R01CA255705

Genomic Biology of the Tandem Duplicator Phenotype in Mouse and Human Cancers - Project Summary

We have identified a group of genome instability configurations called the Tandem Duplicator Phenotypes (TDPS) that are found in approximately 50% of triple negative breast, ovarian, and endometrial cancers. These TDPS are characterized by the massive genome-wide distribution of somatic tandem duplications (TDS) of specific span sizes. We have also identified the genetic drivers of these configurations and demonstrated that the loss of TRP53 and BRCA1 in the mouse mammary gland is sufficient to induce tumors with the short-span TDP configuration found in TP53- and BRCA1-deficient human cancers. Additionally, we have shown that upon loss of BRCA1, TDS are formed through the aberrant repair of stalled replication forks.

In this project, we propose to utilize a combination of computational analyses, in vivo modeling, and in vitro experimentation to achieve a deep mechanistic understanding of how the distinct TDP genomic configurations emerge and impact the course of breast tumorigenesis.

Specifically, we will investigate the molecular mechanisms leading to de novo TD formation across the different TDP groups by exploring how local DNA features associated with DNA replication and fork stalling contribute to the generation of new TDS across a large pan-cancer dataset representing all TDP groups and all TDP genetic drivers (AIM 1A). Furthermore, we will examine how loss of BRCA1 activity may modulate the spread and location of the de novo TDS formed in the context of the short-span TDP (AIM 1B).

To validate our findings, we will establish new genetically engineered mouse models (GEMMS) of breast cancer. These models will allow us to confirm that the activation of the CCNE1 pathway or loss of CDK12 activity, both in conjunction with TRP53 loss of function, induces medium- and long-span TDP configurations that mimic their human counterparts in terms of TD span size and distribution (AIM 2A). Additionally, we will investigate the genomic features and genetic elements associated with and affected by TD formation (AIM 2B). We will also assess the tumor neo-antigen load of the TDP tumors emerging from the newly developed GEMMS and test the effectiveness of immuno-oncology agents against mammary tumors with the TDP configuration, as suggested by recently emerging clinical observations (AIM 2A).

Furthermore, we will utilize isogenic human cancer cell lines that are either proficient or deficient for BRCA1 activity to determine the dynamics of de novo TD formation under different modes of cellular perturbation and as a function of BRCA1 status (AIM 3A). Finally, we will use the newly developed GEMMS to understand the evolutionary path to genome-wide TD distribution in the mammary gland and to discern the dynamics of TDP emergence, both in terms of the rate of de novo TD formation and with respect to the timeline of breast tumorigenesis (AIM 3B).

If successful, this proposal will uncover the root causes of a significant form of genomic instability in human cancer, the TDP. It will define the mutational dynamics leading to cancer formation in this condition and generate model systems that can lead to the development of new and directed therapeutics against cancer growth.

Jackson Laboratory

TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

Connecticut United States

State-Wide

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 391% from $703,993 to $3,456,605.