Sensitivity of Abi1/Pten null tumors to taxane and anti-androgen receptor therapy

摘要 前列腺癌(PCa)是美国男性最常见的诊断癌症，也是导致癌症的第二大原因 美国男性癌症相关死亡。懒惰的局部PCa是可以治愈的，但转移性PCa是致命的。 进展到转移性疾病的特征是雄激素信号的重新激活，包括雄激素 受体(AR)功能。这一认识导致了抗雄激素途径治疗，这是治疗的支柱 进步性前列腺癌。不幸的是，患者最终会对抗雄激素治疗产生抵抗力， 后续以紫杉烷为基础的化疗的好处仅限于将患者的生存期延长至多一年。 仍然迫切需要确定新的可采取行动的目标。这个项目的长期目标是 为晚期前列腺癌的精准医学制定更好的治疗策略和合理的药物治疗。我们的 以往的研究表明，ABI1是一个真正的前列腺癌抑癌基因。ABI1下调监管 促进非规范WNT激活下游的上皮间质转化(EMT)- Fyn-STAT3途径。我们公布的和初步的数据表明，ABI1下调调控，与 PTEN缺失与人前列腺癌的高级别和转移性癌有关。 因为ABI1的表达在雄激素剥夺治疗后被下调，我们假设抗- AR处理导致WNT-FYN-STAT3通路激活。此外，紫杉烷疗法可能会促进 激活WNT通路，并可能在抗AR治疗中引起交叉通路效应。我们的 目的是更全面地了解ABI1和PTEN在肿瘤中的作用 雄激素受体(AR)靶向药物对去势和去势的当前治疗方案的敏感性 敏感(CSPC)和耐药(CRPC)的PCa，以及ABI1/PTEN通路本身的可药性。我们的 中心假说是ABI1缺陷肿瘤对抗AR药物的敏感性较低。此外，我们 提示ABI1基因缺陷的肿瘤对STAT3途径抑制剂敏感。我们建议ABI1是一个 目前治疗前列腺癌的候选肿瘤敏感性标记物。使用新型ABI1/Pten空鼠标和 我们将评估药物敏感性并表征肿瘤的反应，以寻找 治疗耐药靶点。我们的目标是：1)确定Abi1/Pten缺失肿瘤对AR抑制的敏感性 (使用苯扎鲁胺)或紫杉醇化疗(使用卡氮紫杉醇)；2) 检测ABI1/Pten缺失肿瘤对STAT3抑制的敏感性及其与AR抑制的协同作用 (苯扎鲁胺)或紫杉烷(卡巴紫杉醇)化疗。将通过以下方式分析肿瘤基因表达模式 RNA-Seq.已确定的药物反应途径将使用有机化合物和人类异种移植模型进行研究。 缺乏ABI1和PTEN基因的转移性前列腺癌。预期的结果是更好地理解ABI1和 PTEN参与晚期PCa的肿瘤敏感性，抑制STAT3的作用 在前列腺癌治疗中，并确定克服治疗耐药性的潜在靶点。

ABSTRACT Prostate cancer (PCa) is the most frequently diagnosed cancer in American men and the 2nd leading cause of male cancer-related deaths in the U.S. Indolent localized PCa is curable, but metastatic PCa is fatal. Progression to metastatic disease is characterized by reactivation of androgen signaling including androgen receptor (AR) function. This knowledge led to anti-androgen pathway therapy which is a mainstay for treatment of progressive PCa. Unfortunately, patients eventually become resistant to anti-androgen therapy and the benefit of subsequent taxane-based chemotherapy is limited to only extending patient survival for up to a year. An urgent need for identification of novel actionable targets remains. The long-term goal of this project is to develop better treatment strategies and rational drug therapies for precision medicine in advanced PCa. Our previous studies demonstrated ABI1 as a bona fide PCa tumor suppressor gene. ABI1 downregulation promotes epithelial mesenchymal transition (EMT) downstream from activation of the non-canonical WNT- FYN-STAT3 pathway. Our published and preliminary data indicate that ABI1 downregulation, in conjunction with loss of PTEN, is associated with high grade and metastatic PCa in a significant subset of human PCa. Because ABI1 expression is downregulated following androgen deprivation therapy, we hypothesize that anti- AR treatment leads to activation of the WNT-FYN-STAT3 pathway. Moreover, taxane therapies might promote activation of the WNT pathway and potentially cause cross-pathway effects with anti-AR treatment. Our objective is to develop a more comprehensive understanding of the contribution of ABI1 and PTEN on tumor sensitivity to the current treatment regimen of androgen receptor (AR)-targeting agents for both castrate- sensitive (CSPC) and resistant (CRPC) PCa, as well as druggability of the ABI1/PTEN pathway itself. Our central hypothesis is that ABI1-deficient tumors have a low sensitivity to anti-AR agents. In addition, we propose that ABI1-deficient tumors are sensitive to STAT3 pathway inhibitors. We propose that ABI1 is a candidate marker of tumor sensitivity for current treatments of PCa. Using the novel Abi1/Pten null mouse and organoid prostate models, we will assess drug sensitivity and characterize the tumor response in search for treatment resistance targets. We aim to: 1) Determine sensitivity of Abi1/Pten null tumors to AR inhibition (using enzalutamide) or taxane chemotherapy (using cabazitaxel) before and after androgen deprivation; 2) determine sensitivity of Abi1/Pten null tumors to STAT3 inhibition and synergy with AR inhibition (enzalutamide) or taxane (cabazitaxel) chemotherapy. Tumor gene expression patterns will be analyzed by RNA-Seq. Identified drug response-pathways will be studied using organoid and xenograft models of human metastatic PCa lacking ABI1 and PTEN genes. The expected outcome is a better understanding of ABI1 and PTEN involvement in tumor sensitivity to current therapeutics for advanced PCa, the role for STAT3 inhibition in PCa therapy, and identification of potential targets for overcoming treatment resistance.