Assistant Professor, Medicine (Oncology)
Albert Einstein College of Medicine
Bronx, New York
Co-Investigator: Susan B. Horwitz, PhD, Albert Einstein College of Medicine, New York, NY
There is widespread agreement among translational physicians and scientists that the triple negative sub-type of breast cancer (TNBC) is a major therapeutic problem, and that there is an urgent need to develop novel therapeutics for patients with this type of disease. In response to this, Drs. Horwitz and McDaid are focused on testing and refining novel microtubule interacting drugs that they have identified as having promising pre-clinical activity in TNBC cell lines. Some of the drugs they are developing are novel hybrid molecules that possess a chemical moiety of Taxol® fused to another microtubule-stabilizing drug. In testing these unique structures and other derivatives, Drs. Horwitz and McDaid have identified several compounds that have a strong propensity to cause tumor cell death that is comparable or superior to Taxol® in a panel of human TNBC cells. Moreover, these promising drugs have a low propensity to induce senescence; a cellular state that this team has shown contributes to drug resistance.
Drs. Horwitz and McDaid will evolve these initial studies using two major approaches. Firstly, they will evaluate the efficacy and tolerability of these drugs by testing in laboratory models of metastatic TNBC derived from a human patient. They will observe the effect of these novel candidate drugs on tumor growth and metastatic spread, and toxicity. In the second, they will collaborate with colleagues to define how these novel drugs bind to their target to elucidate novel drug-target interactions that could be related to their increased death-inducing properties. A second component of this drug-development focus is to expand studies this group has initiated using specific inhibitors of tumor-promoting signaling pathways that are hyperactivated in breast cancer cells. Specifically, Drs. Horwitz and McDaid are evaluating novel combinations of these signaling inhibitors and assessing their ability to modulate biological processes that influence the progression of TNBC. These are cell death, cancer cell reproduction, metastasis, and differentiation state. These experiments are being done in a human TNBC cells, and laboratory models of metastatic breast cancer. Through this drug development approach, they will gain a deeper understanding into how novel drugs and their combinations modulate the biology of cancer cells independent from their effects on survival and proliferation, and also hopefully identify lead candidates for advanced preclinical development.
This BCRF-funded project is focused on evaluating novel therapeutics for the treatment of breast cancer, specifically the triple negative subtype (TNBC). As part of this program, the researchers have focused on understanding the effects of various drugs on cell fate— the ability of a drug to cause tumor cells to die, or stop proliferating or survive. One class of novel agents that they are developing are derivatives of a marine sponge isolate, discodermolide, that shares the same basic mechanism of action as Taxol. Theyhave tested the efficacy of novel second generation derivatives of discodermolide in TNBC cells, and have now evolved these studies to testing lead candidates in models of human TNBC. They have identified one promising compound that has potent efficacy coupled with a more tolerability toxicity profile in laboratory models. In a related aim, they are also testing the therapeutic efficacy of novel drug combinations for potential use in metastatic TNBC. These drugs are highly specific inhibitors of two major signaling pathways that become hyperactivated in many TNBC cells. The researchers hypothesize that suppressing the survival and proliferative capacity of these two pathways will shut down tumor cell proliferation and diminish cancer cell migration, which ultimately leads to metastatic disease and mortality.
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.