Michael P. DiGiovanna, MD, PhD

Anti-estrogens and Herceptin are among the best treatments for breast cancer, and Dr. DiGiovanna and his team are interested in identifying drugs that can complement these in combination for even better therapeutic efficacy. They found that drugs that inhibit a growth factor receptor called IGF-I receptor dramatically enhanced the killing effect of Herceptin on HER2-overexpressing cells, and surprisingly the combination even dramatically killed breast cancer cells that have low levels of HER2 and don't normally respond to Herceptin at all. They also found that retinoids, which are derivatives of vitamin A, synergistically inhibit the growth of breast cancer cells when used in combination with Herceptin or Tamoxifen, and in combination with Herceptin cause either ER+ or ER- breast cancer cells to undergo cell death.

A major advance in treating cancer can come from using combinations of targeted therapies. A focus of the DiGiovanna team is therefore is to identify other targets for new drugs to complement drugs that target ER or HER2. The researchers believe that their results studying the effects of IGF1R inhibitors are the most novel and of greatest potential impact, and they intend to bring forward a clinical trial at Yale based upon these results.

Mid-Year Progress Report:
While all these drugs individually slow breast cancer cell growth without actually killing the cells, or inducing "apoptosis" (the scientific term for cell killing), Dr. DiGiovanna and his team have found that combining IGF1R inhibitors with tamoxifen or Hercpetin causes massive cancer cell apoptosis (killing). This is especially so for the combination with Herceptin, and this even occurs in cells with low level HER2 that do not normally respond to Herceptin at all by itself. Although not yet applicable for treating patients, this work suggests promise in the future of using Herceptin for a much wider population of breast cancer patients beyond the "HER2-positive" patients, if Herceptin can be used in proper combinations with new drugs.

In recent new work, the researchers found that cells that developed resistance to Herceptin increased their IGF1R activity; however, as single agents IGF1R inhibiting drugs still had weak activity, though combining those with an analog (called GW2974) of a new HER2 drug (called Tykerb) strongly inhibited the growth of these tumor cells. They also have found that retinoids, derivatives of vitamin A, synergistically inhibit the growth of breast cancer cells when used in combination with Herceptin or tamoxifen, and in combination with Herceptin cause ER+ or ER- breast cancer cells to undergo apoptosis, which none of the drugs can do alone, making this a potentially attractive combination to test in breast cancer patients. When added to tamoxifen, which inhibits estrogen signals, retinoids enhanced the inhibition of estrogen signals.

These new drugs and combinations are attractive tactics to study in the lab to learn about breast cancer biology, and as a necessary prelude to testing in breast cancer patients.

Bio:
Dr. DiGiovanna is a native of Long Island, NY, who graduated from Cornell University in 1984 with a B.A. and a double major in the fields of biochemistry and music. He attended Yale Univeristy from 1984 through 1990 where he earned the MD and PhD degrees, with his PhD in Pharmacology. He continued his post-graduate training at Yale, performing internship and residency in Internal Medicine, a laboratory research post-doctoral fellowship, and a clinical fellowship in Medical Oncology. He is currently an attending physician in Medical Oncology and Associate Professor of Medicine (Medical Oncology) and Pharmacology at Yale University. Dr. DiGiovanna is Co-Director of the Yale Cancer Center's Breast Cancer Research Program.

Dr. DiGiovanna's clinical specialty is breast cancer and his laboratory research is also focused on breast cancer. His research has explored signaling by growth factor receptors in the EGF receptor and HER-2/neu/ErbB-2 family, as that relates to the clinical behavior of breast cancers and response to individual therapies. The lab is exploring the therapeutic potential of using inhibitors of these growth factor receptors in combination with drugs that target other biological growth pathways, including the estrogen receptor, retinoid (Vitamin A-like) receptors, and insulin-like growth factor.