Targeting SEMA3C in Castration Resistant Prostate Cancer

项目总结（见说明）： 这项更新申请建立在我们以前研究的主题之上，这些研究机械地定义和治疗靶向驱动去势抵抗性前列腺癌（CRPC）进展的途径。CRPC归因于雄激素受体（AR）轴沿着与应激激活的细胞保护性伴侣和生长因子信号传导途径的再激活。随着新的强效AR通路抑制剂如MDV 3100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代表了下一个主要的临床挑战。最近，我们确定了CRPC和MDV 3100后复发肿瘤中Semaphorin 30（SEMA 3C）信号通路的激活。SEMA 3C是一种与癌症转移和化疗耐药性相关的分泌性生长因子，我们发现其与PTEN丢失、丛生蛋白过表达以及AR蛋白水平和转录活性的调节相关。这些发现将SEMA 3C与PTEN丢失和增加的AKT & AR活性联系起来，这是驱动CRPC和MDV 3100治疗抗性的2个关键途径。SEMA 3C增强去势条件下的PCa细胞存活，我们已经开发了2种新型SEMA 3C抑制剂，可延迟CRPC进展。我们的总体目标是确定SEMA 3C促进去势和MDV 3100治疗耐药性的机制，并开发临床前机制和抗癌活性数据，以支持CRPC中新型SEMA 3C抑制剂的首次人体临床试验。目的1将定义CRPC中以及LNCaP或LUCaP 35 CR模型中MDV 3100或ABI处理后SEMA 3C信号通路的变化。目的2将描述SEMA 3C在MDV 3100治疗耐药性中的功能作用，并确定MDV 3100敏感性与难治性CRPC中SEMA 3C信号传导与AR活性之间的相互作用。目的3将在CRPC临床前模型中检测新型SEMA 3 C融合蛋白和反义抑制剂作为A）单药治疗;和B）与i）MDV 3100; ii）多西他赛和iii）AR伴侣蛋白Hsp 27（OGX-427）或Hsp 90（PF-04928473）抑制剂联合治疗的体内活性。床旁目标4的工作台将在患有CRPC的男性中进行SEMA 3C sema结构域（SD）Fc融合蛋白抑制剂的I/II期临床试验，并检查血清SEMA 3C作为临床生物标志物的效用。

PROJECT SUMMARY (See instructions): 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 reactivation 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 30 (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 MDV3100 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 MDV3100 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 MDV3100 or ABI in LNCaP or LUCaP35CR models, respectively. Aim 2 will characterize the functional role of SEMA3C on MDV3100 treatment resistance and define cross-talk between SEMA3C signaling and AR activity in MDV3100 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) MDV3100; 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/ll clinical trial of SEMA3C sema domain (SD) Fc fusion protein inhibitor in men with CRPC and examine the utility of serum SEMA3C as a clinical biomarker.