Prostate cancer (PCa) represents 28% of all male cancers in the USA. While most prostate cancers are discovered at an early stage, there is still a significant number of patients who present with highly aggressive yet localized PCa. For high risk, non-metastatic PCa, surgery and radiation (RT), in combination with ADT (androgen deprivation therapy) remain the frontline therapies. However both local modalities may fail to eradicate this disease completely;and furthermore, advanced PCa may become radiation resistant. Currently, there are no validated biomarkers that successfully identify patients who wil benefit most from current therapy. Recently, an exploratory genome-wide linkage study from a large population-based case-control study showed that a tumor suppressor gene, DAB2IP, is linked with increased risk of aggressive PCa (1). Gain of function study showed that DAB2IP suppress the PI3K-Akt pathway and enhance ASK1 activation leading to apoptosis, whereas loss of DAB2IP expression resulted in the hyper activation of PI3K-Akt and inactivation of ASK1-JNK leading to accelerated PCa growth. Preclinical data suggests that loss of DAB2IP plays a significant role in prostate cancer cell survival following exposure to ionizing radiation due to enhanced double strand break (DSB) repair and resistance to apoptosis(2, 3). We recently performed a pilot study that demonstrates DAB2IP deficiency in patients portended a significantly worse Freedom From Biochemical Failure (FFBF) after definitive RT;these findings correlate with pre-clinical observations of radioresistance in DAB2IP-deficient PCa cell lines. The broad objective of this study is to identify patients at risk for treatment failure after conventional RT. We will explore whether DAB2IP deficiency as a novel prognostic biomarker indicative of poor outcomes after RT. The long term goal of this study is to develop effective treatments for the advanced stage prostate cancer patients. Therefore, this study will further investigate restoration of the DAB2IP pathway as a potential therapeutic intervention by use the of a small DAB2IP regulatory peptide to enhance the efficacy of RT.
The specific aims are:
Aim 1 : Correlation between DAB2IP levels and its targets (PI3-Akt, ASK1, AIP1, mTOR) with patient outcomes after RT.
This aim will be studied in high risk prostate cancer patients (stage e T3a, or Gleason score (GS) e 8, or PSA e 20) who were free of metastasis at the time of RT. Other potential markers for hypoxia, apoptosis, proliferation, DNA-DSB and vasculature will be analyzed from these samples by immunohistochemistry.
Aim 2 : Investigate the combined effect of RT with a novel DAB2IP peptide as a radiosensitizer. The major role of DAB2IP in prostate cells is regulating Akt activity and the PR domain of DAB2IP binds to Akt. Therefore, it is logical to test the efficacy of a peptide fragment (PPL) of this region. PPL will be conjugated with a cell permeable peptide (CPP) called R11 (11 Arginine) that possesses unique prostate tissue specificity. An orthotopic rat PCa model using DAB2IP-deficient PCa cell lines will be used and RT will be performed using image guidance to reduce normal tissue toxicity.
Despite remarkable progress in early detection and technology, prostate cancer (PCa) remains the most common type of cancer among U.S. men and only 40% of patients who suffer from aggressive PCa are disease free for five years after radiation therapy (RT) or surgery. This study will explore DAB2IP as a possible predictive marker for successful RT and develop novel therapeutic strategies for the treatment advanced stage PCa patients.