Vascular image-guided optimization of response (VIGOR) to therapy in kidney cancer

血管图像引导肾癌治疗反应优化 (VIGOR)

• 批准号: 10171568
• 负责人: RALPH P. MASON
• 金额: $ 47.4万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10171568
• 关键词: Acute; Animals; Antibodies; Antigen Presentation; Blood Vessels; CTLA4 gene; Cancer Patient; Cell Cycle Arrest; Cells; Clinic; Clinical Trials; Combined Modality Therapy; Complement; Development; Disputes; Disseminated Malignant Neoplasm; Dose; Drug Combinations; Endothelium; Exhibits; Foundations; Goals; Growth; Histology; Human; Hypoxia Inducible Factor; Immune checkpoint inhibitor; Immune response; Immunocompetent; Immunotherapy; Infiltration; Investigation; Ischemia; KDR gene; Kidney Neoplasms; Lead; Luciferases; Metastatic Renal Cell Cancer; Modeling; Mus; Necrosis; Patients; Pericytes; Permeability; Pharmacodynamics; Prodrugs; Refractory; Renal Cell Carcinoma; Renal carcinoma; Reporter; Reporting; Resistance; Resources; Structure; Therapeutic; Thymidine Kinase; Toxic effect; Transfection; Translations; Treatment Efficacy; Tumor-Associated Vasculature; Tumor-Derived; Tyrosine Kinase Inhibitor; Up-Regulation; Vascular Permeabilities; Von Hippel-Lindau Tumor Suppressor Protein; Water; anti-CTLA4; anti-PD-1; bHLH-PAS factor HLF; base; bioluminescence imaging; cancer therapy; chemotherapy; cohort; design; early phase clinical trial; effective therapy; image guided; immune activation; immunoreactivity; improved; in vivo; innovation; kinase inhibitor; light emission; macrophage; neovasculature; non-invasive imaging; novel; optoacoustic tomography; patient derived xenograft model; pharmacokinetics and pharmacodynamics; receptor; response; small molecule; success; survivorship; systemic toxicity; targeted cancer therapy; targeted treatment; therapeutic target; therapy resistant; tumor; tumor growth; tumor hypoxia; tumor xenograft

We will develop the application of a promising novel vascular disrupting agent (VDA) in combination with leading therapies to enhance treatment of kidney cancer. Renal cell carcinoma (RCC) is usually characterized by inactivation of the von Hippel Lindau (vHL) tumor suppressor protein, promoting accumulation of Hypoxia Inducible Factor (HIF) and consequent development of extensive vasculature. The endothelium of normal blood vessels is largely quiescent, but the invasive neovasculature of tumors is immature, lacks pericyte support, and exhibits increased permeability providing a selective target for cancer therapy. The therapeutic goal of VDAs is to cause rapid widespread disruption of established tumor vasculature leading to regional ischemia, induction of hypoxia and tumor necrosis. We have identified OXi8007 as a new potent, water-soluble VDA prodrug generating protracted vascular disruption, dose dependent tumor growth delay and no apparent systemic toxicity. However, VDA monotherapy generally results in re-growth at the tumor periphery and OXi8007 will likely be most effective in augmenting current lead therapies based on complementary modes of action. We will investigate a small-molecule HIF-2 antagonist, PT2977 developed by Peloton Therapeutics, which represents a new class of chemotherapeutic in early clinical trials. Meanwhile, cabozantinib, the small- molecule kinase inhibitor that targets the c-MET receptor, AXL, and VEGFR-2 was recently approved as a first line treatment option for patients with metastatic RCC. We also recognize the emerging success of immunotherapy and anticipate that OXi8007-induced necrosis will enhance antigen presentation promoting response. Our overarching hypothesis is that combining these therapeutic approaches will achieve robust long term control of RCC. Investigations will benefit from the resources of the UT Southwestern Kidney Cancer SPORE, which has developed a number of new patient derived tumor lines exhibiting differential sensitivity to HIF-2 antagonists. Effective therapy combination will likely depend on timing of administration of the respective agents and non- invasive imaging will reveal the spatial and temporal pharmacodynamics of tumor response. Bioluminescence imaging (BLI) will effectively interrogate luciferase-transfected RENCA cells in immunocompetent mice. In addition, recently available multispectral optoacoustic tomography (MSOT) non-invasively reveals vascular extent and regional oxygenation without the need for exogenous reporter molecules or cell transfection. Complementary cell-based studies are designed to further explore OXi8007 mechanism of action. Effectively combining targeted therapies should enhance treatment and ultimately survivorship of kidney cancer patients. The goal of these investigations is to demonstrate effective combination therapy as a foundation for investigations in large animals and translation to the clinic.

我们将开发出有希望的新型血管破坏剂（VDA）的应用 领先的疗法可以增强肾癌的治疗。通常表征肾细胞癌（RCC） 通过失活的von Hippel lindau（VHL）抑制蛋白，促进缺氧的积累 诱导因子（HIF）以及随之而来的广泛脉管系统的发展。正常的内皮 血管在很大程度上是静止的，但是肿瘤的侵入性神经系统不成熟，缺乏周细胞 支持，并且表现出提高的渗透性，为癌症治疗提供了选择性的靶标。治疗性 VDA的目标是导致已建立的肿瘤脉管系统的快速破坏导致区域 缺血，诱导缺氧和肿瘤坏死。我们已经确定Oxi8007是一种新的有效的水溶性 VDA前药产生长期的血管破坏，依赖剂量的肿瘤生长延迟，没有明显的 全身毒性。但是，VDA单一疗法通常会导致肿瘤周围的重新生长 OXI8007可能最有效地基于互补模式来增强当前的铅疗法 行动。我们将研究由Peloton Therapeutics开发的小分子HIF-2拮抗剂PT2977， 在早期临床试验中代表了一类新的化学治疗性。同时，小卡博桑蒂尼（Cabozantinib） 靶向C-MET受体，AXL和VEGFR-2的分子激酶抑制剂最近被批准为第一个 转移性RCC患者的线路治疗选择。我们也认识到 免疫疗法，并预计Oxi8007诱导的坏死将增强抗原表现促进 回复。我们的总体假设是将这些治疗方法结合起来将实现强大的长期 RCC的术语控制。 调查将受益于UT西南肾癌孢子的资源 开发了许多新的患者衍生的肿瘤系，对HIF-2拮抗剂表现出差异敏感性。 有效的治疗组合可能取决于相应药物的给药时间和非 - 侵入性成像将揭示肿瘤反应的空间和时间药效学。生物发光 成像（BLI）将有效询问免疫能力小鼠中的荧光素酶转染的Renca细胞。在 加法，最近可用的多光谱光声断层扫描（MSOT）非侵入性揭示血管 不需要外源报告分子或细胞转染的程度和区域氧合。 基于互补的细胞研究旨在进一步探索OXI8007作用机理。有效地 结合靶向疗法应增强肾癌患者的治疗并最终生存。 这些调查的目的是证明有效的组合疗法作为基础 对大型动物进行调查并转化为诊所。