MSK SPORE in Genomic Instability in Breast Cancer

Memorial Sloan Kettering Cancer Center

• Principal Investigator(s) Contact Information
• Overview
• Project 1: Defining and Targeting Homologous Recombination Deficiency in Breast Cancer
• Project 2: Targeting Innate Immune Pathways in Breast Cancers with Chromosomal Instability
• Project 3: Diagnosis and Treatment of APOBEC Mutagenesis in Metastatic Breast Cancer
• Administrative Core
• Biostatistics and Bioinformatics Core
• Biospecimen Repository and Pathology Core
• Biostatistics and Computational Genomics Core
• Developmental Research Program
• Career Enhancement Program
• Institutional SPORE Website

Principal Investigator(s) Contact Information

Simon Powell, MD, PhD
Chair, Department of Radiology Oncology
Memorial Sloan Kettering Cancer Center
Sloan Kettering Institute for Cancer Research
1275 York Avenue
New York, NY 10065-6007
(212) 639-3639

Overview

The research projects proposed in this SPORE address genomic instability in breast cancer. Three areas are the focus of study: homologous recombination deficiency, chromosomal instability and APOBEC mutagenesis. Our ultimate plan is to exploit tumor specific vulnerabilities by virtue of their underlying genomic instability. These different profiles of genomic instability have offered novel insights about the drivers breast cancer development and progression. There are also opportunities for therapeutic advances in breast cancer, which have emerged based on the initial successes, for example, in accurately identifying homologous recombination deficiency and by treatment with specific therapy, such as a PARP inhibitor. The plan is to optimize the use of these agents and develop novel agents for these tumors.

Chromosomal instability, which does not necessarily have a unique pattern of mutations, is associated with a poor prognosis, but no specific therapeutic strategy at present. The link between chromosomal instability and innate immune signaling has been made, and the goal is to exploit this connection for therapy. For APOBEC, we know that a characteristic pattern of SNVs is observed, but in this application, we are highlighting the role of APOBEC in the acquisition of drug resistance and introducing novel approaches for reliably identifying and therapeutically targeting breast cancers with an active APOBEC mutagenesis process. In summary, the goals are to take the risks of genomic instability (poor prognosis, rapid development of resistance) and turn genomic instability into an advantage for therapeutic targeting, thereby improving the prognosis for high-risk breast cancers.

Our SPORE includes:

• Research Project 1. Defining and targeting homologous recombination deficiency in breast cancer
• Research Project 2. Targeting innate immune pathways in breast cancers with chromosomal instability
• Research Project 3. Diagnosis and treatment of APOBEC mutagenesis in Metastatic Breast Cancer

These projects are supported by 3 shared resources and 2 programs: Administrative Core; Core A. Bioinformatics and Biostatistics Data Analysis Core; Core B. Biospecimen Repository and Pathology Core; Career Enhancement Program; and Developmental Research Program.

Project 1: Defining and Targeting Homologous Recombination Deficiency in Breast Cancer

Project Co-Leaders:
Simon N. Powell, MD, PhD (Clinical Co-Leader)
Jorge S. Reis-Filho, MD, PhD (Basic Co-Leader)

Homologous recombination deficiency is prevalent in breast cancer up to a level of ~25%. Large-scale structural variant alterations to the genome have been observed in these tumors, but if double-strand junctions are sequenced in detail, it is possible to categorize these tumors with more specific defects in the DNA repair pathway. We assert that there are fundamentally different patterns of genome instability for the different components of double-strand break repair. One is focused on the function of the BRCA1-BRCA2 pathway, where alterations in function are frequent in breast cancers. Although traditionally perceived as equivalent, there is now evidence to demonstrate that genomic alterations that are BRCA1-like may have functional differences from those that are BRCA2-like and we are working to understand whether there are therapeutic strategies that are different for the two genotypes.

Upstream defects in DNA DSB repair are focused on sensing DNA damage (e.g. ATM or CHK2), which is another well documented mechanism for suppressing cancer formation. The DNA damage signaling defects are less well known, but are observed in many types of cancer including breast cancer. Thus, the goals of this project are to diagnose the DNA repair defect reliably and with greater resolution. Our hypothesis is that different types of DNA repair defects result in the utilization of distinct backup DNA repair mechanisms, which themselves result in specific genomic signatures and sensitivity to different therapeutic agents. Hence, we posit that upstream defects are best targeted by the use of replication checkpoint inhibitors, but that BRCA defective tumors are best treated by targeting the backup pathway, such as PARP-inhibitors or new agents beyond PARP-inhibitors.

The goal of the first aim is to apply the current genomic landscape tests of HR-deficiency and determine which method predicts most accurately the type of homologous recombination DNA repair defect (i.e. upstream DNA damage sensing, downstream BRCA1-like or downstream BRCA2-like). The ultimate goal is to devise a taxonomy based on the genomic features of DNA damage response/ homologous recombination DNA repair-deficiency, in addition to any identified target gene mutations, which will ultimately guide therapeutic options. The second aim is to generate genetically engineered cell lines to understand the developmental drivers of the genomic landscape changes. In addition, we will use these cells to test new synthetic lethal approaches to target specific subsets of breast cancers with distinct types of homologous recombination DNA repair defects. The third aim consists of human clinical trials either being conducted at Memorial Sloan Kettering Cancer Center or elsewhere, where we are conducting the trial or leading the analysis of the clinical bio-specimens for correlative study analyses. We will test the use of ATR-inhibitors and determine the genomic status of the tumors in responders and non-responders. Similarly, we will study the impact of the PARP-inhibitor olaparib in patients who are BRCA1/2 wild-type but harbor a germline and/or somatic genetic alteration affecting homologous recombination DNA repair-related genes. We will extend our studies to also consider the combined effects of radiotherapy in combination with either ATR-inhibitors or PARP-inhibitors. The ultimate goal of this project is to personalize the treatment of breast cancer patients whose tumors display homologous recombination DNA repair-related defects according to their genetic and genomic features, seeking to improve substantially the outcome of these poor prognosis patients and direct the deployment of therapeutic agents already approved (e.g. olaparib) or already in clinical trials (e.g. ATR-inhibitors) or still being developed (e.g. Pol-theta or RAD52 inhibitors).

Project 2: Targeting Innate Immune Pathways in Breast Cancers with Chromosomal Instability

Project Co-Leaders:
Samuel Bakhoum, MD (Clinical Co-Leader)
Lewis C. Cantley, PhD (Basic Co-Leader)

While considerable progress has been made in treating primary breast cancers, metastatic breast cancers remain a challenge. Metastatic breast cancer cells typically have chromosomal instability (CIN) that involves chromosome-level alterations leading to genomic copy number abnormalities. A major challenge in targeting breast cancers driven by CIN is the lack of known targetable alterations. We recently found that CIN promotes chronic inflammatory signaling in cancer cells. As chromosomes missegregate, they often become encapsulated in micronuclei. Subsequent micronuclear rupture exposes genomic double-stranded DNA to the cytosol. Cytosolic DNA activates anti-viral innate immune pathways, chief among which is cGAS-STING signaling. Under normal circumstances, cGAS-STING activation promotes type I interferon and facilitates cell-mediated immunity. Engagement of STING in normal epithelial cells induces senescence and cell death. We have shown that cancer cells, however, are intrinsically resistant to cGAS-STING activation by virtue of their chronic exposure to cytosolic DNA. Instead, they upregulate alternative pathways downstream of STING, such as NF-kB signaling. The extent to which cancer cells depend on chronic inflammatory signaling is poorly understood. More importantly, how they subvert innate immune signaling to avoid immune surveillance remains unknown. Our ongoing work reveals that cGAS-STING signaling is sequestered in cancer cells away from the host. Furthermore, human breast tumors upregulate ENPP1, a negative regulator of cGAS-STING signaling. ENPP1 enables immune evasion by degrading cGAMP, the second messenger produced by cGAS, only in the extracellular space. As such ENPP1 prevents host STING activation in response to tumor-to-host cGAMP transfer. Strikingly, pharmacologic inhibition of STING suppresses metastasis in syngeneic models of melanoma, breast, and colon cancers. We postulate this is because its inhibition in tumor cells outweighs its protective role in the host. Building on this work, we will expand our pre-clinical testing of STING inhibition in breast cancer probing its efficacy in delaying metastasis and therapeutic resistance. We will then examine whether cGAMP contributes toward the formation of an immune suppressive microenvironment through metabolic breakdown in the extracellular space. Finally, we will develop cGAS-STING-based biomarkers in prospectively collected tumor specimens.

Project 3: Diagnosis and Treatment of APOBEC Mutagenesis in Metastatic Breast Cancer

Project Co-Leaders:
Sarat Chandarlapaty, MD (Clinical Co-Leader)
Reuben S Harris, PhD (Basic Co-Leader)

Although the majority of early stage estrogen receptor (ER)-positive breast cancers are cured through multimodality care, metastatic ER-positive breast cancer (MBC) remains a lethal disease. Insights into this discrepancy have come through comparative genomic analyses of primary and metastatic tumors. We and others have identified certain ‘mutational signatures’ appear to be enriched in metastatic disease. These mutational signatures represent the DNA damage and repair processes that shape the cancer genome and can give rise to the individual mutations and the transformed phenotypes they convey. Among these, the APOBEC mutational signature is both enriched and highly prevalent in ER-positive MBC, comprising the dominant mutational signature for these lethal cancers. Our preliminary data confirm that APOBEC activation can promote the development of endocrine resistance in cancer models. In this project, we propose three aims to advance the APOBEC mutational process as a biomarker and therapeutic target in breast cancer. (1) We will develop and utilize robust bioinformatic methods to detect the presence and the timing of onset of the APOBEC mutational signature from clinical NGS datasets of both tumor and cell free DNA (cfDNA). We will further ascertain if a promising IHC assay for the A3B enzyme can identify those ER-positive cancers likely to subsequently develop an APOBEC mutational signature. (2) We will determine the mechanisms and kinetics of APOBEC’s contribution to endocrine resistance. We will use isogenic cell line models and patient derived xenografts to dissect the types of resistance patterns that are caused by APOBEC as well their timing and whether the endocrine therapy itself contributes to the induction of APOBEC activity. (3) We will assess both immunologic and synthetic lethal approaches to targeting tumors in which APOBEC activity is induced and determine their capabilities in killing APOBEC-positive cancers. We anticipate that our findings will uniquely position our team to launch clinical trials testing specific approaches to diagnose APOBEC-positive tumors, to prevent the development of resistance to endocrine therapies, and to target the largest subset of ER-positive endocrine-resistant metastatic breast cancers.

Administrative Core

Core Directors:
Simon N. Powell, MD, PhD (core-director)
Jorge S. Reis-Filho, MD, PhD (co-core-director)

The administrative core serves as the operational hub of the SPORE, arranging all SPORE related functions in scientific review, intra- and inter-SPORE collaborations, financial management of budgeting and monitoring expenses, editorial services as needed and grant administration. We also regard the SPORE as a forum for education and mentoring, above and beyond what is directly assisted in the developmental programs, by creating an environment in which new ideas for projects can be discussed with supportive SPORE key personnel. We are organizing a SPORE retreat, open to breast cancer researchers (and beyond) in which we will review existing projects, consider alternative project options (which could be added or substituted) and also consider unsolved mysteries or provocative questions that have not received significant attention in this area of research. In concert with the retreat, we will coordinate the functions of the internal and external advisory boards. In addition, we will liaise with the Memorial Sloan Kettering Cancer Center (MSKCC) breast cancer disease management team over identification and monitoring of the cancer patient populations required for this SPORE and communicate with our patient advocates about our ongoing results, trials and future planning.

Biospecimen Repository and Pathology Core

Core Directors:
Jorge S. Reis-Filho, MD, PhD (core-director)
George Plitas, MD (co-core-director)

The Biospecimen Repository and Pathology Core will provide support for all translational research efforts of the Genomic Instability in Breast Cancer SPORE. The specific aims of the core include 1) to maintain and expand the systematic collection, annotation, and storage of bio-specimens for translational research of breast cancers with specific patterns of DNA repair defects and/or genomic instability, 2) to perform expert pathologic evaluation of all human breast cancer and animal models of breast cancer samples with specific patterns of DNA repair defects and/or genomic instability and preparation of appropriate material for use by SPORE investigators, and 3) to perform immunophenotypic characterization of human and animal models of breast cancers with specific patterns of DNA repair defects and/or genomic instability. By centralizing and standardizing the pathology review, from both clinical and research settings, and by working in conjunction with other Cores within MSKCC on the processing and curation of the biospecimen materials and digital images obtained from the samples included, the Biospecimen Repository and Pathology Core will help mitigate the impact of common confounders in translational research studies, as well as it will assist in the integration and prioritization of a variety of institutional pathology systems-related development efforts.

Biostatistics and Computational Genomics Core

Core Directors:
Sohrab Shah, PhD (core-director)
Ronglai Shen, PhD (co-core-director)

The Biostatistics and Computational Genomics Core and its team of dedicated personnel with extensive experience and strong track record of developing innovative methods will provide support in statistical and computational analysis of breast cancer sequencing data to assist the design and analysis of the SPORE research projects. The team will support and maintain sequencing pipelines and provide analytical and statistical support for the analysis of genomic instability in breast cancer. They will expand current tools to detect, quantify, and track genomic signatures of specific DNA repair defects and/or genetic instability at the tumor bulk and single cell levels, as well as probe these signatures’ effect on the microenvironment. The Core will also provide centralized support for data collection, processing, quality assessment, and normalization procedures to facilitate data integration and downstream analysis and visualization, accessible to scientists with little computational background. In addition, the Core will synergize with the current infrastructure available at Memorial Sloan Kettering Cancer Center to provide the SPORE investigators not only with the state-of-the-art computational biology methods, but also with novel computational tools to address specific analytical challenges germane to the success of the SPORE Research Projects.

Developmental Research Program

Program Director:
Sarat Chandarlapaty, MD, PhD

Breast cancers frequently harbor specific patterns of homologous recombination (HR) DNA repair defects (HRD) and/or specific patterns of genetic instability, namely chromosomal instability (CIN) and APOBEC mutagenesis. These alterations are present in a substantial proportion of breast cancers and they are enriched in metastatic disease. Biomarkers to identify these patients reliably and to define the optimal treatments for these patients are sorely needed. The Developmental Research Program (DRP) will play an important role in fostering translational research endeavors addressing specific patterns of DNA repair defects and/or genetic instability and their molecular basis. We will use DRP funding supplemented by institutional funds to support innovative projects by new and established investigators, which are critical to the generation of new ideas in the diagnosis and treatment of this large subset of breast cancers. Our goal is to accelerate progress towards the translational research goals of our SPORE. We will annually solicit pilot project proposals with translational potential from clinical and basic investigators within the larger MSKCC community, including Rockefeller University, New York-Presbyterian Hospital and Weill Cornell Medical College of Cornell University. We will then select the most promising new projects for support after rigorous peer review by the Leadership Committee, the Internal Advisory Board and the Patient Advocates. The opinion of external reviewers will be solicited as needed. Pilot projects will be funded for 1 year, but investigators may apply for additional funding through this same competitive process the next year. Every year the Advisory and Leadership Committee members will meet to review each research project, core, career enhancement project and developmental pilot project. Committee members will be asked to assess whether any developmental project has progressed sufficiently and shown enough translational potential, either to add to the existing projects or to eclipse one of the full SPORE Research Projects. The committee members will then vote and decide whether any developmental project should be advanced to full project status. If so, the budgets will be appropriately adjusted and sent for approval with the TRP of the NCI.

Career Enhancement Program

Program Directors:
Simon Powell, MD, PhD (Director)
Jorge Reis-Filho, MD, PhD (Co-Director)

The SPORE Career Enhancement Program (CEP) aims to prepare physicians and scientists for independent careers in translational research in breast cancer. Our goal is that investigators supported through this process will spend their professional lifetimes conducting translational research in breast cancer and become academic leaders in the field. Memorial Sloan Kettering Cancer Center (MSKCC) is ideally suited for this task, because of the scientific and clinical environment at our campus and affiliated institutions, and our long tradition of training physicians and scientists of the highest caliber. The specific aims of the Career Enhancement Program are to support the mentoring and research of junior faculty for careers in translational research in breast cancer, using a dual clinical and laboratory/population science mentorship model, and to recruit and mentor new junior faculty members to work in breast cancer translational research. Our institutional environment includes numerous NIH training grants, including a K12 grant for translational science training, a number of T32 grants to train PhDs or MDs in translational research in Oncology, a Master’s Program in Clinical Oncology (recently developed to partner with the K12 program, but open to a broader group of translational scientists in development), a Certificate Program in Clinical Investigation integrated with the Clinical and Translational Science Program at Weill Cornell, and a well-established junior faculty mentoring program. The SPORE Career Enhancement funds will be employed to enhance the existing formal mentoring programs, while encouraging more physician trainees to focus on translational research, in particular to leverage the emerging knowledge of DNA repair defects and specific patterns of genetic instability in breast cancers to deliver targeted treatments to individual breast cancer patients. We will strive to attract basic, translational and population scientists who are interested in devoting their careers to making discoveries that have a realistic potential to translate into clinical applications.

Institutional SPORE Website

https://www.mskcc.org/research-programs/msk-spore-genomic-instability-breast

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