrea E. Wahner Hendrickson, Amelia M. Huehls, Shari L. Sutor, Scott H. Kaufmann and Larry M. Karnitz. Our approach is to rapidly advance the discovery of potential new therapies and positively impact the care of cancer patients in their lifetime. In other words, ATR inhibitors may potentially be coupled with PARP inhibitors. PARP Inhibitor-Resistant Ovarian Cancer Responds to PARP Plus ATR Inhibitors. 1. Moreover, an ATR inhibitor further enhanced the killing of BRCA1-depleted ovarian cancer cells by cisplatin, topotecan, and veliparib [ 50 ]. Ovarian cancer represents the leading cause of cancer deaths among gynecological malignancies, accounting worldwide for about 225.000 new cancer cases (3.7% of all female cancers) and about 140,000 deaths (4.2% of all deaths in women) every year [].In the United States, 21,980 estimated new cases and 14,270 estimated deaths were ⦠After successful clinical trials, the first PARP inhibitor olaparib (Lynparza) was approved in 2014 as a treatment for advanced ovarian cancer with BRCA mutations. A, Chemical structure of BAY 1895344, a highly potent and selective inhibitor of ATR.B, Growth curves of GRANTA-519 mantle cell lymphoma tumors in female SCID beige mice (n = 10/group) treated with vehicle or different doses of BAY 1895344 (3, 10, 30, or ⦠Mutations to the CHEK2 gene have been linked to a wide range of cancers. Another ongoing clinical trial is combining the ATR inhibitor M6620 with the PARP inhibitor veliparib to evaluate if this combination can impair DNA repair and induce the âBRCAnessâ phenotype in solid tumours, including ovarian cancer, which may increase sensitivity to platinum chemotherapy (NCT02723864) . The lead clinical program, PARP inhibitor (Senaparib/ IMP4297), is in Phase II/III studies for ovarian cancer, prostate cancer, small cell lung cancer and other indications ⦠The addition of an ATR inhibitor brings the stress up to the necessary lethality level.â âOur discovery of a novel biomarker for response to gemcitabine in patients with HGSOC ⦠In addition, in 2020, Merck announced in The Lancet the results of a clinical trial of Berzosertib combined with gemcitabine in the treatment of patients with advanced ovarian â¦
The goal of combination therapy is to improve response rates to PARPi monotherapy and overcome PARPi resistance. Ovarian cancer (OVCA) inevitably acquires resistance to platinum chemotherapy and PARP inhibitors (PARPi). We show that acquisition of PARPi-resistance is accompanied by increased ATR-CHK1 activity and sensitivity to ATR inhibition (ATRi). However, PARPi-resistant cells are remarkably more sensitive to ATRi when combined with PARPi (PARPi-ATRi). ATR coordinates the response to replication stress (RS), a driving force of cancer, as well as the result of treatment with certain types of cancer therapy. Small molecule ATR inhibitors have been in clinical development for several years, and although various novel drugs have come and gone, 2 clear leaders have emerged from the pack. 1 Cytoreductive surgery and platinum-based chemotherapy are considered the treatment of choice for patients with newly diagnosed advanced ovarian ⦠Berzosertibe is a first-in-class ATR Inhibitor M6620 (VX-970) that blocks a key DNA repair protein called ATR that is undergoing clinical evaluation as a single agent or in ⦠As a key player in the RS response and in regulating the S and G2/M cell cycle check-points, ATR Inhibition Broadly Sensitizes Ovarian Cancer Cells to Chemotherapy Independent of BRCA Status. Alpelisib (BYL719) is a potent and selective PI3Kα inhibitor with IC50 of 5 nM in a cell-free assay, and minimal effect on PI3Kβ/γ/δ. the combination of olaparib and AZD6738, an inhibitor of ATR , in relapsed, refractory cancer patients with tumors ⦠About the Societies. As a 501(c)(6) organization, the SGO contributes to the advancement of women's cancer care by encouraging research, providing education, raising standards of practice, advocating for ⦠In other words, ATR inhibitors may potentially be coupled with PARP inhibitors. Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial. The goal of this platform is to identify new drug combinations with strong scientific rationale in the laboratory, with the ultimate goal of moving these regimens to the clinic for patients with â¦
Conclusions Our data provides evidence that ATR inhibition is suitable for synthetic lethality application and cisplatin chemopotentiation in XRCC1 deficient ovarian cancer cells. Epithelial ovarian cancer is the most lethal gynecologic malignancy. Ovarian cancer (OVCA) inevitably acquires resistance to platinum chemotherapy and PARP inhibitors (PARPi). Full Title An Open-Label Phase 1b Study To Determine The Maximum Tolerated And/Or Recommended Phase 2 Dose Of The ATR Inhibitor BAY 1895344 In Combination With PARP Inhibitor Niraparib, In Patients With Recurrent Advanced Solid Tumors And Ovarian Cancer Purpose The purpose of this study is to find the highest dose of the investigational drug BAY ⦠ico_angle_double_right. RNA interference (RNAi)-mediated depletion or inhibition of ATR has been shown to sensitize ovarian cancer cells to cisplatin, topotecan, gemcitabine, and the PARP inhibitor veliparib (ABT-888) . ovarian cancer Sipei Nie ... inhibitor of ATR/CHK1 signaling pathway. Berzosertib blocks a key DNA repair protein, ATR. This cellular inhibition of ATR by NU6027 was observed to sensitise ovarian and breast cancer cells to various DNA-damaging anti-cancer therapeutics, ⦠Combination ATR and PARP Inhibitor (CAPRI) Trial With AZD6738 and Olaparib in Recurrent Ovarian Cancer (CAPRI) The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Because both effective screening strategies and symptoms are lacking in early-stage esophageal cancer, disease is often diagnosed at advanced stages, with 5-year overall survival (OS) rates of only about 15%â20% [2]. Dose-dependent antitumor efficacy and unbound plasma levels of BAY 1895344 as monotherapy. In a first-in-human, Phase I trial, researchers at The University of Texas MD Anderson Cancer Center discovered that ATR inhibitor RP-3500 was safe and well tolerated ⦠This study identied a CXCL2-mediated mechanism in EOC platinum resist - ance. Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors. ATR Inhibitor M6620 (VX-970) as monotherapy or in combination with chemotherapy in Colon and Ovarian Cancer. Merck Advances ATR Inhibitor Berzosertib in Small Cell Lung Cancer With New Published Data and Initiation of Phase II Trial With Registrational Intent Read full article April â¦
suggested that inhibiting ATR/CHK1 broadly sensitizes cancer cells to chemotherapy, which is independent of BRCA status in ovarian cancer . Combination ATR and PARP Inhibitor (CAPRI) trial with AZD6738 and Olaparib in recurrent ovarian cancer Clinical Trial is currently Enrolling By Invitation at University of Pennsylvania (UPenn), Philadelphia, PA However, ATM can also phosphorylate CHK1 ( Gatei et al., 2003, Sørensen et al., 2003, Helt et al., 2005 ), albeit to a lesser extent and a recent study in ovarian cancer has suggested that CHK1 phosphorylation status may not offer a reliable marker for inhibition of the ATR-CHK1 pathway ( Huntoon et al., 2013 ).