Breast Cancer

Current Projects
Jennifer L. Caswell-Jin, MD

The development of HER2-targeted therapies over the past two decades has had tremendous positive impact on the lives of HER2-positive breast cancer patients. However, tumor resistance to these therapies remains a significant challenge: a sizable portion of patients with early-stage HER2-positive breast cancer develop recurrence, and the vast majority of patients with metastatic HER2-positive breast cancer eventually progress through treatment. Jennifer proposes to construct a model of HER2-positive breast cancer evolution that will reveal how the cancer changes over time when treated with HER2-targeted therapy. She will examine each tumor at multiple time points in the course of its treatment: at diagnosis, during initial treatment (with HER2-targeted therapy and/or chemotherapy), after completion of initial treatment, and at one or more sites of metastasis. To create this model, she will analyze multiple regions within each tumor and also test circulating DNA that the tumor sometimes sheds into the blood. She will also examine the specific changes present in the cells that develop resistance to HER2-targeted therapy. A deeper understanding of how tumors evolve under the pressure of treatment will open new avenues to optimizing treatment delivery. Markers of treatment resistance may further allow us to personalize therapy choices, delivering extra therapy to those patients who need it and sparing others unnecessary toxicity.

Project title: "Breast cancer evolution and resistance in response to HER2-targeted therapy"
Institution: Stanford University
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Christina N. Curtis, PhD, and Allison W. Kurian, MD
Cancer Type: Breast
Research Area: Evolution
Siting Gan, PhD

Dr. Gan focuses on brain metastasis in lung and breast cancer, a major cause of death for these patients. She is applying the latest single-cell technologies and developing computational tools to dissect how tumor cells interact with resident brain cells to mediate the progression of metastasis. This research aims to better understand the formation of brain metastasis which may lead to new therapeutic strategies for prevention.

Project title: "In situ single-cell dissection of the tumor-microenvironment interplay mediating brain metastasis"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Joan Massagué, PhD, and Dana Pe'er, PhD
Cancer Type: Brain, Breast, Lung
Christopher A. Klebanoff, MD

A form of cancer immunotherapy termed adoptive T cell transfer (ACT) can induce long-lasting remissions in patients with advanced blood cancers. In this approach, T white blood cells specific for proteins found on the surface of cancer cells (antigens) are activated and expanded outside the immunosuppressive environment of a cancer patient's body before re-infusion as a therapy. Thus far, this promising form of cancer immunotherapy has failed to work in most patients with cancers arising from solid organs, the leading cause of cancer-related deaths in adults. Two critical gaps in knowledge limit the ability of ACT to be successfully applied to solid cancers: 1) understanding which antigens on the surface of cancer cells can be targeted by T cells that do not have the potential to cross-react and injure normal tissues, and 2) insight into what factor(s) limit the ability of transferred T cells to expand and persist following re-infusion into a patient. Dr. Klebanoff seeks to use a genetic engineering approach to simultaneously address both these issues. Success of these efforts would be a decisive step forward toward extending the ability of ACT to deliver potentially curative responses in patients with common cancers, including those arising from the breast, uterus, cervix and colon.

Project title: "Clinical development of next-generation T cell receptor (TCR)-based adoptive immunotherapies for the treatment of patients with common epithelial malignancies"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Michel Sadelain, MD, PhD, and Larry Norton, MD
Cancer Type: Gynecological, Kidney and Bladder, Breast
Research Area: Immunotherapy
Runmin Wei, PhD

Dr. Wei is focusing on inflammatory breast cancer (IBC), an aggressive disease subtype without known genetic signatures. This suggests that IBC could be highly heterogeneous (the cells within a tumor are genetically diverse), and the tumor microenvironment (the environment surrounding a tumor) may be important for disease progression and therapeutic resistance. He is developing a computational toolkit to characterize the IBC tumor spatial heterogeneity and tumor microenvironment. He will leverage cutting-edge deep learning approaches to associate histopathology findings from tumor samples with single cell spatial sequencing information. This project will provide a better understanding of IBC initiation, progression and therapy responses at a molecular level.

Project title: "Integrating single cell genomic and spatial information to delineate tumor heterogeneity and microenvironment interactions in inflammatory breast cancer"
Institution: The University of Texas MD Anderson Cancer Center
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Nicholas E. Navin, PhD, and Ken Chen, PhD
Cancer Type: Breast
Yichen Xu, PhD

Dr. Xu focuses on the estrogen receptor α (ERα), a nuclear hormone receptor that is mutated and hyperactivated in over 70% of breast cancers. Hormone therapy drugs, such as tamoxifen, which target classic ERα signaling are highly potent; however, many patients eventually develop drug resistance. His proposed research will address a previously unknown role of ERα in breast cancer progression and therapy resistance, and may identify a potential second-line therapy to treat breast cancer.

Project title: "Elucidating a non-classical role of ER in gene expression and breast cancer progression"
Institution: University of California, San Francisco
Award Program: Fellow
Sponsor(s) / Mentor(s): Davide Ruggero, PhD
Cancer Type: Breast
Research Area: RNA (RNA processing, miRNA and piRNA mechanisms, enzymatic RNAs, etc.)
Yi Yin, PhD

Dr. Yin has developed single-cell assays that will be combined with statistical modeling to understand homologous recombination (HR). Cells use the process of HR to accurately repair harmful breaks that occur on both strands of DNA. Failure to correct such DNA damage can play a role in cancer initiation and progression. Dr. Yin aims to understand this critical mechanism to help guide treatment approaches for many cancer types.

Project title: "Global analysis of DNA break repair by single-cell sequencing"
Institution: University of California, Los Angeles
Award Program: Dale Frey Scientist
Cancer Type: Blood, Breast, Skin
Research Area: Chromosome and Telomere Biology
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