The research in the Raj laboratory focuses on translational programs in prostate cancer in:
- Molecular characterization of signaling pathways in prostate cancer
- Drug design, development and validation
- Ex vivo development of primary prostate cancer models that maintain the critical signaling pathways in prostate cancer and that can be used to dissect the biology of individual cancers and predict responsiveness to therapeutics
- Delineation of a predictive biomarker panel in prostate cancer
Our work is funded by grants from the Prostate Cancer Foundation, the Department of Defense and private foundations.
About Prostate Cancer
In 2013, there will be approximately 238,590 new cases of Prostate Cancer (PCa) diagnosed and 29,720 deaths in the United States, according to the American Cancer Society. Mortality from PCa can be attributed to its metastasis to bone. For metastatic PCa, androgen deprivation therapy (ADT) is the initial treatment of choice and results in regression of the disease. However, ADT is not curative: the cancer invariably relapses and progresses to castrate-resistant PCa (CRPC). Despite recent FDA approval of chemotherapeutic and immunomodulatory agents, CRPC is incurable and most patients with CRPC will die.
Androgen Receptor Signaling
Our primary focus is to molecularly characterize signaling pathways in prostate cancer. We know that CRPC is characterized by active androgen receptor (AR) signaling, which dictates resistance to therapies. AR is noted to be predominantly nuclear in CRPC and binds to cognate DNA response elements to mediate a robust gene expression programme. Up to 5 percent of genes in CRPC may be regulated by AR. AR forms a productive transcription complex on chromatin in conjunction with several coregulatory proteins (coactivators and corepressors) and collaborating transcription factors.
The interaction between AR and these coactivators is critical for AR signaling and we endeavor to understand the molecular basis of these interactions and their functional import. We characterized the interaction between AR and a coactivator PELP1 and showed that this interaction could couple AR signaling with the activation of other steroid receptors. This novel mechanism of steroid receptor cross-talk has been validated in other systems and may represent an important resistance mechanism in prostate cancer. Current work focuses on potential targeting of this steroid receptor cross-talk in prostate cancer. We are also evaluating the importance of the interaction between AR and other critical coactivators in prostate cancer, including FoxA1, src, hsp27 and hsp90 in AR signaling in CRPC.
Our studies of protein-protein interactions critical for AR signaling, has led to fundamental breakthroughs. With Jung-Mo Ahn, Ph.D., of UT Dallas, we have developed a transformative class of drugs targeting specific protein-protein interactions central to AR function in prostate cancer. These drugs known as peptidomimetics are orally bioavailable, potent, non-toxic small molecules that specifically target the interface between AR and specific cofactors. One such molecule, the D2 peptidomimetic (named D2 or Drug 2) was designed to block the interaction between AR and cofactors containing a LXXLL motif (L=leucine, X= any amino acid) and was the subject of our recent manuscript in Nature communications. The peptidomimetics can target specific sequences in specific structures, making them potent molecules for disrupting specific interactions or genres of interactions between proteins. Ongoing work in the laboratory is focused on both advancing these drugs to clinic and to develop additional agents against other critical protein-protein interactions.
A major impediment to the clinical translation of research findings is the lack of preclinical models that can accurately predict the clinical efficacy of new drugs and, therefore, enable the selection of agents that are most suitable for clinical trials. An approach that we developed with Wayne Tilley is the ex vivo culture of primary human tissues, which retains the native tissue architecture, hormone responsiveness, and cell-to-cell signaling of the tumour microenvironment in a dynamic and manipulable state. Ex vivo culture systems recapitulate the structural complexity and heterogeneity of human prostate cancers in a laboratory setting, making them an important adjunct to current cell-line-based and animal-based models. When incorporated into preclinical studies, ex vivo cultured tissues enable robust quantitative evaluation of clinically relevant end points representing drug efficacy, investigation of therapy resistance, and biomarker discovery. By providing new clinically relevant insights into prostate carcinogenesis, it is likely that ex vivo culture will enhance drug development programmes and improve the translational ‘hit rate’ for prostate cancer research. We have the largest experience in the world with the ex vivo technique and have published extensively with this technique. Our current research is focused on developing second and third generation culture techniques for reliable drug response evaluation.
Our lab is committed to the “bench to bedside” translation of our research endeavors, leading to systemic evaluation of mechanisms of therapy resistance. We have assembled a panel of resistant prostate cancer cell lines that do not respond to the current FDA approved drugs or those in development. Using a systemic bioinformatics approach, we have identified a panel of genes that may have predictive value for both responsiveness to primary radiation therapy and advanced anti-androgen therapy. This ongoing and exciting work we hope will lead to the delineation of a predictive and prognostic biomarker panel of molecular drivers in prostate cancer.