Distinguished University Professor
Albert Einstein College of Medicine
Bronx, New York
Co-Investigator: Hayley M. McDaid, 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. 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.
On April 3, 2011, Dr. Horwitz received the 2011 Lifetime Achievement Award in Cancer Research from the American Association for Cancer Research in recognition of her pioneering work on taxol and its use as first-line treatments for breast and other cancers. Read more.