AZD1775 is a Wee1 inhibitor that has been combined with carboplatin and paclitaxel in the platinum-sensitive recurrent setting of ovarian cancer. Impact: Further study of adavosertib in this cancer and biomarkers of WEE1 inhibition response is warranted. Here, we show the synergy of BET bromodomain inhibition with PARP inhibition in BRCA -proficient ovarian cancers due to mitotic catastrophe. Cancer cells, due to mutations in the p53/pRb pathway, frequently exhibit a deficient G1-arrest and mostly depend on G2-arrest [].WEE1 inhibitors appear to have potential Zentalis Pharma Posts Initial Clinical Data On Its Wee1 Inhibitor In Ovarian Cancer. We considered an increase in genomic instability induced by WEE1 inhibition might be used to augment the effects of drugs targeting DNA repair protein. Normal cells repair damaged DNA during G1 arrest; however, cancer cells often
Cancer cells, due to mutations in the p53/pRb pathway, frequently exhibit a deficient G1-arrest and mostly depend on G2-arrest [ 24 ]. WEE1 inhibitors appear to have potential high efficiency in p53-deficient ovarian cancers, generating a condition of synthetic lethality among p53 mutant tumors. PVs in BRCA1 and BRCA2 genes are responsible for a substantial fraction of hereditary EOC. Vaccines; e.g.,DPX-Survivac . This early phase I trial tests the safety and side effects of ZN-c3 in treating patients with triple-negative breast cancer or ovarian cancer that have spread to other parts of ZN-c3 was generally well-tolerated in combination with chemotherapy and exhibited lower hematologic toxicity and a better gastrointestinal tolerability profile than the Wee1 inhibitor class. Wee1 Inhibition in Recurrent Serous Uterine Cancer: Science Paving the Way in a Challenging Disease Ainhoa Madariaga, MD1,2and Amit M. Oza, MD1,2 The incidence of endometrial The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. Others in this space include Debiopharm, although the French firm appears to have cooled on the mechanism. Cyclin E (CCNE1) is overexpressed in 25% of high grade serous ovarian cancers The cancer cells become very dependent on the checkpoint that is regulated by Wee1. In this review, we summarize recent advances with Wee1 inhibitors, statins, and mevalonate pathway inhibitors in cancers with p53 mutations.
Patients with Advanced Ovarian Cancer at AACR April 8, 2022 profile in comparison to the Wee1 inhibitor class. These platinum-sensitive ovarian cancer
Wee1-like protein kinase (WEE1) contributes to the upstream regulation of the cyclin-dependent kinase Combinations of PARP inhibitors with other anticancer therapies in ovarian cancer; PARP plus novel Wee1 inhibitors; Final Thoughts and Takeaways.
Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. Wee1 is emerging as a potentially important therapeutic target for a range of solid tumors, including ovarian and uterine cancer. In a phase I study, the Pre-clinical studies showed that treatment with adavosertib inhibits the growth of ovarian cancer cells in vitro and in vivo. This randomized phase II clinical trial studies how well gemcitabine hydrochloride and WEE1 inhibitor MK-1775 work compared to gemcitabine hydrochloride alone in treating indicate that disruption of WEE1 may enhance the cell killing effects of some anticancer agents. In ovarian cancer, melanoma, and glioma tumors, high expression of Wee1 is associated with poor outcome. Chief, Division of Gynecologic Oncology Inhibition of wee1 either by the pyrido-pyrimidine derivative (PD0166285) or via siRNA gene knockdown has been shown to sensitize ovarian, colon, cervical, osteosarcoma, Wee1 inhibition remains a promising therapeutic approach to treating an array of solid tumors, including advanced ovarian cancer, and these results further support the class Program Director. Adding the WEE1 inhibitor AZD1775 to carboplatin offered What was the rationale behind adding a Wee1 inhibitor in the EFFORT? "Identifying and overcoming a mechanism of resistance to WEE1 kinase inhibitor AZD1775 in high grade serous ovarian cancer cells." Restriction of the G2/M checkpoint by WEE1 inhibitor AZD1775 results in disturbed proteostasis and UPR activation in ovarian cancer cells with TP53 mutations, which ZN-c3 was generally well-tolerated in combination with chemotherapy and exhibited lower hematologic toxicity and a better gastrointestinal tolerability profile than the
Zentalis Pharmaceuticals is developing a WEE1 inhibitor that it hopes to combine with PARP inhibitors and other cancer medicines to boost their efficacyand its early phase 1 data are promising. Our aim was to characterise resistance mechanisms to WEE1 inhibitor AZD1775 and identify ways to overcome resistance ready for use in the clinic. Purpose AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. Preclinical data indicate that disruption of WEE1 may enhance the cell killing effects of some anticancer agents. The ovarian cancer patient saw targeted tumors shrink by about 56%. High-grade serous ovarian cancer (HGSOC) is characterized by universal p53 mutation, the more common gain of function or a LOF null mutation, the WEE1 inhibitor New results involving the Wee1 inhibitor adavosertib brought improved survival benefits in a hard-to-treat type of ovarian cancer, but trials in the pipeline suggest the positive MedPage Today (1/25, Ingram) reports researchers found in a phase 2 trial that the addition of the Wee1 inhibitor adavosertib to gemcitabine reduced the risk of disease progression and death in women with recurrent, platinum-resistant or -refractory ovarian cancer.The trials results were published in The Lancet. Expert Views on The Future of PARP Inhibitors in Ovarian Cancer. Given the biological significance of in vitro data, we next investigated the antitumor activity induced by AZD1775 and AZD6738 in vivo. Treatment of BRCA -proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. The lead novel candidate, the WEE1 inhibitor
Using our industry expertise, we have developed an integrated approach to identify and overcome the limitations of current cancer therapeutics, enabling us to design better small molecules for improved patient outcomes. Dual inhibition of WEE1 and CHK1 seems to be an interesting option, but PD0407824 has only been tested in ovarian cancer cells as a CHK1 inhibitor, where it led to sensitization to cisplatin . At the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, CancerNetwork spoke with Shannon N. Westin, MD, MPH, of the University of Texas MD WEE1 inhibitor promotes cancer cells to prematurely enter mitosis as a result of bypassing the G2 cell-cycle checkpoint [6]aswellasdelaysmitoticexit,resultinginmitoticarrest[7]. First, we established an ovarian cancer model in C57BL/6 mice using ID8 cells. The study results were recently presented and suggested the efficacy of adavosertib alone and combined with olaparib. Zentaliss earlier work also includes an ovarian cancer trial testing its Wee1 agent in combination with Glaxosmithklines Zejula, a Parp inhibitor that also works by damaging DNA repair pathways. Adding the Wee1 inhibitor adavosertib to gemcitabine reduced the risk of disease progression and death in women with recurrent, platinum-resistant or -refractory ovarian ovarian cancer. These include inhibitors of signaling through the phosphatidylinositol 3-kinase (PI3K) pathway, vascular endothelial growth factor receptor (VEGFR), and cell cycle checkpoints including WEE1 [, , ].
WEE1 inhibition by MK1775 as a single-agent therapy inhibits ovarian cancer viability. Schrdinger is on track to select a Wee1 development candidate later this year. Adding the Wee1 inhibitor adavosertib to gemcitabine reduced the risk of disease progression and death in women with recurrent, platinum-resistant or -refractory ovarian In a phase I study, the Wee1. A fourth to a fifth of unselected EOC patients carry pathogenic variants (PVs) in a number of genes, the majority of which encode for proteins involved in DNA mismatch repair (MMR) pathways. PARP inhibitors such as Merck and AstraZenecas Lynparza have changed the game for patients with ovarian cancer, but theyre still not a cure, as cancers can outsmart Wee1-like protein kinase (WEE1) physiologically serves a key function in maintaining the integrity of the cell genome through mediating the activation of cyclin-dependent kinase (CDK)1 and CDK2. The present study aimed at examining the in vitro and in vivo antitumor activity of MK1775, a potent pharmacological inhibitor of WEE1, as a single agent against ovarian cancer cells. PD0166285 has been used to examine the effect of WEE1 inhibition in cervical cancer, colon cancer, lung cancer, melanoma, ovarian cancer, and hepatocellular carcinoma In cancer cells recurring after chemotherapy for medulloblastoma, vulvar squamous cell carcinoma, and malignant ovarian cancer, a single WEE1 inhibitor, AZD1775, can inhibit tumors. CHICAGO AstraZeneca's investigational WEE1 inhibitor adavosertib showed potential in biomarker-selected advanced ovarian cancer populations in two studies presented [34] verified through animal experiments that Wee1 inhibitor MK1775 as a single preparation has an inhibitory effect on tumor cells of ovarian cancer, and Wee1 may Antibody-drug conjugates (ADC); e.g,Mirvetuximab soravtansine,for which new clinical trial results were published in May 2020 ; Targeted therapies; e.g.,the ATR inhibitor AZD6738,the Wee1 inhibitor adavosertib,and the anti-DLL4/VEGF bispecific antibody navicixizumab In accordance with our results, pharmacologic inhibition of G2 checkpoint kinases Wee1 and Chk1 has been shown to have anti-tumoral effects in neuroblastoma cells both in vitro and in vivo 21 and cause DNA double-strand breaks in cancer cells in the absence of DNA-damaging chemotherapeutic drugs. Objective: As a result of TP53 gene mutation high grade serous ovarian cancer (HGSOC) is dependent on the G2 checkpoint for the repair of DNA damage and survival. The present study aimed at examining the in vitro and in vivo antitumor activity of MK1775, a potent pharmacological inhibitor of WEE1, as a single agent against ovarian cancer cells.
