Susan B. Horwitz, PhD

2009-2010 BCRF Project:
Co-investigator: Hayley M. McDaid, PhD, Albert Einstein College of Medicine, New York, NY

The long-term goal of this research is to understand the mechanisms by which breast tumors become resistant to Taxol. By identifying which mechanisms are prevalent, we can devise alternate treatment strategies to circumvent drug resistance. Drs. Horwitz and McDaid have made Taxol-resistant breast cancer cells by exposing cells to Taxol in a manner that mimics the way patients are administered the drug. They are presently characterizing (i) epigenetic changes (that involves switching genes off or on) and (ii) changes in miRNAs (short RNA's that regulate how genes are made into proteins) in the cells they have generated and in breast tumors derived from clinically resistant patients. To date, the researchers have generated epigenetic and miRNA-based molecular 'signatures' that implicate genes that have prior known association with Taxol resistance and interestingly, many novel pathways and genes that have never been associated with Taxol resistance. Their future studies will build upon these pilot 'signatures' and include different histological subtypes of the disease, to generate histologically-relevant profiles that can be exploited clinically.

Mid-Year Progress Report:
Drs. Horwitz and McDaid have generated a pilot signature for miRNA's that is associated with Taxol-resistance in breast cancer. The remaining funding term will focus on analyzing additional tumor specimens to their analyses to generate a statistically robust molecular signature for both miRNA and DNA methylation changes involved in Taxol®-resistance. In addition, they will also begin to characterize the function of some of the differentially-expressed miRNA's that they have identified to date.

These studies will generate a more thorough understanding of the molecular mechanisms that underlie Taxol resistance and may be used to refine the current treatment options for patients with metastatic breast disease who are eligible for Taxol-based treatment. Furthermore, the researchers have also characterized the expression of a cell cycle-regulatory protein, CENP-E, in drug resistant breast cancer cells that they generated in the laboratory, and determined that overexpression of this protein is correlated with acquired Taxol-resistance.

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 Ph.D in Biochemistry at 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.