Progress from our group and others has led to the identification of normal prostate tissue stem cells and the definition of important signaling pathways that regulate their growth and maintenance. Human cancers utilize these same pathways to promote malignancy and drive tumor progression. Our recent studies have uncovered an important regulatory molecule (Trop2) that is expressed on a subset of prostate cancer cells capable of regenerating tumors. Trop2 expression is selected for in advanced disease and predicts poor prognosis for many tumors including prostate, ovarian, pancreatic, breast, gastric and colorectal cancer. We predict that blocking Trop2 and other regulatory signaling pathways will be an effective strategy to prevent disease progression in prostate and other human cancers.
In 2012 alone in the state of California, an estimated 29,000 men will be diagnosed with prostate cancer and almost 3,400 men will die from the disease. The advanced stages of prostate cancer are treated with hormonal therapy which causes significant changes in mood, body weight and composition, impotence and gynecomastia in addition to the pain and suffering from the disease. Our proposed experiments will define new therapeutic targets and combinatorial therapies with the potential to significantly extend life and minimize suffering of men with advanced prostate cancer. Many of the molecules that we are investigating are implicated in a range of tumors, suggesting that our findings may provide benefit to patients suffering from numerous cancers.
This goal of this proposal is to examine the mechanism and functional role an important regulatory molecule, Trop2, in prostate cancer stem cells (CSCs) and to develop possible therapeutic strategies for blocking Trop2 function. Trop2 expression on prostate cancer cells is indicative of advanced disease and a poor prognosis. The first specific aim is to define the functional role of Trop2 and develop approaches to block its function in prostate cancer. The second aim is to investigate relationships between Trop2 and a key signaling pathway in human prostate CSCs. The third specific aim is to explore strategies for combinatorial targeting of Trop2 and other cellular processes that contribute to prostate CSC proliferation.
Significance and Innovation
- Reviewers agreed that focusing on detailed molecular mechanisms by which Trop2 contributes to self-renewal of cancer stem cells (CSC) is an innovative and promising approach.
- Proposed work could add to the fundamental knowledge about human prostate cancer.
- If proposed research is successful, the results may lead to novel strategies for targeting prostate cancer.
Feasibility and Experimental Design
- Experiments are presented logically and are well designed to be achievable within the three-year timeline.
- Reviewers recognized the strong the preliminary and published data and appreciated that the key experimental system for generation of human prostate cancers in immune-deficient mice was developed by the PI's team.
- The proposed study of the regenerative prostate tumors is feasible given the experience of the investigative team.
- One reviewer pointed out the difficulty of isolating prostate CSC and expressed concern about whether the models of prostate cancer the PI has selected recapitulate completely the biology of primary human tumors.
Principal Investigator (PI) and Research Team
- The PI is a major leader in the study of prostate cancer stem cells.
- The PI and research team are exceptionally strong with extensive experience and appropriate expertise.
Responsiveness to the RFA
- Reviewers agreed the project is responsive to the RFA by focusing on basic molecular mechanisms in cancer, specifically addressing mechanisms of self-renewal in prostate CSCs.