Targeting Replication Stress in Uterine and Endometrial Cancers
In the United States, uterine cancer rates and mortality are rising, with survival rates showing decreasing trends. Most uterine cancers are endometrial cancers, originating from the lining of the uterus.
Dana-Farber Cancer Institute received a five-year Research Program Project (P01) grant from the National Cancer Institute (NCI) in May 2024 funding research focused on improving outcomes for patients with hard-to-treat uterine and endometrial cancers that have underlying replication stress. These types of uterine cancers include endometrial serous, carcinosarcoma, and clear cell. These pathologic types of uterine cancer are rising in incidence and are contributing to worsening survival rates of patients diagnosed with uterine cancer.
P01 Research Grant Overview: Innovative Approaches to Targeting Replication Stress in Endometrial Cancer
Our research aims to develop new therapies for advanced or relapsed endometrial cancer by targeting replication stress. Replication stress (RS) slows or stops the DNA duplication process during the cell cycle, leading to genomic instability — a known characteristic of cancer.
The P01 grant includes three innovative projects and four supportive cores, each designed to investigate different methods of addressing replication stress as a vulnerability in endometrial cancer cells.
Research Objectives
- Enhance understanding of endometrial cancers and develop novel therapies.
- Reduce treatment disparities, addressing the need for new endometrial cancer therapies in underserved populations.
- Collaborate with the research community and the public, translating findings into positive patient outcomes.
Project 1:
WEE1 Inhibition in Uterine Serous and p53-Mutated Cancers
Project Leads:
Dipanjan Chowdhury, PhD
Jean Zhao, PhD
This project explores the potential of WEE1 inhibitors to target replication stress in uterine serous cancer (USC) and p53-mutated uterine cancers. By understanding the correlation between WEE1 activity and replication stress, the project aims to improve clinical outcomes through a biopsy-driven trial. This trial includes a clinical trial testing the WEE1 inhibitor azenosertib for recurrent endometrial serous cancers (NCT06369155).
Project 2:
Combined ATR/PI3K Inhibition in Uterine Cancers
Project Leads:
Panagiotis Konstantinopoulos, MD, PhD
Dipanjan Chowdhury, PhD
This project focuses on studying the synergy with combining ATR and PI3K inhibitors, and this project seeks to enhance treatment efficacy in uterine cancers. A Phase 1b trial will assess the combination's effectiveness in uterine serous and ARID1A-mutated tumors, offering new hope for patients.
Project 3:
Engaging DNA Sensing STING Pathway for Anti-Tumor Immunity
Project Leads:
Jean Zhao, PhD
Ursula Matulonis, MD
This project aims to boost anti-tumor immunity by combining DNA damage checkpoint inhibitors with immune checkpoint inhibitors. By activating the STING pathway, the project seeks to provide a foundation for future clinical trials targeting uterine cancer.
Administrative Core
Core Leads:
Ursula Matulonis, MD
Panagiotis Konstantinopoulos, MD, PhD
Joyce Liu, MD, MPH
The Administrative Core provides essential leadership and management for the P01 grant. It ensures effective communication among projects and cores, monitors progress, and facilitates the dissemination of research findings.
Biostatistics and Computational Biology Core
Core Leads:
Nabihah Tayob, MD
This core offers critical statistical and computational support, ensuring scientific rigor and data integrity across all research activities. It plays a vital role in study design, data management, and analysis.
Preclinical Modeling Core
Core Leads:
Joyce Liu, MD, MPH
Jean Zhao, PhD
The Preclinical Modeling Core develops and maintains model systems, such as PDX, PDO, and GEMM models, to study replication stress in uterine cancer. These models are crucial for understanding treatment mechanisms and responses.
Pathology Core
Core Leads:
Marisa Nucci
Geoffrey Shapiro
Supporting pathology and DNA repair studies, the Pathology Core develops and validates assays for replication stress and DNA damage. It provides essential resources for research across all projects.
P01 Grant Leadership
Principal Investigators
This grant is a collaborative effort between Dana-Farber Cancer Institute and Brigham and Women’s Hospital. Led by renowned experts in gynecologic oncology, Drs. Konstantinopoulos, Liu, and Matulonis, the project teams bring together a wealth of expertise in:
- Uterine cancer biology
- Replication stress mechanisms
- Preclinical model development
- Immunotherapy strategies
- Drug development processes
- Clinical trial implementation
This multidisciplinary approach enables us to accelerate the development of effective treatments. Explore more research initiatives and clinical trials led by Dana-Farber's Gynecologic Oncology Program.
