Targeting SEMA3C in Castration Resistant Prostate Cancer

这一更新应用程序建立在我们之前的研究主题的基础上，从机械上定义和治疗目标是驱动去势耐受前列腺癌(CRPC)进展的途径。CRPC归因于雄激素受体(AR)轴的重新激活以及应激激活的细胞保护性伴侣和生长因子信号通路。随着新的有效的AR途径抑制剂如MDV3100和阿比特龙(ABI)在CRPC中获得批准，对这些药物的耐药性的出现是下一个主要的临床挑战。最近，我们发现在CRPC和MDV3100复发后的肿瘤中，Semaphorin 3C(SEMA3C)信号通路被激活。SEMA3C是一种与肿瘤转移和化疗耐药相关的分泌型生长因子，我们发现它与PTEN缺失、聚集素过度表达以及AR蛋白水平和转录活性的调节有关。这些发现将SEMA3C与PTEN缺失和AKT&AR活性增加联系在一起，这是导致CRPC和MDVS100耐药的两个关键途径。SEMA3C在去势条件下提高了PCA细胞的存活率，我们开发了两种新型的SEMA3C抑制剂，可以延缓CRPC的进展。我们的总体目标是确定SEMA3C在促进对去势和MDVS100疗法的抵抗方面的机制，并开发临床前机制和抗癌活性数据，以支持一种新型SEMA3C抑制剂在CRPC中的首次临床试验。目的1在LNCaP或LUCaP35CR模型中，分别确定SEMA3C信号通路在CRPC和MDVS100或ABI治疗后的变化。目的2研究SEMA3C在MDVS100耐药中的作用，明确MDVS100敏感与耐药CRPC中SEMA3C信号与AR活性之间的相互作用。目的3将测试新的SEMA3C融合蛋白和反义抑制剂在CRPC临床前模型中的体内活性，A)单一治疗；B)联合I)MDVS100；II)多西紫杉醇；III)AR伴侣蛋白抑制剂HSP27(OGX-427)或HSP90(PF-04928473)。床边AIM 4的工作台将对患有慢性前列腺癌的男性患者进行SEMA3C胞体结构域(SD)Fc融合蛋白抑制剂的L/II期临床试验，并检查血清SEMA3C作为临床生物标志物的实用性。

This renewal application builds on themes of our previous studies mechanistically defining & therapeutically targeting pathways driving castration-resistant prostate cancer (CRPC) progression. CRPC is attributed to re-activation of the androgen-receptor (AR) axis along with stress-activated cytoprotective chaperone and growth factor signaling pathways. With new potent AR pathway inhibitors like MDV3100 and abiraterone (ABI) approved in CRPC, emergence of resistance to these agents represents the next major clinical challenge. Recently, we identified activation of the Semaphorin 3C (SEMA3C) signaling pathway in CRPC and post-MDV3100 recurrent tumors. SEMA3C is a secreted growth factor associated with cancer metastasis and chemoresistance that we found associated with PTEN loss, clusterin over-expression, and regulation of AR protein levels and transcriptional activity. These findings link SEMA3C with PTEN loss and increased AKT & AR activity, 2 key pathways driving CRPC and MDVS100 treatment resistance. SEMA3C enhances PCa cell survival under castrate conditions, and we have developed 2 novel SEMA3C inhibitors that delay CRPC progression. Our overall aim is to define mechanisms of SEMA3C in promoting resistance to castration and MDVS100 therapies, and to develop preclinical mechanistic and anti-cancer activity data to support a first-in-man clinical trial of a novel SEMA3C inhibitor in CRPC. Aim 1 will define changes in SEMA3C signaling pathway in CRPC and after treatment with MDVS100 or ABI in LNCaP or LUCaP35CR models, respectively. Aim 2 will characterize the functional role of SEMA3C on MDVS100 treatment resistance and define cross-talk between SEMA3C signaling and AR activity in MDVS100 sensitive vs. refractory CRPC. Aim 3 will test in vivo activity of novel SEMA3C fusion protein and antisense inhibitors in preclinical models of CRPC as A) monotherapy; and B) in combination with i) MDVS100; ii) docetaxel, and iii) inhibitors of AR chaperone proteins Hsp27 (OGX-427), or Hsp90 (PF-04928473). The bench to bedside Aim 4 will conduct a Phase l/II clinical trial of SEMA3C soma domain (SD) Fc fusion protein inhibitor in men with CRPC and examine the utility of serum SEMA3C as a clinical biomarker.