Hayley McDaid, PhD

2012-2013 BCRF Project:
(made possible by generous support from The Housewares Charity Foundation)
Co-Investigator: Susan B. Horwitz, 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. 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.