Identification of clinically relevant lysosomotropic agents to treat aggressive prostate cancer.
Dr. Spencer Gibson, CancerCare Manitoba
Despite tremendous progress in prostate cancer therapy, a significant proportion of prostate cancer patients will develop drug resistance and succumb to their disease. We require new therapies that can be incorporated quickly into clinical practice. By investigating FDA approved, and well tolerated agents, our goal is to re-purpose them in the clinic to improve the efficacy of current therapies and overcome drug resistance in prostate cancer patients. We will investigated how effective antihistamine drugs commonly used to treat allergies can target lysosomes or “garbage cans” of the cells. We want to know if they can kill prostate cancer cells, and how they are killing the cells. We will then investigate how effective these drugs are when combined with standard therapies. Our ultimate goal is to take these FDA approved drugs in combination with conventional chemotherapies to clinical trials for patients with advanced prostate cancer.
Drug resistance remains as significant obstacle in the treatment of prostate cancer. We have discovered that lysosome disruption mediates cell death through a process known as Lysosome Membrane Permeabilization (LMP). We discovered that siramesine (originally developed as an anti-depressant) induce LMP in breast cancer cells and gave synergistic cell death responses when combined with HER2 kinase inhibitor lapatinib. In preliminary data, we found that antihistamine drugs induce lysosome mediated cell death in prostate cancer cells. Thus, we hypothesize that antihistamines alone or in combination with tyrosine kinases inhibitors will kill prostate cancer cells through lysosome disruption. In the first aim, we will determine the amount of LMP and increased in reactive oxygens species in prostate cancer cells following treatment with antihistamines. We will further determine the amount of cathepsins released from lysosomes and the type of cell death induced by antihistamine drugs. In the second aim, we will determine whether standard chemotherapy or targeted therapies give a synergistic cell death response with antihistamine drugs. This will provide evidence that FDA approved drugs causing lysosome mediated cell death could be an innovative strategy to treat drug resistant prostate cancer.
Impact on prostate cancer patients:
This project could lead to clinical trials for advanced stage prostate cancer patients with well tolerated drugs that are already FDA approved.