Posted May 17, 2017

Ping Mu, Ph.D., Memorial Sloan Kettering Cancer Center

Despite the clinical success of targeted therapies for advanced prostate cancer (PCa), such as next generation hormone therapies, many patients have a very limited response and will eventually develop resistance to those therapies. Clear elucidations of novel mechanisms of drug resistance will not only advance our understanding of PCa pathogenesis, but may also lead to new therapeutic approaches to preventing or overcoming resistance. To work towards the goal of eliminating PCa drug resistance, Dr. Ping Mu and his colleagues at Memorial Sloan Kettering Cancer Center sought to examine the precise mechanisms by which PCa cells evade targeted therapies.

With support from a FY14 PCRP Postdoctoral Research Award, Dr. Mu identified a novel mechanism of hormone therapy resistance in advanced PCa mediated by increased lineage plasticity, or �identity fraud�. PCa cells that have genetic alterations in two genes called TP53 and RB1 can escape targeting by the current therapy by changing their tumor cell identity to a different cell type, which is not responsive to the therapy that was targeting their original identity. Dr. Mu has also demonstrated that this therapy resistance caused by �identity fraud� can be reversed by inhibition of a gene named SOX2. This work not only provides critical new insights into the mechanisms of drug resistance, but also sheds light on potential therapeutic strategies to overcome therapy resistance by interruption of this SOX2-driven lineage plasticity.

Although Dr. Mu's efforts to inhibit the SOX2 gene in PCa models have shown promising results at reversing antiandrogen drug resistance, direct therapeutic inhibition of the SOX2 gene in PCa patients is not currently feasible. Therefore, Dr. Mu is currently working towards characterizing the downstream effectors of the SOX2 gene as well as the exact mechanism of how the SOX2 gene becomes activated in these cells. This work will not only further contribute to our understanding of drug resistance but also help to identify new therapeutic targets to improve clinical outcomes for patients with advanced PCa.

Model depicting the tumor cell lineage plasticity and resistance to hormone therapy in prostate cancer with genetic alterations in TP53 and RB1 genes (Mu P, Zhang Z, Benelli B et al. 2017.SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science. 355(6320):84-88)

Publication:

Mu P, Zhang Z, Benelli B et al. 2017.SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science. 355(6320):84-88

Public and Technical Abstract:

Public and Technical Abstracts: Identifying Biomarkers of Antiandrogen Resistance: An shRNA-Based in Vivo Screening Approach

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