Robert J. Matusik, PhD
In North America, one in ten men is diagnosed with prostate cancer. Hormonal therapy, developed more than fifty years ago, is initially successful in 85-90% of patients; however, metastatic prostate cancer patients eventually develop resistance to this androgen withdrawal therapy with progression to castrate resistant prostate cancer (CRPC). New research has demonstrated that androgen receptor (AR) addiction is a driving force for the continued growth of CRPC. Thus, new drugs have been developed that target the AR. However, failure to this second generation of hormonal therapy occurs. Failure is accompanied by the expression of AR variants (AR-V) that are lacking the ligand binding domain (LBD) of the receptor. The absence of the LBD in the AR-Vs creates a receptor that is constitutively active resulting in continued tumor growth. Additionally, hormonal blockade results in greater than 25% of the tumors to progress to a neuroendocrine prostate cancer (NEPCa). NEPCa is AR negative and does not respond to current therapy.
In order to target genes to the mouse prostate and create new animal models of prostate cancer, we have identified a fragment of DNA in the probasin promoter that controls androgen regulation and limits the expression of a gene to the prostate in mice. Using the probasin promoter, we and others have now created multiple mouse models that reproduces the full spectrum of transformation seen in human prostate disease including benign hyperplasia, pre-neoplastic lesions, local invasive carcinoma, androgen-dependent cancer and progression to NEPCa. The information gained from our animal models is complemented by our human prostatic tissue acquisition program which assists in the translation of these basic research findings to the analysis of patient samples.
By studying androgen regulated promoters, we identified Forkhead BoxA1 (FOXA1) as an important AR co-regulator and that FOXA1 plays a critical role in prostate development. We now have identified the Nuclear Factor I family (NFIA, NFIB, NFIC, NFIX) as important transcription factors in the AR/FOXA1 complex. Also, we have determined that the NFкB pathway plays a major role in AR function by inducing the AR variants (AR-Vs). We are working on developing new drugs that will target the AR/FOXA1 complex, with the goal of inhibiting the AR-Vs where current anti-androgens fail.
Based upon a prostatic hyperplasia in a mouse prostate that overexpresses NFкB, we have developed a gene signature that successfully predicts disease-specific survival and distant metastasis-free survival in prostate cancer patients. Further, our work shows that by inhibiting the NFкB pathway we can down-regulate AR full length and AR-Vs to restore the responsiveness of castrate resistant prostate cancer xenografts to anti-androgen. This work demonstrates that the NFкB pathway plays a major role in AR function during prostate cancer failure of androgen deprivation therapy. These result indicated that a therapeutic approach that both inhibits the AR function as well as down-regulates the NFкB pathway may delay or reverse progress to CRPC. To prove this strategy, we are planning clinical trials to treat advanced CRPC.
Renjie Jin, MD, PhD
If prostate cancer remains localized, a prostatectomy or radiation therapy can cure the patient. For metastatic prostate cancer, the standard treatment uses approaches to block androgen receptor (AR) activity. Androgen deprivation therapy (ADT) uses luteinizing hormone-releasing hormone analogs that block the production of testicular androgens and/or anti-androgens that directly block AR activation. The majority of patients initially respond by regression of disease and a dramatic decrease in serum PSA. Eventually, the patients will fail hormonal therapy and the cancer is commonly referred to as “androgen refractory”, or “Castrate Resistant Prostate Cancer (CRPC)”. At this stage, although there is modest proven benefit with docetaxel treatment, there is no curative treatment.
My laboratory focuses on understanding the mechanism(s) by which the prostate cancer progresses to metastatic and castrate resistant cancer. We have been particularly interested in the understanding the role of NF-κB signaling in the metastatic and CRPC progression. Our work has shown that long term ADT induces neuroendocrine differentiation (NED) and increases NE peptides expression in prostate cancer cells. The increased NE peptides contribute to castrate resistant growth of prostate cancer through activation of NF-κB pathway. In addition, we have found that activation of NF-κB signaling promotes the development of osseous metastasis, and contributes to the development of castrate resistance by activating the expression of AR splice variant(s) (AR-Vs) in prostate cancer. We are developing an innovative approach by targeting both the cells that undergo transdifferentiation to NE cancer and by blocking the NF-κB pathway to down-regulate AR-Vs expression and restore the responsiveness of the CRPC to hormonal therapy.