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.

项目概要 摘要 肾细胞癌 (RCC) 预计到 2021 年将导致 76,080 例新发病例和 13,780 例死亡。透明细胞 肾细胞癌 (ccRCC) 是最常见的 RCC 亚型（>75% 的 RCC 患者），并且 其特点是高度血管化的肿瘤微环境（TME）。抗血管生成和血管 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耐药性 疗法。因此，需要寻找 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，已证明Profilin1 (Pfn1) 是一种 肌动蛋白驱动过程的重要调节因子，如细胞迁移和增殖（包括 VEC、 影响血管生成潜力）。 Pfn1 在人类 ccRCC 中也过表达，并且 Pfn1 的表达更高 与不良的临床结果和晚期疾病特征有关。本研究的目的是进一步 证明 Pfn1 通过调节肿瘤-在调节 ccRCC 进展中的基本作用 促进血管化，Pfn1 可作为 RCC 的治疗靶点。我们的初步数据 表明过表达的 Pfn1 主要存在于肿瘤相关 VEC (TAEC) 中。我们进一步 证明体内基因缺失导致 Pfn1 丢失或小分子抑制剂抑制 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 RCC 体内进展。该提案的目标 1 旨在测试内皮 Pfn1 促进亲- 致瘤性 TME 驱动 ccRCC 肿瘤进展，并且可以通过肿瘤局部递送来减少 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 将测试以下假设：Pfn1 通过增强线粒体功能来调节 VEC 的内在血管生成能力。目标 3 测试 假设 VEC 分泌的 Pfn1 作为旁分泌信号传导介质来促进 ccRCC 的侵袭性。 目标1和2将主要在K99指导阶段进行，在此期间我将继续我的训练 对比超声、免疫和线粒体生物学。这些培训对我的人生至关重要 在 R00 阶段过渡到独立，其中将执行目标 3 和目标 2 的其余部分。