Mechanisms and Treatment of PTEN Mutant Prostate Tumorigenesis PTEN is a tumor suppressor that is among the most frequently lost or mutated genes of human cancer. More than half of the 220,000 men diagnosed with prostate cancer in the United States each year will likely exhibit alterations of PTEN at the gene or protein level. PTEN is unique in its reversal of PI 3-Kinase activity, which promotes cell survival and proliferation, a signaling pathway which is deregulated in a majority of human prostate, breast and brain cancers. My research is combining mouse modeling with genetic analysis of human cancer to understand the molecular mechanism of prostate cancer. Previously, I demonstrated that haploinsufficiency of PTEN can lead directly to prostate cancer without an obligatory """"""""second-hit"""""""" in the PTEN gene. Moreover haploinsufficiency of additional tumor suppressor genes such as PML can cooperate with partial PTEN-loss to form cancer. We have further shown that in normal prostate cells, complete loss of PTEN prevents tumorigenesis by triggering cellular senescence, an irreversible cell growth arrest. Together, these findings provide the first evidence of why haploinsufficiency of a major tumor suppressor can be favored over complete loss in tumors. Since the senescence response is entirely dependent on intact p53 function, these insights led to a conceptual breakthrough in the mechanism of interaction between these two major tumor suppressors. Now, we are using a cross-species oncogenomics approach as our collaborators at Memorial Sloan Kettering Cancer Center are generating comprehensive libraries of molecular alterations in over 200 patient samples. Through this effort, we are now uncovering the causal link between loss of PTEN and novel genes in metastatic prostate cancer.
Our aims are: (1) to use comprehensive analysis of primary and metastatic human prostate cancer to identify tumor suppressors in the PI 3-Kinase pathway that cooperate with PTEN-alteration and to then explore their mechanisms of action in vitro and in vivo. Our preliminary work has already successfully identified a novel PTEN-cooperating tumor suppressor of metastatic prostate cancer. (2) to determine when, in which genetic context, and how Pten-restoration can revert established tumors using our newly developed in vivo inducible RNA-interference technology. Our primary objective is to determine if tumors with Pten-loss alone or when combined with the newly identified tumor suppressor from Aim 1 still respond to Pten restoration (addiction), or if they become pathway independent due to additional spontaneous genomic alterations. We monitor recurrent alterations through genome-wide copy number analysis to identify the potential escape routes. This research thus will lay the groundwork for therapeutic decisions in advanced prostate cancer by identifying a potential signature that is associated with PI 3-Kinase inhibitor sensitivity or resistance.

Public Health Relevance

Mechanisms and Treatment of PTEN Mutant Prostate Tumorigenesis The PTEN tumor suppressor is frequently affected in human cancer and our recent findings have unraveled an unexpected mechanism for tumor initiation and progression in this event. We are now investigating novel components of this prostate cancer pathway and explore how our insights can be translated into therapy. Relevance The function of the PTEN tumor suppressor is compromised in a majority of human cancer malignancies. We are just beginning to understand how cells and tissues react to this insult since it is becoming clear that PTEN is haploinsufficient and that complete loss triggers cellular senescence. These findings have led us to explore the human cancer genome and to a process for identification of novel genes that cause metastatic prostate cancer. By identifying how haploinsufficiency and senescence shape PTEN-mutant lethal prostate cancer we will better understand the principles that underlie much of this disease and create new therapeutic approaches.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cancer Genetics Study Section (CG)
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Jhappan, Chamelli
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Cold Spring Harbor Laboratory
Cold Spring Harbor
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