Development of a first-in-class combination of DNA damage response inhibitors for the treatment of high-grade serous ovarian cancer

PROJECT SUMMARY High-grade serous ovarian carcinoma (HGSOC) is a devastating disease responsible for the deaths of ~125,000 women worldwide each year. HGSOC has the lowest survival rates. More than 20% of HGSOCs harbor genetic mutations (e.g. BRCA1/2MUT) that cause defects in homologous recombination (HR), which causes sensitivity to PARPi. However, responses to PARPi are rarely durable and resistance is acquired rapidly. Another 50% of HGSOCs do not harbor defects in HR and instead overexpress Cyclin E (CCNE1) through amplification, copy number gain, or transcriptional means. Unlike BRCA1/BRCA2-mutant tumors, which initially respond to platinum- based chemotherapy, CCNE1-amplified tumors are associated with primary platinum failure. A recent study revealed that 1) Cyclin E (CCNE1) induction increases ATR signaling and sensitivity to WEE1 kinase inhibitor and ATR inhibitor (WEE1i-ATRi) treatment, 2) WEE1i-ATRi increases tumor regression in a CCNE1-level- dependent manner in PDXs, 3) Differential molecular effects of WEE1i and ATRi promote replication fork collapse, and 4) CCNE1 amplification is a reliable biomarker predictive of response to WEE1i-ATRi. These findings indicated that a combination of WEE1 kinase inhibitor (WEE1i) and ATR inhibitor (ATRi) is a feasible approach for the treatment of PARPi-resistant Cyclin E (CCNE1) overexpressing (CCNE1HIGH) high-grade serous ovarian cancer (HGSOC). These results provide a strong rationale for Atrin to develop a first-in-class combination of WEE1i and ATRi that can allow lower-dosing strategies to mitigate off-target toxicity for the treatment of HGSOCs. Atrin Pharmaceuticals, Inc has been in the field of DDR for over a decade and is pioneering the development of next-generation, selective ATRi. We have discovered ATRN-119 as a highly selective ATRi and have received FDA IND approval (IND #141317). In parallel, we have also discovered a highly selective WEE1 inhibitor demonstrating high potency on WEE1 kinase, superior selectivity over PLK1, and significant anti-growth activity against various cancer cell lines of NCI-60 panel with high potency. In addition, our WEE1i exhibits superior potency in OVCAR8 cells compared to AZD1775. Pharmacokinetic (PK) study in mice shows superior oral bioavailability compared to AZD1775. In an OVCAR-3 xenograft tumor model, it alone completely halts tumor growth without causing loss of body weight. Importantly, our WEE1i sensitizes the ovarian cancer cell line (OVCAR8) to ATRN-119. Given these promising results, we proposed to 1) Quantify sensitivity of HGSOC to our WEE1i and ATRN-119 alone as well the combination in PDX models of HGSOC. 2) Identify additional biomarkers to expand target patient populations, 3) Evaluate the toxicity, and 4) Obtain a GMP batch of API. The success of our Direct-to-Phase II project will further support chemistry, manufacturing, and controls (CMC) to manufacture clinical supply of our novel WEE1i and complete FDA-required IND-enabling pharmacology safety and toxicology studies. In addition, findings from this project will inform clinical trial protocols using our first-in-class combination for the treatment of HGSOC, which critically needs more efficacious treatments.