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但局限性的PCa。对于高风险、非转移性PCa，手术和放疗（RT）联合ADT（雄激素剥夺治疗）仍然是一线治疗。然而，这两种局部方法可能无法完全根除这种疾病;此外，晚期PCa可能会产生辐射抗性。目前，还没有经过验证的生物标志物可以成功识别从当前治疗中获益最多的患者。最近，一项来自大规模人群病例对照研究的探索性全基因组连锁研究显示，肿瘤抑制基因DAB 2 IP与侵袭性PCa风险增加有关（1）。功能获得研究表明，DAB 2 IP抑制PI 3 K-Akt通路并增强ASK 1活化，导致细胞凋亡，而DAB 2 IP表达的缺失导致PI 3 K-Akt的过度活化和ASK 1-JNK的失活，导致PCa生长加速。临床前数据表明，由于增强的双链断裂（DSB）修复和对细胞凋亡的抗性，DAB 2 IP的丢失在暴露于电离辐射后的前列腺癌细胞存活中起重要作用（2，3）。我们最近进行了一项初步研究，表明患者中DAB 2 IP缺乏预示着明确的RT后无生化失败（FFBF）的情况明显更糟;这些发现与DAB 2 IP缺乏PCa细胞系中放射抗性的临床前观察结果相关。本研究的主要目的是确定常规RT后治疗失败的风险患者。我们将探讨是否DAB 2 IP缺陷作为一种新的预后生物标志物，表明RT后不良结局。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，本研究将通过使用小的DAB 2 IP调节肽来增强RT的功效，进一步研究DAB 2 IP通路的恢复作为潜在的治疗干预。具体目的是：DAB 2 IP水平与其靶点之间的相关性（PI 3-Akt，ASK 1，AIP 1，mTOR）与RT后患者结局的关系。在RT时无转移的患者（eT 3a期，或Gleason评分（GS）e8，或PSA e20）。通过免疫组织化学从这些样品分析缺氧、凋亡、增殖、DNA-DSB和脉管系统的其他潜在标志物。目的2：研究RT与新型DAB 2 IP肽作为放射增敏剂的联合作用。DAB 2 IP在前列腺细胞中的主要作用是调节Akt活性，并且DAB 2 IP的PR结构域与Akt结合。因此， 以测试该区域的肽片段（PPL）的功效。PPL将与细胞结合 R11（11精氨酸）是一种具有独特前列腺组织特异性的渗透性肽（CPP）。将使用使用DAB 2 IP缺陷型PCa细胞系的原位大鼠PCa模型，并将使用图像引导进行RT以降低正常组织毒性。

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.