Role of DAB2IP in Prostate Cancer Patients Treated with Radiation Therapy

描述（由申请人提供）：前列腺癌（PCa）占美国所有男性癌症的28%。虽然大多数前列腺癌是在早期发现的，但仍有相当数量的患者表现为高度侵袭性的局部前列腺癌。对于高风险，非转移性PCa，手术和放疗（RT）联合ADT（雄激素剥夺疗法）仍然是一线治疗方法。然而，两种局部方式都可能无法完全根除这种疾病；此外，晚期前列腺癌可能具有抗辐射性。目前，还没有经过验证的生物标志物能够成功地识别出哪些患者将从目前的治疗中获益最多。最近，一项基于大型人群病例对照研究的探索性全基因组连锁研究表明，肿瘤抑制基因DAB2IP与侵袭性PCa风险增加有关(1)。功能增益研究表明，DAB2IP抑制PI3K-Akt通路，增强ASK1激活导致凋亡，而DAB2IP表达缺失导致PI3K-Akt超激活，ASK1- jnk失活，导致PCa生长加速。临床前数据表明，由于双链断裂（DSB）修复增强和对凋亡的抵抗，DAB2IP的缺失在电离辐射暴露后的前列腺癌细胞存活中起着重要作用（2,3）。我们最近进行了一项试点研究，表明患者DAB2IP缺乏预示着最终RT后生化失败自由（FFBF）明显恶化；这些发现与临床前观察到的缺乏dab2ip的PCa细胞系的放射耐药相关。本研究的主要目的是确定常规放疗后存在治疗失败风险的患者。我们将探讨DAB2IP缺乏是否可以作为一种新的预后生物标志物，表明放疗后预后不良。本研究的长期目标是为晚期前列腺癌患者开发有效的治疗方法。因此，本研究将进一步探讨恢复DAB2IP通路作为一种潜在的治疗干预手段，利用小的DAB2IP调节肽来增强rt的疗效。DAB2IP水平及其靶点（PI3-Akt, ASK1, AIP1, mTOR）与rt后患者预后的相关性。该目的将在rt时无转移的高危前列腺癌患者（分期T3a，或Gleason评分（GS） e8，或PSA e20）中进行研究。其他潜在的缺氧，细胞凋亡，增殖，DNA-DSB和血管系统的标志物将通过免疫组织化学分析这些样本。目的2：探讨RT与新型DAB2IP肽作为放射增敏剂的联合作用。DAB2IP在前列腺细胞中的主要作用是调节Akt活性，并且其PR结构域与Akt结合。因此，这是合乎逻辑的

DESCRIPTION (provided by applicant): 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.