David A. Frank, MD, PhD

2008-2010 BCRF Project:
American Association of Cancer Research
"Targeting STAT3 for the Molecular Therapy of Breast Cancer"

The goal of Dr. Frank's research is to develop drugs to specifically target the molecular abnormalities found in breast cancer cells, to establish treatments that are more effective and less toxic than those currently in use. Since the behavior of a cell is largely driven by the spectrum of genes expressed in that cell, he and his team have focused on understanding the proteins that control this process. In particular, they have concentrated on a protein called STAT3, which normally regulates genes controlling cell growth, survival, and spread.

In a normal cell, this protein is turned on and off in a very controlled manner. In greater than 70% of breast cancers, however, STAT3 is stuck in the "on" or active state. This leads to increased expression of the genes it regulates, resulting in a breast cancer cell that grows rapidly, has a propensity to spread, and is difficult to kill. Thus, the Frank team has worked to identify drugs that can potently and specifically inhibit the function of STAT3. Importantly, they have found that normal cells can tolerate the loss of STAT3 with minimal effects, due to back-up systems present in a healthy cell. Cancer cells, by contrast, are "addicted" to continual STAT3 activity, and rapidly stop growing and die when this protein is blocked. The researchers have now identified three drugs that are already known to be safe in humans, and which block STAT3 activity.

The goal of this current project is to determine the effects of these drugs on breast cancer cells in the laboratory and in laboratory models, to determine how this targeted strategy can best be incorporated into the treatment of women with breast cancer. They have already found that these STAT3 inhibitors are effective at killing breast cancer cells in the laboratory, and enhance the activity of treatments currently in use. At the conclusion of the two year funding period, the researchers plan to be in a position to propose a clinical trial of this strategy in patients with breast cancer.

Mid-Year Progress Report:
In Dr. Frank's previous progress report, submitted in July 2009, he described identification of a drug, designated 2482-5594, that specifically blocks STAT3 function in breast cancer cells. This drug has minimal effects on normal cells, but causes breast cancer cells to slow their growth, and to become more sensitive to being killed. In the last six months, he and his team have focused on how to best combine this drug (and other drugs they have identified with similar properties), with other forms of therapy to achieve maximal therapeutic effects. It is known that STAT3 can associate with a cell component called the microtubule. It turns out that two of the most active chemotherapy drugs currently in use in the treatment of breast cancer, paclitaxel and vinorelbine, target this structure.

The researchers have now found that these drugs also inhibit STAT3 function. Furthermore, it appears that paclitaxel and vinorelbine are even more effective when combined with these STAT3 inhibitors. In the next several months, they will continue to optimize the STAT3 inhibitors they have developed, understand the mechanism by which they work, and determine strategies to maximize their effects. The clear goal of this work remains to translate these laboratory advances into more effective therapies for women with advanced breast cancer.

Bio:
David Frank joined the faculty of Dana-Farber Cancer Institute (DFCI) at Harvard in 1994 where he is currently an Associate Professor of Medicine. Dr. Frank obtained his MD degree in 1986 and PhD degree in 1987, both from Yale University. After serving as an intern, resident, and chief resident in internal medicine at Yale, he completed his training in medical oncology at DFCI, followed by a postdoctoral fellowship in intracellular signal transduction at Harvard Medical School. In 1995, he brought his laboratory group back to DFCI, where he maintains a clinical practice and an active research program. Dr. Frank has received several awards including the Kittredge Research Award in 2002 and a Biological and Biomedical Sciences Teaching Award in 2003.

Dr. Frank's laboratory takes special interest in the intracellular signaling events that control the growth and differentiation of normal and malignant cells. In particular they have focused on STAT transcription factors, which can be modulated by both tyrosine and serine phosphorylation, and thus may serve as a convergence point for multiple signaling pathways. Dr. Frank's lab is currently developing targeted molecular inhibitors of STATs and other transcription factors using both rational design and chemical-biology approaches and they are pursuing the introduction of these inhibitors into clinical trials for patients with cancer.