Targeting Replication Stress and DNA Damage Response in Uterine Cancer

PROJECT SUMMARY Uterine cancer (UC) incidence and death rates are both significantly increasing in the United States. Most UCs are endometrial cancers which arise from the inner lining of the uterus and are defined by several different histologic subtypes, the most common of which is endometrioid. Additionally, survival outcomes are worse for

black women. Because of the worsening survival of women with advanced and relapsed endometrial cancer, this P01 grant is focused on targeting replication stress (RS) in order to improve therapeutic outcomes in these patients. RS is defined as the slowing or stalling of the replication fork progression during DNA synthesis and is

widely recognized as a significant cause of genomic instability and a critical feature of cancer cells. This P01 grant investigates 3 different strategies for targeting RS in UC with the goal of translating these into effective salvage therapies for women with advanced/relapsed UC. We have assembled a team of internationally

recognized researchers from the Dana-Farber Cancer Institute and the Brigham and Women’s Hospital, both in Boston MA, with multidisciplinary expertise in UC, DNA repair and RS, immunotherapy, preclinical models, biostatistics, computational biology, gynecologic pathology, drug development and clinical trials. This P01 grant

is being led by Drs. Panagiotis Konstantinopoulos, Joyce Liu, and Ursula Matulonis who are recognized international leaders in the field of gynecologic cancer and endometrial cancer research. This P01 grant consists of 3 Projects and 4 Cores. The leadership team for each Project is comprised of paired

investigators with complementary expertise in basic science and clinical/translational research. Project 1 focuses on studying the mechanism of WEE1 inhibition in recurrent USC or p53-mutated UCs and the correlation of WEE1 activity with functional and immunohistochemical (IHC) measures of RS. Based upon the results of a

clinical trial of the WEE1 inhibitor adavosertib which previously demonstrated significant clinical activity in USCs, this project leverages a collection of patient-derived xenografts (PDXs), patient-derived organoids (PDOs), and genetically engineered mouse models (GEMMs) of p53-mutated/null endometrial cancer to examine the effects

of WEE1 inhibition on functional and IHC measures of RS in the in vitro and in vivo setting. Additionally, through a biopsy-driven investigator-initiated protocol of the WEE1 inhibitor ZN-c3 in USC, Project 1 will examine the effects of WEE1 inhibition on measures of RS in co-clinical PDOs and correlation of these measures with clinical

activity. Project 2 focuses on the hypothesis that inhibition of the PI3K pathway can increase RS and therefore create synergy with ATR inhibitors. In previously performed PRISM and CRISPR screens, inhibition of PI3K signaling together with ATR inhibition was identified as potentially synergistic and subsequent experiments have

demonstrated synergism between the PI3K inhibitor copanlisib and the ATR inhibitor elimusertib. Project 2 will examine in PDX, PDO, and GEMM model systems the potential for synergy between ATR and PI3K inhibition and will explore the clinical activity of this combination in a Phase 1b dose escalation clinical trial with dose

expansion in uterine serous and ARID1A mutated uterine tumors, both enriched in concomitant PI3K pathway alterations and genomic alterations associated with high RS. Project 3 focuses on further investigating preliminary data showing that targeting the RS response through inhibition of DNA damage checkpoint kinases

ATR and WEE1 leads to increased DNA damage and activation of the STING/TBK1/IRF3 pathway, resulting in enhanced anti-tumor immunity and improved response to immune checkpoint inhibition (ICI). Based on these, a novel strategy is proposed to extend the benefit of immunotherapy in mismatch repair proficient (MMRP) cancers

by using DNA damage checkpoint kinase inhibitors in combination with ICIs. The main hypothesis is that priming the immunologically “cold” MMRP UCs into “hot” tumors using DNA damage checkpoint kinase inhibition, combined with ICIs to overcome tumor-mediated immunosuppression, will lead to effective antitumor immunity

against MMRP UCs. The 4 Cores in this grant include Administrative; Biostatistics and Computational Biology; Preclinical Model Systems; and Pathology. Review of our P01 grant external to the Project and Core teams will occur through an External Advisory Board (EAB), an Internal Advisory Board (IAB), and an advocate core.