Congratulations to Drs.Daugaard, Wang, Wyatt and their teams on being awarded multi-year grants in the CIHR Project Grant: Fall 2021 competition.
The Project Grant program is designed to capture ideas with the greatest potential to advance health-related fundamental or applied knowledge, health research, health care, health systems, and/or health outcomes. It supports projects with a specific purpose and a defined endpoint. The best ideas may stem from new, incremental, innovative, and/or high-risk lines of inquiry or knowledge translation approaches.
Successful proposals from our Centre are:
Glycocalyx plasticity as an adaptive response to AR pathway-inhibition in prostate cancer
PI: Daugaard; co-Is: Al Nakouzi, Gleave, Shoichet
5 years, $688,500
Cancer cells are coated with sugar molecules that play important roles in cell-cell communication as well as cell-to-cell signaling. Tumor cells have the ability to reconfigure the sugar coat to support various aspects of disease progression. In prostate cancer, a portion of the sugar coat consists of chondroitin sulfate that is regulated by the male sex hormone androgen. Chondroitin sulfate becomes particularly important in the context of androgen-deprivation therapy and seems to be essential for tumor cell proliferation and motility under these conditions. This provides a strong rationale for studying chondroitin sulfate sugars in prostate cancer. In this project, we aim to investigate the role of the chondroitin sulfate coat during prostate cancer progression.
Optimization and Validation of MCT4-targeting Small Molecule Inhibitors for Treatment of Advanced Cancers
PI: Wang; co-Is: Cherkasov, Choi, Collins, Gleave, Hsing, Kang, Niu, Young, Zhang
5 years, $1,147,500
Late-stage, therapy-resistant cancers remain difficult to treat and urgently requires better therapeutics. A common feature of advanced cancers is the altered processing of glucose (sugar) as an energy source. In contrast to normal cells, many cancer cells use glucose to substantially increase lactic acid secretion into the surrounding environment. This extra lactic acid supports cancer growth in many important ways. Most vitally, it can help cancer cells avoid destruction by the patient's immune system. One critical protein involved in this process is MCT4, which transports lactic acid out of cells. We have previously shown that advanced prostate cancer (PCa) is one type of cancer that exhibits this altered metabolism. Blocking lactic acid secretion by reducing MCT4 levels can stop advanced PCa cells from growing. It can also restore the immune system's abilities to destroy cancer cells. We recently used a special, computer-based, state-of-the-art drug discovery platform (one of the few available in Canada) to quickly develop a new class of anti-MCT4 drugs. Here, we propose to further improve these MCT4 inhibitors. Additionally, we have a unique panel of lab-grown tumours taken from real patients with advanced cancers. Experiments using these tumours can accurately predict patient response to therapy and can show us whether the improved MCT4 drugs are effective at stopping advanced cancer growth. By 1) targeting a fundamental aspect of cancer biology, 2) using a unique computational approach, and 3) accurately predicting patient response, we will be able to successfully develop an effective anticancer drug. Funding this project will accelerate the development of a new MCT4-targeting therapeutic useful for clinical trials in patients with advanced cancers. Given the fact that this method of utilizing sugar is widespread among many aggressive cancers, the successful completion of this project will broadly improve therapy for a wide range of cancer patients.
Refining the clinical utility of circulating tumour DNA in metastatic bladder cancer
PIs: Wyatt, Eigl; co-Is: Black, Chi, Vanderkerkhove
4 years, $841,500
Bladder cancer that has spread to other organs (metastatic cancer) is generally not curable and few people survive beyond five years. Excitingly, new and emerging therapies can significantly improve life expectancy. However, while providing meaningful benefit to some, most patients gain little or no benefit from new treatments, yet endure toxic side effects. Unfortunately there are currently no tests that can profile metastatic cancer to predict treatment benefit. A major barrier to developing such tests is that they usually need to be performed on metastatic tissue. Obtaining biopsies of metastases is invasive and has risks of complications and so we have very little understanding of the biology of metastatic cancer. To address this, we have developed new methods to isolate and study each patient's cancer using a blood sample. We profile cancer DNA that is shed into the blood: known as circulating tumour DNA (ctDNA). Our early data suggests that ctDNA tests can provide the same information that is present in a tissue biopsy. To bring this technological advance to the clinic, the next step is to examine large numbers of Canadian patients, to use novel technologies to learn more from blood-derived ctDNA and to match this with their treatment outcomes. To this end, we have compiled the first large standardized cohort of serially collected blood samples from people with metastatic bladder cancer. We have assembled a unique team including a urologist, medical oncologist, pathologist, and genomic scientist. We plan to determine the precise relationship between genetic alterations detected in ctDNA and bladder cancer response or resistance to different types of therapy. Our work will establish the clinically-important DNA features of metastatic bladder cancer that can be identified via blood tests. This framework can then be used in clinical trials to test new strategies that direct treatments only to those patients whose quality or length of life will be improved.