Posted August 12, 2016
Dr. Edwin Posadas, Cedars-Sinai Medical Center

A large majority of prostate cancers (PCa) are adenocarcinomas, meaning they arise from the dysregulated growth of epithelial cells.   In rare cases, aggressive variants of the disease called neuroendocrine prostate cancers (NEPC) and small cell prostate cancers (SCPCs) can occur.  Both of these subtypes are considered very important clinically since they possess the ability to spread to visceral sites (e.g. lung or liver) as opposed to the bone like the more typical adenocarcinoma of the prostate.  It is recognized that this type of clinical behavior is associated with extremely poor patient outcomes that include accelerated death from organ failure.  Additionally, these tumors are often treated with cytotoxic chemotherapy, which are non-curative and relatively toxic, thus new therapies are greatly needed to treat these cancers. 

In order to increase the biological understanding of NEPC and SCPC, Dr. Edwin Posadas and his team at Cedars-Sinai Medical Center began studying elements in the bloodstream that may predict this type of aggressive behavior of prostate cancer tumors.  Through work supported by a FY07 Physician Research Training Award and continued by a FY10 Idea Development Award, his team has used a novel nanotechnology approach to identify a subset of circulating tumor cells (CTCs) in the bloodstream which are associated with the development of visceral metastases.  This subgroup of CTCs is characterized by particularly small nuclei which they have called as very-small nuclear CTCs (vsnCTCs). These findings will aid in identifying men at risk for visceral metastases, and provide treatment options sooner that may prevent progression.

Dr. Posadas also characterized the presence of SRC-related protein kinases in clinical cases of advanced prostate cancers, and discovered that the FYN kinase protein was upregulated in these advanced tumors.  To explore the potential of FYN as a therapeutic target, Dr. Posadas created variants of FYN in animal models.  He found that FYN overexpression caused cancer cells to preferentially metastasize to the lungs instead of bone, confirming that these animal models effectively simulate the clinical behavior of NEPC or SCPC.  Dr. Posadas and his team are now investigating the relationship of FYN to the vsnCTC, and plan to continue exploring mechanisms of FYN inhibition with the hopes of developing treatment to improve outcomes for men with advanced prostate cancer.

Links:

Public and Technical Abstracts:

Targeting FYN in Prostate Cancer: A Key Regulator of Growth and Motility

FYN Is a Key Regulator of Metastasis in Prostate Cancer

 

Research Links:

Jiang R, Lu Y-T, Ho H, et al. 2015. A comparision of isolated circulating tumor cells and tissue biopsies using whole-genome sequencing in prosate cancer. Oncotarget 6(42):44781-93.

Gururajan M, Cavassani KA, Sievert M, et al. 2015. SRC family kinase FYN promotes the neuroedeocrine phenotype and visceral metastasis in advanced prostate cancer. Oncotarget 6(42):44072-44083.

Chen JF, Ho H, Lichterman J, et al. 2015. Subclassification of prostate cancer circulating tumor cells by nuclear size reveals very small nuclear circulating tumor cells in patients with visceral metastases. Cancer 121(18):3240-51

Jensen AR, David SY, Liao C, et al. 2011. Fyn is downstream of the HGF/MET signaling axis and affects cellular shape and tropism in PC3 cells. Clin Cancer Res 17(10):3112-3122.

Saito YD, Jensen AR, Salgia R, et al. 2010. Fyn: A novel molecular target in cancer. Cancer 116(7):1629-1637.

Posadas EM, Al-Ahmadie H, Robinson VL, et al. 2009. FYN is overexpressed in human prostate cancer. BJU Int 103(2): 171-177.

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