Mechanism-Informed Combination Strategies Targeting Metabolism in Prostate Cancer
Abstract
Cancer cells divide and grow much faster than normal cells, and therefore, they have an increased need for energy and for the building blocks (proteins, lipids, nucleotides, etc.) required for cell division. To satisfy these requirements, most cancer cells upregulate the pathways needed to uptake glucose, a molecule that can be used as an energy source and for the biosynthesis of macromolecules. It is this proclivity for glucose uptake that is exploited for tumor imaging using positron emission tomography (PET). It is not surprising, therefore, that the activity of the signaling pathways that increase glucose uptake and utilization (a process called glycolysis) are upregulated in most tumors. Notably, increased PI3K/Akt/mTOR pathway activity has been reported in 100% of metastatic prostate tumors and is associated with the development of therapeutic resistance. Drugs targeting this pathway are in clinical trials. Specifically, BEZ235 and GDC-0980, two PI3K/mTOR inhibitors, are in Phase I/II clinical trials for patients with metastatic castration-resistant prostate cancer (CRPC). Although a partial response was observed with BEZ235 in a recent Phase I trial, it is expected that, as with any single agent, resistance will be an impediment to durable clinical responses. It is likely that the full potential of this class of drugs will only be realized when used in combination with another appropriately selected drug. Until recently, it was puzzling as to how tumor cells could survive interventions, like PI3K inhibitors, that completely inhibit glucose utilization. However, it has become apparent that when tumors are deprived of glucose, they can rapidly adapt and switch to using oxidative phosphorylation (OXPHOS), a very efficient energy generation pathway. The importance of this "escape" mechanism in tumor pathology and in therapeutic resistance has only recently been realized and is relatively unexplored in any cancer. Thus, we hypothesize that improved clinical responses in prostate cancer should be achievable using a combination of inhibitors that target the PI3K/Akt/mTOR and the OXPHOS pathways. One of the potential limitations of therapeutic approaches that simultaneously inhibit glycolysis and OXPHOS is that these pathways are also used by normal cells. Indeed, this is likely to be a reason that this particular therapeutic approach has not been explored to a significant degree. However, we believe we have identified a new approach that may circumvent this issue. Most of the approaches that have been developed to inhibit OXPHOS target one or other enzymes in the pathways that are required for mitochondrial function. However, as best we know, these enzymes are biochemically similar (or identical) in all cells and thus not amenable to selective inhibition. Our approach is different. We propose to target the estrogen-related receptor alpha (ERR-alpha), a master regulator of OXPHOS, which is dramatically overexpressed in prostate, breast, and ovarian cancers relative to normal cells. We believe that inhibition of this receptor will allow a tumor-selective inhibition of OXPHOS and that these inhibitors will have particular utility in combination with inhibitors of glycolysis, in this case, the PI3K/mTOR inhibitor, the targets of which are also dysregulated in CRPC. Whereas ERR-alpha has shown promise as a therapeutic target in preclinical models of breast and ovarian cancers, its utility as a therapeutic target has not been explored in prostate cancer. Importantly, orally bioavailable small molecule inhibitors of ERR-alpha have been developed and demonstrated to be safe in animal models. All of the reagents and models are in place to test this novel, innovative, therapeutic approach. We expect that this mechanism-informed combination strategy, targeting metabolism in prostate cancer, should be more effective than either molecule alone, an approach that we believe will be clinically translatable. Thus, th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510241
Entities
People
- Ching-Yi Chang
Organizations
- Duke University
- United States Army