Molecular Foundations for Personalized Therapy in Prostate Cancer
Fisher KW, Montironi R, Lopez Beltran A, Moch H, Wang L, Scarpelli M, Williamson SR, Koch MO, Cheng L. Molecular Foundations for Personalized Therapy in Prostate Cancer. Current drug targets 2015; 16(2):103-114.
Current drug targets
Prostate cancer is the most common and second most lethal cancer in men. The majority of prostate cancers are histologically similar to acinar adenocarcinomas and rely on androgen-dependent signaling for their development and progression. Androgen deprivation therapy is a mainstay of treatment regimens and we discuss the recent advancements in androgen-deprivation therapy. Recent advances in defining the genetic landscape of prostate cancer have shown that the depth of genetic heterogeneity surpasses what can be seen histologically and has the ability to redefine treatments. TMPRSS2-ETS family fusion proteins are unique to prostate cancer and we discuss their role in carcinogenesis, prognosis, and the development of TMPRSS2-ETS family gene fusion targeted therapy. Inactivation of the tumor suppressor PTEN leads to activation of the PI3K/Akt/mTOR pathway and we discuss the prognostic and treatment implications. Molecular genetic analysis has recently demonstrated that clinically aggressive high grade neuroendocrine prostate carcinomas contain a high prevalence of overexpression of Aurora A kinase and N-myc. We discuss the role of Aurora A kinase and N-myc in the development of the aggressive neuroendocrine phenotype and the development of targeted inhibitors of this specific genetic subtype. Lastly, we briefly discuss emerging genetic subtypes defined by either SPINK1 overexpression, CHD1 inactivation, or SPOP mutations. By reviewing the associations between the morphologic features and the molecular genetics of prostate cancer we hope to provide insight and guidance to the emerging options for targeted therapy.
Medical Subject Headings
Antineoplastic Agents; Aurora Kinase A; Carrier Proteins; Clinical Trials as Topic; DNA Helicases; DNA-Binding Proteins; Humans; Male; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Precision Medicine; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Trypsin Inhibitor, Kazal Pancreatic