The Stromal Contribution to the Development of Resistance to New-Generation Drugs by Castration-Resistant Prostate Cancer

Prostate cancer (PCa) that is detected early (while localized to the prostate gland) can be treated by surgery and/or radiation that is often curative. However, once PCa has spread to other tissues (especially the bone), the patient is treated with hormone therapies that suppress the ability of the testis to make the androgens needed for prostate cancer cell growth. While hormone therapy provides a survival benefit to the treated patient, it is most often only temporary as the tumor often recurs in a castration-resistant (CR) form that is no longer dependent on testicular androgens. Once CRPC has developed, it is notoriously difficult to treat. We now know that CRPC tumors can acquire the ability to synthesize their own androgens in a process referred to as 'intratumoral steroidogenesis.' A new drug (abiraterone or abi) has recently become available that partially blocks intratumoral steroidogenesis, and there was much excitement over the finding that this drug can prolong patient survival further than hormone therapy by itself. Unfortunately, some CRPC patients do not respond to abi whereas responsive patients often develop resistance after several months. Researchers are now focused on determining how the CR cancer cell develops this resistance, and there is some evidence that they can adapt to abi by increasing their production of androgens. However, all of this work ignores any potential contribution of benign (stromal) cells that surround and infiltrate the prostate metastasis, despite new evidence that stromal cells can become highly steroidogenic when they are exposed to certain hormones (referred to as Hedgehogs) that are secreted from androgen-deprived prostate cancer cells.

I am a recent graduate who was previously involved in characterizing the acquired steroidogenic capability of prostate cancer cells in the work for my graduate thesis. My training in prostate cancer research will be facilitated by a highly innovative research project that will test whether benign bone stromal cells (BSMCs) can become androgen-producing cells when they are exposed to a Hedgehog-like stimulus, similar to that released from androgen-deprived prostate cancer cells. This finding would identify a potential role of the benign support cells in the metastatic bone microenvironment in promoting the development of CRPC. But more important, the project will test whether Hedgehog-activated, androgen-producing BMSCs can also adapt to abi by increasing their synthesis and output of androgens, thus showing that it is not only the tumor cells at the metastatic sites that are adapting to the new generation of anti-prostate cancer drugs, but also the benign cells surrounding the bone metastases. This finding would have many implications for CRPC patients by indicating a role for the stromal cells surrounding a prostate tumor in the development of therapy resistance. Likewise, the finding would indicate that we need a modified drug strategy that blocks enzymes required for androgen biosynthesis in the cancer cells as well as in the surrounding benign cells to overcome resistance to new-generation drugs and further increase survival of the advanced prostate cancer patient.

I have chosen a Mentor (Ralph Buttyan) who is highly experienced in the study of advanced prostate cancer and who has previously successfully trained many Postdocs and Students. Likewise, his mentorship will be very valuable for the project since it was his work that described the ability of prostate stromal cells to become steroidogenic under the influence of Hedgehog hormones released from prostate tumor cells. Since I am determined to pursue a career in prostate cancer research, the project will require me to learn laboratory experimental procedures (especially involving the study of genes important for prostate cancer) that I was not previously exposed to, thus increasing my ability to develop more complex experiments to study prostate cancer in the future. Likewise, the training program plan is also designed to significantly enhance my potential for becoming a Senior Research Investigator by providing me with effective knowledge acquisition, communication and networking skills. In summary, this project is strategically designed not only to promote my career development in prostate cancer research but it also involves a highly impactful project that will change the way that we think about the development of drug resistance in prostate cancer patients and potentially provide rational for new and effective treatments.