Assistant Professor, Department of Medicine (Oncology)
Assistant Professor, Department of Molecular Pharmacology
My research is broadly focused on investigating molecular mechanisms of action and resistance to standard and novel therapeutics. More specifically, it focuses on accurately defining the fate of cells within a tumor population following therapy; especially fates that confer drug-tolerance. Drug-tolerant tumor cells often manifest as dormant phenotypes that evade cell death and are a source for re-population of a primary tumor mass and development of metastatic disease that eventually culminates in mortality.
Senescence is a form of growth arrest that can result from anti-cancer therapy. Senescence is largely perceived to be a permanent state in ‘normal’ cells; however recent data now indicate that in the context of cancer, senescence is transient. Persistent senescent tumor cells within the tumor microenvironment are detrimental due to pro-inflammatory secretions that promote migration and disease progression. Moreover, senescent cells often revert to a proliferative state and retain this pro-inflammatory signaling milieu that drives chemoresistance. Certain anti-cancer drugs with reactive moieties can preferentially induce senescence not only in tumor cells, but also in organs such as the heart and lung, resulting in unacceptable toxicity that can be fatal. These often irreversible toxicities also prevent patients with progressive cancer from receiving subsequent therapy.
The study of dormant phenotypes in cancer biology is challenging; however to truly evolve anti-cancer therapeutics to improve long-term survival and quality of life for patients, we need to adopt a more rigorous pre-clinical evaluation program. One important aspect of this research is the design and selection of novel anti-cancer drugs that have potent tumor cell death-inducing capabilities in both asynchronous and dormant-type cells, including senescent and tumor-initiating cancer cells. Coupled with that, new therapeutics must be efficacious in limiting the development of senescence in non-tumor tissue to lessen the risk of therapy-induced toxicity.
Areas of current research focus include:
1. Therapy-mediated senescence in cancer as a cause of intrinsic and acquired resistance associated with residual disease, and/or progressive disease leading to metastasis.
2. Biomarker development to accurately detect senescent cells from solid or liquid biopsies both at diagnosis, and during the course of therapy.
(i) In collaboration with Drs. Susan Horwitz and Amos B. Smith - design, synthesis and testing of novel chemotherapeutics, screening primarily for high tumor cell kill and low senescence induction, and
(ii) Testing existing and novel drugs for the ability to kill senescent tumor cells, or inhibit the inflammatory secretions of senescent cells.
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Albert Einstein College of Medicine
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