Carcinogenesis in the Mouse Prostate

Research in First Pay Period

We developed transgenic mice to produce human prostate cancer. In these mice we have shown that mutations to the Pten locus leading to the loss of expression of the Pten protein plays a central role in the initiation of prostate cancer. The loss of other genes -- such as p27, PML, TSC2, and p53 -- were determined to be involved in cancer progression, but their absence was not sufficient to initiate the cancer growth. Further research is needed to increase our understanding of the molecular changes involved in prostate cancer initiation and progression. Results of our preliminary studies have been encouraging, raising new questions and suggesting new therapeutic strategies.

[Enlarge Image] New players in the pathogenesis of CaP

Prostate Cancer Pathogenesis

Our clinicopathological analysis of human prostate cancer has pointed to novel genes and proteins of potential importance in the pathogenesis of prostate cancer, which now need to be studied in the mouse. Reciprocally, our modeling efforts in the mouse have indicated new players and pathways for analysis in human prostate cancer. In 2001, when the SPORE was originally funded, we proposed to focus on PTEN, p53 and Rb as these were the genes known to be potentially important at that time. The list has now grown to no less than 14 genes/proteins that we are actively investigating. We are systematically determining the status of these genes and proteins in prostate cancer progression. In addition, our current studies will focus on the genetic determinants of metastatic prostate cancer.

Aims of Current Study

1. Use genetically engineered mice to pioneer a possible preclinical strategy that is not yet feasible with specific pharmacologic agents.
2. Follow-up on our recent paper showing the importance of cellular senescence as a barrier for tumorigenesis and will test whether pharmacologic potentiation of the p53 dependent senescence response can prevent the development of cancers initiated by loss of Pten.
3. Use novel strategies to identify genes that are specifically involved in prostate cancer metastasis, recognizing that human patients typically die from consequences of metastatic disease.

In summary, over the next five years, we propose to explore important new areas with immediate clinical relevance for cancer therapeutics, cancer prevention, and for prevention of metastasis.

Project Leaders

• Principle Investigator
  Pier Paolo Pandolfi, MD, PhD

Collaborators

• Brett Carver, MD
• David Shaffer, MD, PhD
• Zhenbang Chen, PhD