Identifying Druggable Modulators of Response to High-Dose Androgen Treatment
Abstract
The ability to treat prostate cancer with high dose androgen therapy would transform the lives of men being treated for this disease. While it has been recognized for many years that some prostate cancer cells can be inhibited by androgens, our understanding of what makes tumor cells sensitive to high dose androgen therapy is very limited. To date, a number of studies, using a very limited number of prostate tumor models, have shown that strategies that increase cellular levels of the androgen receptor (AR) can make some tumor cells more sensitive to being killed by androgens. However, other studies show that an elevated AR level does not necessarily make cells more sensitive to being killed, some cells with low levels of AR are still very sensitive to being killed, and many cell lines show no inhibition by androgens at all. Thus, while important, the current high dose androgen strategies relying on AR manipulation are likely to be applicable to only a subset of patients and to have no anti-tumor activity in others. We propose that progress in understanding how high dose androgen therapy works, and more importantly, how to make it work in patients, has been stagnated by this limited focus on manipulating the AR. Instead, we propose that there are multiple other growth factors and signaling pathways that also play a role in determining whether or not a cell is sensitive to being killed by androgens. The primary goal of this proposal is to go beyond the AR and find other factors and pathways that can be manipulated to make prostate tumor cells sensitive to high dose androgen therapy. Our strategy is to treat prostate cancer cell lines with high dose androgens in combination with 1 of 300 different drugs that target "kinases" (a type of gene that drives cancer signaling). To identify pathways that are important in the response to high dose androgens, we will look for drugs that make the cells either more or less sensitive to being killed by androgens. To look more broadly, we will repeat the experiment but instead of testing a panel of drugs, we will use genetic tools to individually knock down 19,000 different genes to see how the loss of each gene alters the response to high dose androgens. The power of targeting so many genes is that if a particular pathway is truly important in sensitizing cells to high dose androgens, then multiple genes in that pathway should show up as "hits," which greatly increases confidence that our findings are not the result of chance. In order to be applicable to as many patients as possible, our studies will be carried out using a large panel of prostate cancer cells lines, which span the range from being very sensitive to high dose androgens to those that show no response. We can then compare how these genes and pathways that confer sensitivity to high dose androgens differ or are similar between the different cell lines. This will reveal whether there are targets that are globally effective in synergizing with high dose androgens or whether certain targets are more important in different tumor types. This will greatly facilitate designing clinical trials that can assign men receiving high dose androgen to different drugs depending on which set of targets is predicted to be most important for their tumor. Because kinases are so critical in driving cancer cells, it is very likely that kinases will be among the gene pathways that show up as "hits." For this reason, including the drug panel that targets kinases in the cell line testing is particularly useful. First, it should corroborate the genetic screen (i.e., knocking down the kinase gene should have the same effect on response to high dose androgen as a drug that inhibits the kinase). Second, any kinase inhibitor drug that has this corroborating gene data will be a clear candidate for testing in clinical trials. Third, as many kinase inhibitors are already under development for a variety of cancers, it is very likely
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510319
Entities
People
- Elahe Mostaghel
Organizations
- Fred Hutchinson Cancer Center
- United States Army