Ovarian, Uterine, and Cervical Cancers

Current Projects
Edmond M. Chan, MD

Defects in the cellular DNA repair machinery can promote cancer formation and cause cancer cells to rely on back-up DNA repair processes. These cancer cells are particularly vulnerable to drugs called PARP inhibitors, which target a DNA repair process known as homologous recombination. Dr. Chan hypothesizes that a similar treatment strategy can be used for cancers with deficiencies in DNA mismatch repair, which causes microsatellite—short, repeated sequences of DNA—instability (MSI). Microsatellite instability is found most often in certain colon, stomach, uterine and ovarian cancers. Using CRISPR screening technology, Dr. Chan discovered that cancer cells with faulty mismatch repair become dependent on a gene called WRN to survive. He is characterizing this vulnerability for MSI cancers with the goal of finding new drugs that inhibit this pathway.

Project title: "Validating a novel synthetic lethal target for microsatellite unstable cancers"
Institution: Dana-Farber Cancer Institute
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Adam J. Bass, MD
Cancer Type: Gastric, Gynecological, Colorectal
Research Area: Cancer Genetics
Jonathan C. Dudley, MD

Earlier cancer detection usually means a greater chance of remission or cure, but cost-effective and highly specific cancer screening is not yet available for most cancers. More than 90 percent of cancers harbor aneuploidy, an abnormal number of chromosomes in a cell; this abnormality is highly specific for cancer and can be detected with DNA sequencing. Dr. Dudley is developing a new approach for detecting cells with abnormal amounts of DNA, which could identify cancer sooner. He aims to apply this approach to urine and Pap smear samples to create an inexpensive and sensitive screening test for bladder, ovarian and endometrial cancers.

Project title: "Earlier detection of cancer in body cavity fluids through aneuploidy analysis after cell enrichment and partitioning"
Institution: The Johns Hopkins University School of Medicine
Named Award: Gordon Family Physician-Scientist
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Bert Vogelstein, MD
Cancer Type: Gynecological, Kidney and Bladder
Research Area: Diagnostics
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
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