Our current research projects are
Currently, there is no curable therapy for metastatic prostate cancer. We and others have demonstrated that the androgen receptor itself other than the hormone (androgens) is critical for prostate cancer. Thus, it will be more clinically relevant to shift the therapeutic target from androgens to its receptor, the AR.
We developed a construct expressing a hairpin-structured small interference RNA against human androgen receptor gene. Our preliminary data demonstrated that transfection of this construct dramatically knocked down androgen receptor expression in prostate cancer cells. Now, we generated a recombinant adeno-associate virus (rAAV) for stably expressing the siRNA hairpin in prostate cancer cells to trigger androgen receptor gene silencing in an in vivo animal xenograft model. We will also use nanoparticle-based cancer cell-specific delivery approach to determine the efficacy of the AR siRNA for hormone-refractory prostate cancer. Eventually, the recombinant AAV approach for androgen receptor gene silencing may be used as a novel therapeutic agent for prostate cancer. A US patent is pending for this technique. This project was supported by a pilot grant from HOPE Foundation of Southwestern Oncology Group, KUMC Mason’s foundation, and has been continuously funded by US Department of Defense PCRP program (PC031120 and PC060214).
Recent reports demonstrated that the AR is critical and functional in both androgen- dependent and -independent survival of prostate cancer cells. However, the downstream effecters involved in AR-mediated survival are not clear. In our preliminary studies, we found that Bcl-xL, the anti-apoptotic protein of Bcl-2 family, and SGK-1, an Akt sister kinase downstream of PI3K pathway, are transcriptionally regulated by androgen and involved in AR-mediated cellular survival. We are currently seeking to answer the question of if and how the anti-apoptotic proteins Bcl-xL and SGK-1 are involved in AR-mediated survival and androgen-independent progression of prostate cancer. Meanwhile, we are searching other novel downstream effectors involved in AR-mediated survival in prostate cancer cells. By discovering the mechanisms for AR-mediated survival or insight into the mechanisms of hormone-refractory prostate cancer will be gained. The newly identified AR-mediated survival pathway will provide us a clue if interrupting this particular pathway leads to an effective therapy for prostate cancers.
Activation of cellular survival signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)/Akt and related pathways is responsible for the survival of androgen-independent prostate cancer cells. A variety of evidence has shown that androgen ablation alone can result in an increase in Akt activity, which may support survival after acute androgen ablation and proliferation during chronic androgen deprivation. And a functional genomic analysis revealed that altered expression of genes that converge on the PI3K/Akt pathway is observed in androgen-independent prostate tumors. Is Akt playing a causative role in the process, either initiation or maintenance, of androgen-independent progression in prostate cancer cells? Determining the role of Akt signaling will lead to a better understanding of androgen-independent progression in prostate cancer and to the identification of novel therapeutic targets. Therefore, we used a novel conditional inducible Akt (iAKT) system to address this issue. Detailed information about the iAKT system is available in Li et al Gene Therapy 2002 9:233, Li et al Carcinogenesis 2007, and The Protocols page of this site. We demonstrated that CID-mediated activation of iAKT promotes cancer cell survival/growth of prostate cancer cells after androgen withdrawal in cell culture system, in an animal xenograft model and a transgenic mouse model. This project was supported by a grant from the Department of Defense Prostate Cancer Research Program (PC020015).
Kinase or oncogene-specific inhibitor is a powerful tool for human cancer treatment, such as GleevecTM for CML patients. Several kinases or oncogenes are found to be critical for human prostate cancers but the kinase-specific inhibitor is not currently available. We are utilizing a HTS system to develop an isoform-specific chemical targeting PI3K/AKT pathway for human prostate cancer treatment. This project is currently supported by NIH Kansas-COBRE program project (NCRR1P20RR015563).
©
The University of Kansas Medical Center