Profilin as a Novel Target for Vascular Normalization in Renal Cancer

项目摘要摘要 据估计，2021年肾细胞癌(RCC)将导致76,080例新病例和13,780例死亡。清除单元格 肾细胞癌(CcRCC)是肾细胞癌最常见的亚型(75%的肾细胞癌患者)。 以高度血管化的肿瘤微环境(TME)为特征。抗血管生成和血管生成 正常化(VN)诱导疗法最初是有效的，几乎所有患者都会对这些疗法产生抵抗力。 治疗。因此，有必要确定治疗慢性肾细胞癌的替代基础疗法。我们的实验室和 另一些研究表明，肌动蛋白细胞骨架在血管内皮细胞的调节中起着关键作用。 (VEC)在血管生成和屏障功能中的作用。此外，已经证明Profilin1(PFN1)是一种 肌动蛋白驱动的过程的重要调节因子，如细胞迁移和增殖(包括在血管内皮细胞中， 影响血管生成潜能)。PFN1在人肾细胞癌中高表达，在人肾细胞癌中高表达 一直与不良的临床结果和先进的疾病特征有关。这项研究的目标是进一步 Pfn1‘S通过调节肿瘤--在调节肾细胞癌进展中的基础作用 促进血管形成，而PFN1可作为肾癌的治疗靶点。我们的初步数据 结果表明，高表达的PFN1主要存在于肿瘤相关的血管内皮细胞(TAEC)。我们进一步 证明通过体内基因缺失或通过小分子抑制剂抑制PFN1而丢失PFN1 减少各种病理环境(包括视网膜和肾脏)中的异常血管形成，并减弱 肾细胞癌在体内的进展。这项提案的目标1试图检验一种假设，即内皮细胞PFN1促进亲- 致瘤性TME在ccRCC中驱动肿瘤进展，并可通过肿瘤局部递送减少 新型pfn1-肌动蛋白相互作用小分子拮抗剂。这项提案的目标2将检验一个假设，即PFN1 通过增强线粒体功能来调节血管内皮细胞的内在血管生成能力。AIM 3测试a 假设血管内皮细胞分泌的PFN1作为旁分泌信号媒介促进ccRCC的侵袭性。 目标1和目标2将主要在K99指导阶段进行，在此期间我将继续我的培训 启用对比的超声波、免疫和线粒体生物学。这些培训将在我的 在R00阶段过渡到独立，在该阶段将执行目标3和目标2的其余部分。

Project Summary Abstract Renal cell carcinoma (RCC) is estimated to result in 76,080 new cases and 13,780 deaths in 2021. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC (>75% of RCC patients) and is characterized by a high vascularized tumor microenvironment (TME). Anti- angiogenic and vascular normalization (VN) inducing therapies are initially effective, almost all patients develop resistance to these therapies. Therefore, there is a need to identify alternative fundamental therapies for ccRCC. Our lab and others have demonstrated that actin cytoskeleton plays a key role in regulation of vascular endothelial cell (VEC) in angiogenesis and barrier function. Furthermore, it has been demonstrated that Profilin1 (Pfn1) is an important regulator of actin-driven processes such as cell migration and proliferation (including in VEC, affecting angiogenic potential). Pfn1 is also overexpressed in human ccRCC and higher expression of Pfn1 has been linked to poor clinical outcome and advanced disease features. The goal of this study is to further demonstrate Pfn1’s fundamental role in regulation of progression of ccRCC through modulation of tumor- promoted vascularization and that Pfn1 serves as a therapeutic target for RCC. Our preliminary data demonstrates that overexpressed Pfn1 is primarily found in tumor-associated VEC (TAEC). We further demonstrate that loss of Pfn1 by genetic deletion in vivo or inhibition of Pfn1 by small molecule inhibitor reduces aberrant vascularization in various pathological settings (including retina and kidney) and attenuates RCC progression in vivo. Aim 1 of this proposal seeks to test a postulate that endothelial Pfn1 promotes a pro- tumorigenic TME driving tumor progression in ccRCC and can be diminished by tumor-localized delivery of novel small molecule antagonist of Pfn1-actin interaction. Aim 2 of this proposal will test a postulate that Pfn1 regulates the intrinsic angiogenic capability of VEC through augmenting mitochondrial function. Aim 3 tests a postulate that VEC-secreted Pfn1 acts as a paracrine signaling mediator to promote ccRCC aggressiveness. Aims 1 and 2 will mostly be performed in the K99 mentored stage, during which I will continue my training in contrast-enabled ultrasound, immuno-, and mitochondrial biology. These trainings will be pivotal in my transition to independence in the R00 stage where Aim 3 and the rest of Aim 2 will be executed.