Targeting the Methionine Salvage Pathway as a Metabolic Point of Leverage in Novel Therapeutic Approaches for Prostate Cancer
Abstract
The rationale for the proposed work is based in prostate physiology. Prostate is a gland whose function is to secrete prostatic fluid, which is rich in polyamines. Polyamines are small alkaline molecules that, among other things, are needed to help neutralize the acidic environment of the vaginal tract in order to help with fertilization. Polyamine biosynthesis requires folate (vitamin B9), which is also required to sustain cellular proliferation. We recently demonstrated that because of its high polyamine biosynthesis, prostate, and even more so prostate cancer, needs more folate than other organs in order to sustain cell growth. This is because the constant secretion of polyamines requires constant replenishment of the intracellular pools. This places strain on the metabolic pathways for one-carbon metabolism and the methionine cycle, which require folate. These pathways are susceptible to perturbation by drugs. Our rationale, therefore, is to take advantage of the inherently high strain on these metabolic pathways caused by the uniquely high level of polyamine biosynthesis in prostate. We propose to do so by (1) adding to that strain by even further upregulating polyamine biosynthesis with the polyamine analogue drug BENSpm and (2) eliminating a salvage pathway that prostate cells depend on to recover some of what is lost through polyamine biosynthesis. In other words, we will force the cells to waste even more resources while at the same time block their ability to recover those resources. For our proposal, we intend to use cell lines and xenograft models of prostate cancer to study the effects of a novel therapeutic strategy that takes advantage of the metabolic requirements of prostate cells caused by their very high polyamine production. Our preliminary data show that prostate cancer cells protect their ability to continue creating polyamines by upregulating a key salvage pathway enzyme, MTAP. This enzyme recycles a byproduct of polyamine biosynthesis that allows the cells to maintain high levels of polyamine biosynthesis. Recently, a specific inhibitor of this enzyme has been synthesized and successfully used in mice to inhibit recycling of this byproduct. We hypothesize that use of this MTAP inhibitor will prevent recycling of the polyamine byproducts and will cause metabolic stress by causing one key metabolite, s-adenosylmethionine, to become depleted. When combined with BENSpm, which causes the cells to produce even more polyamines, we expect these two approaches to synergize in the prostate and stop or significantly delay cancer growth and/or progression to advanced prostate cancer. We have already found that knocking out the function of MTAP in prostate cancer cells makes them more dependent on folate for growth, and furthermore that human cell line xenografts are unable to grow in mice when the gene is knocked down. In addition, we have found that inhibition of MTAP by a pharmacological agent also blocks xenograft growth in mice. Treating cells with BENSpm upregulates the activity of a key enzyme that drives the need for more polyamine biosynthesis. When we combined inhibition of MTAP with BENSpm treatment, we found a synergistic effect in blocking growth of the LNCaP cell line. Importantly, this effect was also seen in the DU145 cell line, which is AR-negative, suggesting the approach may be appropriate for treating castration-recurrent prostate cancer. In addition, the drug BENSpm was found to greatly increase the activity of the enzyme driving polyamine biosynthesis in the absence of androgens in the androgen-sensitive cell line LNCaP. These lines of evidence provide a rationale for expecting this approach to be effective in the castrate environment. This approach is not dependent on androgens or the AR, nor is it another way to make androgen deprivation more complete. Instead, this approach attacks a completely new aspect of prostate metabolism in the hope of adding to the effect
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510665
Entities
People
- Dominic Smiraglia
Organizations
- United States Army