Breast Cancer

Current Projects
Harihar Basnet, PhD

Dr. Basnet is investigating the mechanisms responsible for cancer relapse. During cancer progression, cancer cells can spread to secondary sites where they can stay latent for months to decades before developing into metastases. His goal is to identify the genes that are important for regulating latency in metastatic cancer cells. This study will uncover potential therapeutic targets to eliminate latent metastatic cells and thus prevent cancer relapse.

Project title: "Identifying determinants of latency in brain metastatic breast cancer cells"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Fellow
Sponsor(s) / Mentor(s): Joan Massague, PhD
Cancer Type: Breast
Research Area: Epigenetics
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, MSc
Cancer Type: Breast
Research Area: Evolution
Mary Williard Elting, PhD

Dr. Elting studies the mechanics of cell division, with the goal of understanding how cells accurately transmit one copy of their genetic information into each of two daughter cells. Mistakes in this process are implicated in cancer, as well as birth defects and miscarriage. She will mechanically disrupt dividing cells and then detect how these perturbations affect the forces generated during division.

Project title: "Probing how kinetochore-fibers anchor to spindles to robustly and accurately segregate chromosomes"
Institution: University of California, San Francisco
Award Program: Fellow
Sponsor(s) / Mentor(s): Sophie Dumont, PhD
Cancer Type: Breast, All Cancers
Research Area: Cell Biology
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
Kathrin Leppek, PhD

Dr. Leppek [Layton Family Fellow] aims to combine RNA and ribosome biology with developmental biology to investigate how cells regulate protein synthesis through a process called translation. This process requires regulatory mechanisms to fine-tune when and where genes are expressed. Defective expression of certain genes gives rise to uncontrolled growth and metastasis of cancer cells. She will identify and characterize molecular components that play a functional role in mediating translational control during embryogenesis. This will be invaluable for our understanding of how deregulation of accurate gene expression underlies human diseases such as cancer.

Project title: "Mechanistic characterization of 5’UTR RNA elements that confer translational specificity to shape vertebrate embryonic development"
Institution: Stanford University
Named Award: Layton Family Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Maria Barna, PhD
Cancer Type: Blood, Gastric, Gynecological, Breast, Colorectal, Lung, Pancreatic
Research Area: Developmental Biology
Lyndsay M. Murrow, PhD

Dr. Murrow is using an engineered 3D model of the human mammary gland to determine how stem cells in the breast sense and respond to overall cellular composition. She aims to understand how sparsely distributed stem cells use local cues in the tissue to sense global changes in cell number. Since loss of tissue organization and abnormal stem cell differentiation are two key features underlying breast cancer development, this work will help identify new strategies for breast cancer prevention and treatment.

Project title: "Fate specification of mammary stem cells by cell self-sorting"
Institution: University of California, San Francisco
Award Program: Fellow
Sponsor(s) / Mentor(s): Zev J. Gartner, PhD
Cancer Type: Breast
Research Area: Systems Biology
Sigrid Nachtergaele, PhD

Dr. Nachtergaele [HHMI Fellow] is investigating the roles of a chemical modification of mRNA called methylation. Many enzymes that add and remove RNA modifications impact developmental processes and cancer proliferation, but how they are regulated remains a mystery. She aims to identify the mechanisms by which mRNA methylation alters gene expression and eventually results in altered cell signaling and growth. Her goals are to understand these regulatory principles, to uncover how they become misregulated in disease, and to exploit these processes to identify novel cancer therapeutic targets.

Project title: "The dynamic N1-methyladenosine methylome in eukaryotic mRNA"
Institution: The University of Chicago
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Chuan He, PhD
Cancer Type: Blood, Breast, Lung
Research Area: Chemical Biology
Philip A. Romero, PhD

Dr. Romero is a biomedical engineer whose expertise is in the area of microfluidics. He proposes to develop new technology that can be used to detect circulating tumor cells (CTCs) in the bloodstream. CTCs are cells that have detached from a solid primary tumor and entered into the bloodstream; they can go on to colonize distant sites and form metastases. Detecting CTCs is an enormous challenge, as the cells are present at an ultra-low abundance (1 out of billions of blood cells). His approach is to develop a highly specific system, a “DNA-based logic circuit,” to detect and profile CTCs, which could ultimately be applied for cancer diagnosis, prognosis indication, and measurement of a patient’s response to treatment.

Project title: "Digital circulating tumor cell detection using scalable molecular logic"
Institution: University of Wisconsin, Madison
Award Program: Innovator
Cancer Type: Breast, Colorectal, Lung, Prostate, Sarcoma
Research Area: Biomedical Engineering
Seyed Fakhreddin Torabi, PhD

Dr. Torabi is studying a highly abundant cellular long noncoding RNA (lncRNA) called MALAT1 (metastasis associated lung adenocarcinoma transcript 1), which serves as a prognostic factor in several human cancers.  MALAT1 is stabilized via formation of a complex triplex structure called expression and nuclear retention element (ENE). He aims to identify additional MALAT1-like ENEs in the genome through an in vitro evolutionary process in combination with bioinformatics studies. Novel ENEs may facilitate the discovery of novel cancer biomarkers and a better understanding of MALAT1 accumulation in cancer cells. 

Project title: "Evolution of triplex-forming RNAs from random sequences: a search for additional MALAT1-like triplex motifs"
Institution: Yale University
Named Award: Robert Black Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Joan Steitz, PhD
Cancer Type: Breast
Research Area: RNA (RNA processing, miRNA and piRNA mechanisms, enzymatic RNAs, etc.)
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.)
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