Exploiting autophagy for therapeutic gain in prostate cancer

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I am pleased to have the opportunity to share some insight into my current research proposal that is supported though one of Prostate Cancer Canada’s Rising Star in Prostate Cancer Research awards, funded by Movember. In its inaugural year, the Rising Star program provides funding to four scientists to support careers as independent investigators researching prostate cancer. The program allows for research scientists in the first five years of their first academic or research appointment to work under the guidance of an experienced mentor, providing intensive career development in prostate cancer research. Each recipient receives a grant of $150,000 a year for salary support and research expenses, for a period of three years. The awards provide the opportunity for junior research scientists to develop and demonstrate independence in initiating and conducting prostate cancer research.

Currently, with an estimated 26,500 new cases of prostate cancer diagnosed and 4,000 deaths in Canada in 2012 alone, novel treatments and approaches for prostate cancer are sorely needed. Despite important advances in understanding molecular events that drive the progression of prostate cancer, most mechanisms responsible for acquired resistance to radiation, hormonal therapy and chemotherapy remain unclear despite recent advances in the development of novel hormonal agents in the prostate cancer armamentarium such as enzalutamide (a potent androgen receptor antagonist).

In our current research study, we aim to take advantage of recent insights into prostate cancer tumour biology based on our previous work to propose a novel paradigm for a treatment adjunct across a broad range of prostate cancer treatments outlined above. Cancer cells are often under stress in the cancer microenvironment, commonly lacking oxygen, sugar as well as other essential nutrients. When this occurs, the cancer cells may turn to a newly discovered strategy known as autophagy to survive. This process involves recycling parts of the cell that are no longer needed to be used as fuel for survival. Therefore, the central hypothesis of my Rising Star research project is that autophagy can be used for therapeutic gain in prostate cancer.

In the grant we hope to fulfill three objectives: 1. To develop therapeutic approaches for prostate cancer including castrate-resistant prostate cancer (CRPC) based on inhibition of autophagy 2. To validate the utility of autophagy inhibition in combination with docetaxel chemotherapy 3. To develop novel therapeutic strategies in cases of prostate cancer that are resistant to enzalutamide (ENZ).

In greater detail, we have recently refined the use of a non-toxic autophagy inhibitor, which is actually the commonly used anti-acid medication pantoprazole, in high doses. In addition, we have data suggesting that this approach will be even more potent in stressing and therefore killing the cancer cells if we treat the cells with metformin. Metformin a commonly used diabetic medication that we have recently proved can fool the cancer cell into thinking it is starving but inhibiting a protein known as mTOR. By using these two treatments together, we hope to improve the efficacy of radiation, hormonal and chemotherapy for prostate cancer. We will also explore alternative stressors to cancer cells such as hypoxia (low oxygen) and low glucose to mimic the cancer environment. We will explore these synergies with hormonal, chemotherapeutic and radiation therapies.  To supplement this work, we will look at the importance of autophagy in a clinical trial we are running with pantoprazole to see if we can predict outcomes by examining prostate tissue for markers of autophagy.  Finally, using the unique facilities in our laboratory, we will carry out a “screen” for new ways to target and kill prostate cancer by reducing 78,000 different genes in the prostate cancer and seeing what effect they have on the survival ability of the cells in particular in the setting of resistance to the latest prostate cancer anti-androgen, enzalutamide.

Significance of Research

The significance of this work is that it provides a novel and controllable therapeutic mechanism to increase the utility of a number of treatments in prostate cancer with minimal increase in toxicities. Specifically, this research is aligned with the goals of Prostate Cancer Canada in that it proposes a novel treatment paradigm for men that will rapidly be adaptable to the clinic across a number of treatment modalities in prostate cancer care to improve outcomes.