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Angela M. Hartley Brodie, Ph.D.
Leisha A. Emens, M.D.
Funded by the Kay Yow Cancer Fund
Current therapies fail to cure 40% of breast cancer patients, who relapse and die from drug-resistant disease. Immune-based therapies work differently than drugs that destroy tumor cells directly by recruiting the patient’s own immune system to seek out and kill tumor cells. Immune-based therapies are not limited by drug resistance, are highly specific, and typically have few side effects. Importantly, they uniquely result in a durable therapeutic impact due to memory. Immune-based therapy includes vaccines and antibodies. Vaccines activate long-lasting T cells that kill existing cancers, and can remember to kill tumors should they arise again. Antibodies target proteins such as HER-2 on cancer cells, and immune cells bind these antibodies to kill tumors. HerceptinR is a HER-2-specific antibody that significantly improves the survival of patients with early and metastatic HER-2hi breast cancer.
Because tumors arise from the patient’s own tissues, the immune system sees them as “self” rather than as dangerous invaders (like an infection). A special type of regulatory T cell (Treg) keeps the immune system from recognizing “self”, and prevents tumor immunity. Low doses of the chemotherapy drug cyclophosphamide (CY) can reduce Tregs in breast cancer patients, sparing the good T cells needed to fight cancer. HER-2-specific antibodies can supercharge our cell-based vaccine by forming a bridge between HER-2 on the vaccine cells and host dendritic cells. Antibody-supercharged dendritic cells generate more killer/memory T cells of higher quality than dendritic cells alone. Our ongoing analysis of T cells from patients treated with CY, Herceptin and vaccine suggests that the T cells are of higher quality. We continue to test this strategy in patients with HER-2lo metastatic breast cancer, where Herceptin does not fight breast cancer directly. We have enrolled about 65% of the planned 60 patients. Our integrated clinical studies will identify the most active combination vaccine regimen to test for preventing relapse patients with early breast cancer, regardless of HER-2 expression level.
Cynthia Zahnow, M.D.
Funded by Papa John’s International
Atul Bedi, M.D.
Christoph Lengauer, Ph.D.
Jin Jen, M.D., Ph.D.
James Herman, M.D.
Linzhao Cheng, Ph.D., Hyam I. Levitsky, M.D., Martin G. Pomper, M.D. , Ph.D. Richard Wahl, M.D.
Andrew Feinberg, M.D., MPH, Philip Cole, M.D., Ph.D.
While genetic mutations, changes in DNA sequence, are central to the development of Cancer, it is increasingly recognized that associated alterations in the chemical structure of the DNA packing material, known as chromatin, are linked to cancer causation. These distinct chromatin states and the molecules that regulate then form the basis of the field of epigenetics. While epigenetics is generally understood to be important in oncology, it is not yet clear how specific epigenetic changes are generated by different environmental conditions such as UV light exposure. Moreover, it is not understood what epigenetic changes are most impactful for the progression of malignancy and what therapeutic approaches can be used to successfully intervene to prevent or cure cancer. Our team will address how UV exposure in patients can induce particular epigenetic changes in skin lesions, whether existing epigenetic therapies can achieve desired effects of preventing epigenetic changes and progression to cancer, and design and develop new epigenetic therapies that could be useful for skin cancer and other malignancies. We hope to illuminate the factors that dictate patiets’ skin cancer’s responsiveness to epigenetic therapies which could ultimately lead to a new standard of care for treatment. We also plan to synthesize at least one new dual action epigenetic modulator compound that can serve as a clinical candidate for patient cancer trials.
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