Profilin as a Novel Target for Vascular Normalization in Renal Cancer

Profilin 作为肾癌血管正常化的新靶点

• 批准号: 10525305
• 负责人: David Martin Gau
• 金额: $ 12.6万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525305
• 关键词: Actin-Binding Protein; Actins; Affect; Agonist; Attenuated; Automobile Driving; Autophagocytosis; Bioenergetics; Biological Process; Biology; Blood Vessels; Cell Proliferation; Cells; Cessation of life; Clear cell renal cell carcinoma; Clinical; Cytoskeleton; Data; Disease; Endothelium; Genes; Genetic; Glycolysis; Goals; Growth; Human; Hypoxia; Immunologics; In Vitro; Kidney; Lead; Link; Malignant Epithelial Cell; Mediating; Mediator of activation protein; Mentors; Microvascular Permeability; Mitochondria; Molecular Target; Neoplasms in Vascular Tissue; Outcome; Paracrine Communication; Pathologic; Patients; Perfusion; Permeability; Pharmaceutical Preparations; Phenotype; Physiological; Play; Process; Refractory Disease; Regulation; Renal Cell Carcinoma; Renal carcinoma; Resistance; Resistance development; Respiration; Rest; Retina; Role; Signal Transduction; Testing; Therapeutic; Training; Tumor Cell Migration; Vaccines; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascularization; advanced disease; angiogenesis; antagonist; base; cell motility; extracellular; improved; in vivo; neoplastic cell; normoxia; novel; overexpression; paracrine; patient prognosis; polymerization; profilin; receptor; small molecule; small molecule inhibitor; targeted treatment; therapeutic target; therapy outcome; therapy resistant; treatment strategy; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenic; ultrasound; virtual

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.

项目摘要摘要 估计肾细胞癌（RCC）在2021年导致76,080例新病例和13,780例死亡。 肾细胞癌（CCRCC）是RCC最常见的亚型（> 75％的RCC患者），IS 以高血管化肿瘤微环境（TME）为特征。抗血管生成和血管 归一化（VN）诱导的疗法最初是有效的，几乎所有患者都会对这些疗法产生抗药性 疗法。因此，有必要确定CCRCC的替代基本疗法。我们的实验室和 其他人已经证明肌动蛋白细胞骨架在调节血管内皮细胞中起关键作用 （VEC）血管生成和屏障功能。此外，已经证明Profilin1（PFN1）是 肌动蛋白驱动过程的重要调节剂，例如细胞迁移和增殖（包括在VEC中， 影响血管生成潜力）。 PFN1在人CCRC中也过表达PFN1的较高表达 与临床结局不良和晚期疾病特征有关。这项研究的目的是进一步 通过调节肿瘤的调节，证明了PFN1在调节CCRC的进展中的基本作用 促进血管形成，PFN1是RCC的治疗靶标。我们的初步数据 证明过表达的PFN1主要在肿瘤相关的VEC（TAEC）中发现。我们进一步 证明通过体内遗传缺失或小分子抑制剂对PFN1的遗传缺失的损失 在各种病理环境（包括视网膜和肾脏）中减少异常血管化并减轻 RCC在体内进展。该提案的目标1试图测试一个假定内皮PFN1促进促进的假设 肿瘤性TME在CCRCC中驱动肿瘤进展，可以通过肿瘤定位的递送来减少 PFN1-肌动蛋白相互作用的新型小分子拮抗剂。该提案的目标2将测试PFN1的假设 通过增强线粒体功能来调节VEC的内在血管生成能力。 AIM 3测试A 假设将VEC分泌的PFN1充当旁分泌信号介质，以促进CCRCC侵略性。 目标1和2主要是在K99 Mendored阶段进行的，在此期间我将继续进行培训 启用对比度的超声，免疫和线粒体生物学。这些培训将是我的关键 将在R00阶段过渡到AIM 3和AIM 2的其余部分的R00阶段。