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Deciphering the Biology and the Therapeutic Implications of SPOP Mutant Prostate Cancer



Theurillat J. P.



Prostate cancer is the most prevalent cancer type in men and an increasing public health care problem world-wide. Current treatment options for recurrent disease focus primarily on inhibition of androgen receptor (AR) signaling – a key oncogenic pathway in this disease. That said, most prostate cancers are defined by distinct truncal driver mutations in either the ubiquitin ligase adaptor protein SPOP or translocations in ETS transcription factors, mostly commonly ERG. The better understanding of these clonal driver mutations may open new therapeutic opportunities for the development more effective combination therapies with the hope for cure. Here, we will build on our own first in class observations and explore the biology and the therapeutic opportunities of prostate cancers driven by different truncal mutations in patient-derived xenograft (PDX) tumor models with particular focus on SPOP-mutant prostate cancer. We previously established that stabilization of the nuclear receptor activator TRIM24 is a key feature of SPOP-mutant tumors. Using chimeric small molecule degraders of TRIM24, we will determine the phenotypic and molecular consequences of its pharmacological degradation in SPOP-mutant PDX models. Second, we recently discovered that SPOP- and ERG-mutant prostate cancers are driven by divergent and antagonizing tumorigenic pathways. We will further characterize the molecular differences in tumorigenesis at the chromatin level and systematically search for specific therapeutic susceptibilities. Third, we will study how oncogenic point mutations in SPOP occur during early tumorigenesis. Using these insights, we will further develop approaches to prevent their occurrence. The results may be relevant for patients with an inheritable regulatory element at chromosome 7p14.3 that predisposes for SPOP-mutant prostate cancer.

Informazioni aggiuntive

Data d'inizio
Data di fine
48 Mesi
Enti finanziatori
In corso
Swiss National Science Foundation / Project Funding / Life Sciences (Division III)