Novel Mechanism-Based Preclinical CRPC Modeling Impacts Personalized Treatments
Abstract
Androgen-deprivation therapy (ADT) aims to stop androgen synthesis by using drugs such as abiraterone or to cut off androgen receptor (AR) signaling by using antiandrogens such as MDV3100 (Enzalutamide). Introduced >60 years ago to the clinic, ADT achieves impressive short-term clinical effects by de-bulking primary tumor volumes, reducing serum PSA (prostate-specific antigen) levels, and improving patient symptoms. The reported survival advantage, however, is measured only in months and most "castrated" patients eventually develop castration-resistant PCa or CRPC. Why do ~30,000 PCa patients still die each year in this country from CRPC/metastasis after ever-increasing aggressiveness of castration? Because ADT targets the androgen/AR signaling pathway, one plausible explanation for the overall poor survival benefits of PCa patients from ADT is that some "undifferentiated" PCa cells lack the expression of AR and do not require androgen-AR signaling for their survival. Indeed, overwhelming clinical and laboratory evidence supports the presence of such AR-/lo PCa cells, which would theoretically respond poorly to ADT. Our lab, in the past 13 years, has been attempting to test the above possibility by first addressing a fundamental PCa biology question, i.e., what are the cells that can generate CRPC upon ADT? Our lab is among the first to report the presence of stem cell-like PCa cells generically termed prostate cancer stem cells (PCSCs). We have recently provided definitive evidence that the undifferentiated PCa cell population that lacks the expression of the differentiation marker PSA (i.e., PSA-/lo) harbors PCSCs that may well represent a cell-of-the-origin for CRPC. Similar studies from another group have reported findings that undifferentiated PCa cells lacking the expression of another differentiation marker HLA (human leukocyte antigen) also have many stem cell traits. Of clinical importance, such undifferentiated PCSCs seem to generally lack the expression of AR, which could help explain their intrinsic resistance to ADT. In response to ADT as well as other therapies such as docetaxel, these undifferentiated PCSCs tend to expand, explaining the acquired therapy resistance. The goals herein are to employ xenograft modeling to uncover novel mechanisms (e.g., Eicosanoid Signaling) of castration resistance and provide preclinical rationale for personalized treatment. Our preliminary studies have revealed numerous insightful and novel findings with tremendous translational values. Briefly, we have demonstrated that for castration-resistant prostate tumors/clones like LNCaP AI in which there is prominent accumulation of nuc-AR, they can be treated with MDV3100 together with ABT-199 and perhaps with Myc inhibitor or inhibitors of eicosanoid and WNT signaling. On the other hand, for CRPCs/clones like LAPC9 AI in which there is a prominent loss of AR, they should not be treated with MDV3100 but instead with a combination of therapeutics targeting CSC molecules such as Myc together with eicosanoid inhibitors. Finally, for CRPCs that contain both AR+ and AR-/lo tumor clones, they can be potentially treated with MDV3100 in combination with ABT199 and inhibitors of stemness genes (Myc, WNT signaling) and eicosanoid inhibitors. Excitingly, a phase clinical trial, based on our results, of treating metastatic CRPC patients with a combination of MDV3100 and ABT-199 is already under way at MD Anderson Cancer Center. The current project represents a truly high-risk and high-reward type of project and has the ultimate significance in employing xenograft modeling to elucidate the novel mechanisms underlying CRPC and to generate crucial preclinical data for personalized treatment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610575
Entities
People
- Dean Tang
Organizations
- Roswell Park Comprehensive Cancer Center
- United States Army