Metastatic disease and the castration resistance remain tremendous challenges in the treatment of prostate cancer. New targeted treatments, such as the ant-testosterone medication enzalutamide, have improved the survival of men with advanced disease, but a majority develops treatment resistance. The field of cancer stem cells hypothesizes that treatment resistance emerges because stem cells are inherently resistant to our current therapies and eventually repopulate tumors. One mechanism by which cancer stem cells resist therapy is through acquisition of an epithelial to mesenchymal transition (EMT), a phenomenon of normal development used by cancers to survive and metastasize. Our laboratory has shown that prostate cancers undergo an EMT that leads to invasion, metastasis and treatment resistance. N-cadherin, a critical regulator of EMT, is expressed in most castration resistant prostate cancers (CRPC) and is sufficient to promote treatment resistance. We therefore developed antibodies against N-cadherin, which are able to inhibit growth, metastasis and progression of prostate cancers in vivo. The goal of this translational application is to move this promising treatment from the laboratory to the clinic by making the antibody human, making it bind more strongly, and then testing it for toxicity, behavior and anti-tumor activity. At the completion of this project, we will be poised to manufacture this lead molecule and move expeditiously to Phase I clinical studies.
Prostate cancer is the second leading cause of cancer-related death in Californian men. With an aging population, this problem is expected to continue to grow despite recent advances in treatment. The goal of this application is to develop a novel antibody targeting a cancer stem cell target in hormone and treatment refractory prostate cancer. The benefit to the California, if successful, will be the development of a novel therapy against this common disease.
This application for a Development Candidate Award is focused on developing a monoclonal antibody to target N-Cadherin-expressing castration-resistant prostate cancer stem cells, and inhibit their growth and metastasis. This approach is based on evidence that N-Cadherin-positive cells have certain cancer stem cell properties and are highly tumorigenic and invasive. The goal is to engineer for human use an antibody identified by the applicant, and to test its safety and its efficacy in several disease models.
The applicant proposes five milestones: 1. Humanize lead candidate murine antibodies; 2. Select a lead humanized candidate antibody; 3. Develop a stable high-expressing clone, develop cell banks and scale up production of the lead antibody for preclinical studies; 4. Perform non-clinical proof-of-concept (POC) and preliminary toxicology studies and 5. Perform combination studies and POC studies in non-prostate models to identify potential other indications.
Objective and Milestones
- Reviewers judged the objective of the proposal to be appropriate since castration-resistant prostate cancer is still an unmet medical need.
- The Target Product Profile was considered scientifically sound and reasonable.
- The milestones have a logical progression and were considered appropriate for a development candidate proposal. However, since the last milestone involves therapeutic combination studies and studies in non-prostrate cancer models, reviewers deemed it unnecessary for the filing of an Investigational New Drug (IND) application and possibly out-of-scope.
Rationale and Significance
- The scientific rationale is strong due to the specific targeting of N-Cadherin, a cell surface molecule associated with cancer stem cells.
- This potential therapy could provide a significant improvement to the standard of care and could be transformative if it eliminates the cancer stem cells and leads to long-term remissions.
- The proposed therapeutic approach could have an impact on the development of treatments for other cancers.
Feasibility and Design
- The research plan is well focused and was deemed achievable in three years. Alternative approaches are outlined.
- Compelling preliminary data provided in vivo evidence that targeting N-cadherin-positive cells may be an effective approach for the treatment of prostate cancer.
- Reviewers expressed concerns about the potential for cardiac toxicity, since N-cadherin is expressed in cardiac cells. They were not convinced that the preliminary toxicology studies appropriately addressed this issue, and stressed the need to design robust safety studies in non-rodent species
- Another concern relates to a potential for cross-reactivity of the antibody with other off target tissues in addition to the heart, since N-Cadherin is expressed on the surface of a number of cell types.
Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team
- The PI is well qualified with a good track record in prostate cancer research and experience in supporting IND-enabling work.
- The Co-PI has multiple years of experience with engineering anti-cancer antibodies.
Collaborations, Assets, Resources and Environment
- There are adequate laboratory and institutional resources, along with excellent collaborations that provide expertise in the in vivo models.
Responsiveness to the RFA
- The proposal is responsive to the RFA in that it addresses an unmet medical need and targets cancer stem cells in prostate cancer with a novel monoclonal antibody therapeutic.
- While the applicant did make a good case that cancer stem cells are being targeted with the proposed studies, reviewers pointed out that the most stringent test for the presence of cancer stem cells, based on serial xenotransplantation, has not been performed.
- Nancy Parenteau