Ovarian cancer (EOC) remains the most lethal gynecologic malignancy, of which high grade serous EOC (HGSOC) represents 70% of cases. Current standard of care treatment with platinum-based chemotherapy results in complete remissions in >70% of EOC patients, however relapse occurs in >90% of those responders. Those with platinum-resistant EOC (PROC) have limited therapeutic options, typically single agent chemotherapies with or without bevacizumab. Overall, there are few effective treatment options, and novel strategies are critically needed.
Half of HGSOC cases possess genetic and epigenetic alterations that affect the homologous recombination DNA repair pathway (HRR), of which 20% are comprised of inherited BRCA1 and BRCA2 mutations, and the remaining 30% include alternative homologous recombination-related alterations such as somatic BRCA1/2 mutations, and ATM and ATR mutations. Ordinarily, ATR senses DNA damage, stabilizes the site of DNA replication, and, through interaction with the CHK1 protein, induces cell cycle arrest. Likewise, ATM separately senses DNA damage to induce cell cycle arrest via the CHK2 protein. Overall, these molecular alterations lead to genomically unstable HGSOC cells, which render them reliant on DNA repair pathways, such as that mediated by ATR, for continued survival. Should DNA repair be inhibited, the progressive accumulation of DNA lesions induces replicative catastrophe and cell death. The genomic instability and types of genetic alterations seen in HGSOC make it a prime setting to evaluate targeted therapies that take advantage of these alterations.
M6620, also known as VX-970, is a highly selective ATR inhibitor. The effect of ATR inhibition by M6620 is particularly pronounced when combined with gemcitabine (an antimetabolite chemotherapy), showing greater antitumor activity as a combination compared to either agent alone. In vitro, ATR inhibition is also shown to increase cancer cell death when given in situations of increased replication stress, such as when ATM signaling is impaired or when particular cell cycle-associated proteins, such as Cyclin E1, are upregulated.
We therefore conducted a randomized phase II trial of gemcitabine+M6620 vs. gemcitabine alone in recurrent platinum resistant HGSOC, for which accrual has completed. Sixty-four evaluable patients’ archival tumor specimens are available for correlative studies. We hypothesize that tumors with high replicative stress are more susceptible to treatment with combination gemcitabine+M6620 compared to gemcitabine alone. Specifically, we predict that baseline alterations in HRR or alternative repair-related genes, mutations in TP53 and ATM, and mutations or amplifications in other proteins (e.g. MYC, CCNE1) involved in cell cycle or detection of DNA damage, correlate with clinical outcomes.
This grant was made possible by a generous donation from the Lemonade Fund.