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Prostate cancer is among the most common adult malignancies, with an estimated 220,000 American men diagnosed yearly. Some men will develop metastatic prostate cancer and receive primary androgen deprivation therapy (ADT). However, almost all men with metastatic prostate cancer develop resistance to primary ADT, a state known as metastatic castration-resistant prostate cancer (mCRPC). In the U.S., approximately 30,000 men die of prostate cancer every year.
Prostate cancer is a heterogenous disease whose underlying pathogenic mechanisms are being increasingly elucidated. Androgen deprivation therapy with Luteinizing hormone releasing hormone (LHRH) analogs or orchidectomy is usually initially effective at controlling metastatic disease, but patients inevitably progress from an androgen-sensitive to a castration resistant phenotype. Effective treatment has been largely limited to docetaxel chemotherapy at this stage. Improved understanding of the molecular events underlying prostate carcinogenesis and castration resistance is vital to improving outcome. Multiple studies have identified recurrent somatic mutations, copy number alterations, and oncogenic structural DNA rearrangements (chromoplexy) in primary prostate cancer. These include point mutations in FOXA1, SPOP, and TP53; copy number alterations involving MYC, PTEN, RB1, and CHD1; and E26 transformation-specific (ETS) fusions, among other biologically relevant genes.
One of the most prominent alternate pathways in prostate cancer is the PI3K/Akt signaling pathway. Activation of this pathway is implicated in a number of aggressive human cancers. Therefore, there has been a significant investment in developing targeted inhibitors of this pathway in various hematologic and solid cancers. In addition, there is now incontrovertible evidence that androgen receptor (AR) signaling continues to play an important role in many patients with castration-resistant disease.
Activation of the PI3K/Akt pathway plays a major role in the aggressive nature of many prostate cancers. The mechanisms through which the PI3K pathway could induce carcinogenesis include the activation of growth and survival pathways. Moreover, activation of this pathway may also alter epigenetic regulators, such as BIM1. The PI3K/Akt pathway is also important to the survival and proliferation of prostate cancer stem cells. Currently, several novel PI3K/Akt/mTOR pathway inhibitors are in clinical development for advanced prostate cancer. Two studies have evaluated monotherapy with the Akt inhibitor perifosine in prostate cancer. In addition, with the use of newer AR pathway inhibitors and combination therapy, this non-androgen receptor pathway may become increasingly relevant as more patients develop non-AR driven tumors. Clinical trials are now assessing the efficacy of targeting this pathway in CRPC.
An improved understanding of the biology and relevant biomarkers of this pathway in prostate cancer will be important to understand which patients will benefit from PI3K/Akt/mTOR inhibitors and at what point in the disease course they should be given. Creative Biogene, as a leading biotechnology company, is able to offer various prostate cancer pathway related products including stable cell lines, viral particles and clones for your drug discovery projects.