Tumour cell plasticity in treatment-resistant prostate cancer

Despite a growing number of therapies used to fight prostate cancer, 4,000 Canadian men will die of it this year. These deaths are caused by failures of current therapies to control the disease. While an individual therapy can kill a sizable fraction of prostate cancer cells in a patient, another fraction inevitably survives. The surviving fraction may be contained by the therapy for a while, but eventually patients experience treatment-resistance when prostate cancer cells find the means to continue to grow despite the presence of the therapy. We have assembled a team of distinguished Canadian investigators into a research program whose goal is to develop breakthrough treatments for high-risk or metastatic prostate cancer. The team will attack the �plasticity� of prostate cancer cells that allows them to change when exposed to therapy and advance to resistant disease. We already know that prostate cancer cells can adapt to hormonal therapies by augmenting their ability to make or respond to androgens. Most ongoing efforts to improve therapies for prostate cancer attack this plasticity. Instead, our research will address three novel types of tumour plasticity. One involves an outgrowth of �stem cell-like� cancer cells (CSCs) under treatment. These CSCs can transition back to cancer cells with more aggressive properties that include treatment-resistance. The second involves a remarkable change of prostate cancer cells into neuro-secretory prostate cancer cells, called �neuroendocrines�. They are equally unaffected by androgen-deprivation. The third is mediated by tumour cell �stresses� endured under therapy that allow production of protective proteins that confer resistance. Three projects will develop means to block these new plasticities. Our fourth project seeks to improve responses of early-stage high-risk patients to radiotherapy. This project will work to prevent high-risk patients from developing metastases by blocking radiation-resistance. Projects have identified best molecular targets to block prostate cancer cell plasticities and will develop strategies to do this. The new targets will be validated in human treatment-resistant tumours and new therapies against the targets will be tested in our special animal models to establish their potential for overcoming treatment-resistance. The program is led by a scientist with a history of seminal contributions to the understanding of treatment-resistant prostate cancer. The program cements collaborations between investigators and cross-interactions between projects. Research is augmented by a vast bank of prostate tumours and by core services that will provide unparalleled technical assistance to the projects. Finally, the program has a training core to promote development of promising young prostate cancer research scientists.