Investigating RIOK2 ribosomal and extra-ribosomal functions in prostate cancer.
RIOK2 is critical for de novo ribosome maturation and assembly, which is essential to maintain the high proliferation rates in cancer cells. Indeed, we found that RIOK2 loss reduced de novo protein synthesis in PC cells, decreased cell proliferation and matrigel invasion. Pharmacologically, lead small molecule compounds we identified and validated to inhibit RIOK2 kinase activity, phenocopy RIOK2 genetic depletion. RIOK2-ChIP-Seq studies also show RIOK2 has added an added extra-ribosomal functional role as a DNA binding protein. Efforts are underway to further elucidate the role of RIOK2 in prostate cancer and to optimize lead RIOK2 kinase inhibitors.
Hippo Tumor Suppressor Kinase STK3 non-canonical role in prostate and breast cancer.
STK3 along with STK4 are key players in the Hippo Tumor Suppressor pathway that inhibit the YAP and TAZ transcriptional oncogenes. Yet, our preliminary data argue against the current signaling dogma that in the context of PC, STK3 has a non-canonical tumor supportive role. Analysis of human PC cohorts show frequent gene amplification of STK3 in PCs. We also found that STK3 knockdown inhibits PC cell growth, migration, invasion, and stemness behavior in vitro. Likewise, pharmacologic inhibition with a semi-specific STK3/4 kinase inhibitor significantly slowed PC cell proliferation and prostasphere growth while reducing migration and invasion.The overarching goal of our studies is to test if STK3 is a molecular target that can be exploited to help slow the progression of or treat advanced metastatic castrate resistant prostate cancer. Our studies will provide mechanistic insight into STK3 in the context of prostate cancer and pharmacological tools for chemical genetic studies. In the long-term, this study may provide a new molecular targeted therapy for metastatic castrate resistant prostate cancer.
Fig 1. Genetic depletion of STK3 slows prostate cancer tumor spheroid growth.
Fig 2. Prostate cancer spheroids embedded in matrigel treated with increasing concentrations (0-5 uM) of a novel STK3 inhibitor we are developing significantly slows tumor cell invasion.
Targeting NUAK2 to mitigate obesity enhanced prostate cancer progression and metastasis.
Obesity is linked with greater risk of high-grade prostate cancer, recurrence after therapy, metastases, and prostate cancer specific death. We exploited the link between obesity and the increased chances of dying from prostate cancer to identify potential drug targets. In a kinome wide screen, we found that the protein NUAK Family Kinase 2 (NUAK2), is essential for tumors grown in mice on high fat western diets. Our hypothesis is that NUAK2 is essential for obesity-enhanced progression of PC to metastatic disease. Preclinical genetic and pharmacological studies are underway to determine if NUAK2 mediates obesity-enhanced prostate cancer aggressiveness. If successful, our studies will validate and provide a therapeutic strategy against a molecular target (NUAK2) by which obesity makes PCs more aggressive and allows them to metastasize and cause prostate cancer mortality.
Fig 1. Working Model of NUAK2 in obesity-enhanced prostate cancer
