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FEB 26, 2020 7:30 AM PST

Keynote Presentation: Emerging Drug Combinations: Evolution From Pre-Clinical Discovery to Clinical Development

C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • Post Doctoral Research Scholar at University of California, San Francisco
    Biography
      Khyati Shah received her Ph.D. in Molecular Pharmacology from the University of the Pacific, Stockton, California. Her graduate research was completed in the lab of Jesika Faridi, Ph.D. Her work focused on the investigation of the mechanism of Akt induced tamoxifen resistance in breast cancer.

      Currently, Khyati is the research fellow in Bandyopadhyay Lab since 2015. Her project involves investigation of the mechanism of resistance to targeted and immuno-therapy using systems biology approach. She has three-first author publications in the reputed peer-reviewed journals and 7 oral and 15 poster talks on the use of systemic genomics and proteomic approach to design rational combination therapy and to increase the durability of therapeutic response.

    Abstract

    Recent advances in DNA sequencing and omics-based capabilities are revealing incredible therapeutic opportunities and quickly transforming drug discovery. Molecularly targeted drugs aim to exploit key tumor-specific vulnerabilities such as oncogenic or non-oncogenic addiction and synthetic lethality. The non-oncogenic addiction to tamoxifen creates the dependency on ribonucleotide reductase enzymes in Estrogen Receptor positive breast cancer cells. Moreover, targeting the host immune system with immunotherapies is proving to be another promising and complementary approach. Because of substantial genomic heterogeneity and immunologic complexities, combination strategies are required to interrupt intricate molecular signaling networks to achieve durable clinical responses in patients. The drug combinations have the potential to improve treatment response, minimize the development of resistance or minimize adverse events. Currently, designing combination trials relies mainly on clinical and experimental experience. While empirical experience has indeed crafted efficacious combination therapy clinical trials (combination trials), however, garnering experience with patients can take a lifetime. Therefore, to enhance the therapeutic success of combination therapies, we discovered that Ribonucleotide reductase inhibitors such as Didox, when combined with tamoxifen, created a novel combination therapeutics. Therefore, we proposed this most effective use of this combination should be directed towards eliminating polyclonal and heterogeneous cancer cells. Our results call to action a proactive paradigm aimed at preventing resistance rather than the current reactive paradigm of intercepting and treating drug resistance incrementally. Indeed, a paradigm shift is required from the traditional “drug-centric” model of clinical development to a “strategy-centric” model to provide personalized treatments in molecularly stratified subsets of patients or even in individual patients. Importantly, to battle the numerous challenges in combination drug development—including limited understanding of tumor biology, methodological and informatics limitations, regulatory challenges and ever-increasing monetary costs. This requires aligned goals and multidisciplinary collaboration to collectively harness knowledge and fuel continual innovation.
     
    Learning Objectives:
    1.     Defining the effective combination therapy
    2.     Identifying various challenges in designing the rational combination therapy
    3.     Current approaches to combination therapy in the clinic


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