Susan B. Horwitz, PhD

2012-2013 BCRF Project:
(made possible by generous support from The Housewares Charity Foundation)
Co-Investigator: Hayley M. McDaid, PhD, Albert Einstein College of Medicine, New York, NY

Drs. Horwitz and McDaid have focused their efforts on understanding the mechanisms by which microtubule stabilizing drugs, such as taxol and discodermolide, cause cell death and suppress cell division by inducing senescence, which permanently arrests the growth cells. Their studies indicate that several microRNAs become altered during senescence and that treatment of breast cancer cells with a specific microRNA causes cell death instead of senescence, which is a novel finding that is therapeutically promising. Drs. Horwitz and McDaid also have evaluated the anti-tumor activity of unique taxol-like molecules in breast cancer cells and several have emerged as potential lead candidates that have a stronger ability to induce cell death than taxol.

In 2012-2013, Drs. Horwitz and McDaid will center on three major areas. First, they will further characterize drug-resistant breast cancer cell lines that have entered senescence as triggered by chemotherapies but then reverted back to cell-growth again. Secondly, this team will perform structure-activity relationship (SAR) analyses of novel microtubule-stabilizing drugs to provide additional insights into the interactions between these compounds with breast cancer cells. Third, Drs. Horwitz and McDaid aim to determine whether mitosis, or the process in cell division by which the nucleus divides and replicates, influences the induction of senescence in response to chemotherapy.

Mid-year Progress: The BCRF-funded project led by Drs. Horwitz and McDaid is focused on elucidating novel mechanisms of action and resistance to microtubule-stabilizing drugs, such as taxol. As part of this program, Drs. Horwitz and McDaid have focused efforts on understanding the effects of chemotherapy drugs on cell fate, that is, the ability of a drug to cause tumor cells to die, stop proliferating, or even survive.

One of the outcomes of chemotherapy in which Drs. Horwitz and McDaid are interested is senescence, a form of growth arrest that can sometimes be beneficial but in other contexts can be harmful and actually promote relapse. This is caused by the unique ability of many senescent cells to release inflammatory signals that attract and modify the behaviors of immune cells so that they favor the ability of the cancer cells to survive, grow and migrate to other tissues. Drs. Horwitz and McDaid have generated several chemotherapy-resistant cancer cell lines that were derived from a senescent precursor state; thus senescent tumor cells occasionally resume cell growth. They have studied the characteristics of these resistant cells and have identified key proteins that they rely on for survival, and production of proinflammatory molecules. They are now testing the efficacy of specific drugs that target these key proteins to determine their potential to prevent or limit senescence induction in tumors, and/or to suppress production of pro-inflammatory molecules in senescent cells, or drug-resistant cells that originate from a senescent state. In a related aim, Drs. Horwitz and McDaid are also testing novel drugs that are hybrid molecules that possess the chemical moieties of taxol fused to the chemical components of another microtubule-stabilizing drug. These novel drugs are being tested for their ability to cause cell death rather than senescence in breast cancer cells. Combined, these studies have the potential to advance our understanding of why some patients respond poorly to chemotherapy; develop novel strategies to identify these patients in the clinical; and develop alternate treatment therapies to improve survival.

Bio:
Dr. Susan Band Horwitz is a Distinguished University Professor at the Albert Einstein College of Medicine and Associate Director for Therapeutics at the Albert Einstein Cancer Center. She grew up in Boston and after graduating from Bryn Mawr College, received her PhD in Biochemistry from Brandeis University.

Dr. Horwitz has had a continuing interest in natural products as a source of new drugs for the treatment of cancer. Her laboratory has made Taxol, a drug isolated from the yew plant, Taxus brevifolia, a major focus of its work. Although no one was interested in Taxol when she began her studies, today it is an important anti-tumor drug that has been given to over a million patients. Dr. Horwitz' research played an important role in encouraging the development of Taxol by the National Cancer Institute.

Dr. Horwitz and her collaborators demonstrated that the effects of Taxol were due to a novel interaction between the drug and microtubules, the latter being essential for the pairing and segregation of chromosomes during cell division. Her pioneering investigations and perceptive analysis of the results identified Taxol as a prototype of a new class of anti-tumor drugs. Extensive research has led to major insights into several aspects of the chemistry and biology of Taxol. Dr. Horwitz also has made significant contributions to our understanding of the molecular mechanisms underlying Taxol resistance in tumor cells.