Hayley McDaid, PhD

2009-2010 BCRF Project:
Co-investigator: Susan B. Horwitz, 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. McDaid and Horwitz 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. McDaid and Horwitz 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. Hayley McDaid received her PhD from Queens University Belfast, where she characterized the role of the RIá subunit of the cAMP-dependent protein kinase A in ovarian and breast cancer and utilized a cAMP modulator to suppress the growth of cancer cells lines addicted to this pathway. These studies pioneered her present-day interest in targeted therapies, pharmacogenomics and rationally designed drug combinations.

She completed postgraduate training in Molecular Pharmacology and Experimental Therapeutics at the Albert Einstein College of Medicine (AECOM) in the laboratory of Dr. Susan Band Horwitz. These studies focused on characterizing the mechanism of action and resistance of novel Taxol-like microtubule-stabilizing drugs. After, she joined the Department of Medicine (Oncology) at AECOM as an Assistant Professor in Medicine (Oncology) and continued to work on novel mechanisms of resistance to tubulin-directed therapies, such as Taxol and the epothilones. Another major focus of Dr. McDaid's group is the origins of oncogene dependence in RAS- and RAF- driven malignancies and pharmacogenomic profiling utilizing RAS- and RAF-directed therapeutics.

Drug resistance is mechanistically multifactorial, partially due to the inherent genetic instability of cancer cells. This genetic plasticity results in aberrant gene expression that may be mediated by multiple mechanisms, including changes in epigenetics and microRNAs. The involvement of these in mediating drug resistance has been under-investigated and is the focus of this work. Therefore, the long-term goal here is to identify such changes in Taxol-resistant breast cancer model systems and experimentally manipulate target genes to determine their overall contribution to the resistant phenotype.