According to Canadian Cancer Society, one in eight men will be diagnosed with prostate cancer (PCa) in his lifetime. Most of the PCa initially respond to the treatment but eventually, some of the tumors become resistant and develop into an incurable disease. Mechanisms promoting the treatment-acquired resistance are still elusive. Our study exploring the alterations of global protein abundance unveiled an elevation of the Asparagine Endopeptidase (AEP) in the treated PCa cells, and repression of the elevation delayed cancer cell growth. AEP is a protease enzyme functioning in the cellular organelle lysosome to cleave and degrade specific substrate proteins. The role of AEP in the treatment resistance in PCa has not been investigated, we therefore propose to explore the mechanisms of AEP elevation upon the treatment and the role of AEP in cell division, cell death and cell spread under treatment stress. We also plan to develop small-molecule inhibitors targeting AEP to evaluate the co-targeting efficacy in combination with the conventional treatment approach. Our work may identify a novel mechanism promoting the treatment-acquired resistance and highlight AEP as a potential therapeutic target in PCa.
Research Location: Vancouver Prostate Centre
Leveraging computational modelling and 3D bioprinting in pursuit of a regenerative therapeutic approach for male infertility
A desperate need exists to develop technology to regenerate sperm that can be used for in vitro fertilization (IVF) among men who lack sperm production, such as pediatric cancer survivors. In Canada, approximately 2,440 boys aged less than 15 will be diagnosed with cancer each year. Fortunately, the field of oncology has made significant improvements in survival rates, which are estimated to be 83%. However, treatments will render up to 97% of paediatric cancer survivors infertile with no sperm production, despite over 75% eventually desiring to have biological children. While stem cells (sperm precursors) can be retrieved prior to cancer therapies, no technology currently exists to regenerate sperm, which is required to achieve a pregnancy. This project proposes to utilize single cell sequencing and along with state-of-the-art computational modelling to reveal molecules and pathways that are key regulators of developing sperm from stem cells. These findings will be screened and tested to identify critical molecules that help generate sperm in 3D bioprinted structures. Results from this study will contribute to developing the understanding and technology to regenerate sperm for men lacking any ability to father biological children.
Impact of prostate cancer subtypes on bone remodeling and microarchitecture in metastatic lesions of the spine: A combined cellular, genetic and mineralization study
One in nine men will develop prostate cancer (PC) in their lifetime. Although modern therapies have increased the survival rate, almost all advanced cases will metastasize to bone, with the axial skeleton being the most frequent location. Bone metastases (BM) are the most severe complications of PC generating severe pain, fractures, and spinal cord compression. So far, it is not clear how PC BM are related to pain and fracture. Most cancers that generate bone complications, are associated with bone loss. However, PC is associated with bone formation. The aims of this project are to understand the structure of this new formed bone, how prostate cancer cells induce these changes, and if there are any specific types of PC associated with these changes. The ultimate goal is improving disease management and preventing complications of PC BM.
I have observed the microstructure structure of PC BM in mineral and protein content. Also, I have identified different types of PC cells in the PC BM, meaning the cells are undergoing a transformation process in the bone. These results are unprecedented, and my aim is now to expand the sample size and to explore the structure of PC BM in greater detail in order to prevent its severe consequences.
Moving towards a biology-based care model in germ cell tumors
Testicular germ cell tumors (GCTs) are the most frequent solid tumors in young men. Chemotherapy can cure most patients even when the tumor is advanced. However, there are still two main issues of concern.
- Survivors have an increased risk of developing other diseases (e.g. heart disease, new tumors, strokes, etc.) as results of the late side effects of chemo- and radiation- therapies.
- Current methods to detect GCTs rely on a CT scan and blood work for tumor markers which are not specific enough for GCTs. This means there are patients who are falsely considered as having the tumor and more importantly, being treated unnecessarily with chemotherapy, radiation or surgery.
Our research program aims to reduce this uncertainty by analyzing some small RNA fragments (micro-RNAs) in the blood of GCTs patients that are produced only by the GCTs cells. Although several small studies have demonstrated those micro-RNAs are better than the CT scan and serum tumor markers to detect GCTs, we still need to validate this test in a larger number of patients before it can routinely be used in clinical practice. We have therefore designed two clinical trials to validate the clinical utility of micro-RNAs in the management of GCTs.
A microfluidic cell migration assay enabling anticancer drug testing of patient-derived tumour cells
The dispersal of tumour cells within malignant tissue relies on a process called chemotaxis, where tumour cells migrate in response to chemical signals in the local microenvironment. There has been longstanding interest in using chemotaxis assays to deduce how invasive a tumour is, and how it might respond to drug therapy. However, current chemotaxis assays are prone to extreme inter-assay variability, due to the inherent instability of the chemical gradient. Additionally, existing assays require a large number of cells, making it impossible to test primary patient tissue, which typically only yields a few hundred tumour cells.
Dr. Park’s research will work towards developing a microfluidic platform to generate highly stable and uniform chemical gradients for the chemotaxis assay of a small number of tumour cells. She will validate the technology by examining the response of cultured tumour cells to chemotherapy. Cells from murine tumour xenograft will further establish the relationship between migration with disease progression and drug-efficacy.
The results of this research could provide a reliable means to evaluate the migratory potential of patient tumour cells both before and in response to therapy, ultimately guiding clinical decisions in practice and within personalized clinical trials.
Unraveling disparate roles of Notch-1 and Notch-2 signaling in bladder cancer
Bladder cancer is the fifth most common cancer, yet it remains understudied and we are only now making strides in understanding it’s molecular make-up. Recently we and others have discovered that loss of the cell surface receptor Notch-1 drives growth of some bladder cancers, while increased Notch-2 activity drives growth of other bladder cancers. Here we aim to determine how Notch-1 and Notch-2 can lead to such differing effects on cancer growth even though they share many features. From this we aim to design a new drug to inhibit Notch-2.
We will:
- Create a mouse model that over-expresses Notch-2 in the bladder. We expect this will cause bladder tumours to form.
- Use advanced techniques to study the differences between Notch-1 and Notch- 2 signaling that make them have such different effects. We will especially investigate how each Notch protein controls the reading of genes in the cell nucleus.
- Develop a new a new drug to inhibit Notch-2 using computer-aided drug design.
End of Award Update – April 2024
Results
We have identified a candidate Notch-2 inhibitor that requires further testing in pre-clinical models before potential testing in patients with bladder cancer.
Impacts
Our work has explained an important pathway that drives growth and progression of bladder cancer in some patients.
Potential Influence
This new inhibitor could represent a novel way to treat bladder cancer.
Next Steps
We will publish the results on Notch when completed.