Targeting Pim Kinase/lncH19 Axis in Enzalutamide Resistant Prostate Cancer
Technical Report,30 Sep 2018,29 Sep 2019
University of Arizona Tucson United States
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Prostate cancer PCa is the most common non-skin cancer in American men and contributes to a leading number of cancer-related mortalities. With the advent of anti-androgen drugs for instance enzalutamide Enza, most tumors that advance to metastatic castration-resistant PCa develop resistance to this therapy which is generally incurable. There is an urgent need to come up with therapeutic interventions to overcome such resistance. The mechanism of Enza resistance leading to aggressive PCa disease is not very well understood. Recently, the resistance to Enza due to deletionsmutations in the TP53 p53 and retinoblastoma Rb genes have been linked to the overexpression of SOX2 gene - a reprogramming transcription factor SOX2 knockdown in these cells restores the sensitivity to Enza. In this proposal, we identified a novel signaling cascade showing that Pim kinase, a serine threonine protein kinase that is overexpressed in PCa, control a long noncoding RNA H19 H19, which in turn regulates the expression of SOX2 along with other stem cell genes, Oct4, Klf4, and Nanog. The knowledge gained through the studies proposed in this application during the first year have unravel mechanistic details of PimH19 mediated p53-Rb induction of stem cell genes that is responsible for the ADT. Additionally, the rational and novel therapeutic strategies proposed to overcome resistance to Enza by inhibiting the PimH19 axis were demonstrated to be effective in PCa cells. As a young investigator award, the career development plan and research support outlined in this proposal is also strengthening my long-term goal of becoming an independent investigator with focus on PCa research.
- Medicine and Medical Research