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)

基本信息

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
项目类别：
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

项目摘要

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.

我们将开发一种有前景的新型血管破坏剂（VDA）与增强肾癌治疗的领先疗法。肾细胞癌 (RCC) 通常具有以下特征通过 von Hippel Lindau (vHL) 肿瘤抑制蛋白的失活，促进缺氧的积累诱导因子（HIF）和随后广泛脉管系统的发展。正常的内皮细胞血管大部分处于静止状态，但肿瘤的侵袭性新血管系统不成熟，缺乏周细胞支持，并表现出增加的渗透性，为癌症治疗提供选择性靶点。治疗性的 VDA 的目标是对已建立的肿瘤脉管系统造成快速广泛的破坏，从而导致区域性缺血、缺氧诱导和肿瘤坏死。我们已将 OXi8007 确定为一种新型强效水溶性 VDA 前药产生持久的血管破坏、剂量依赖性肿瘤生长延迟并且没有明显的全身毒性。然而，VDA 单一疗法通常会导致肿瘤外围重新生长，并且 OXi8007 可能最有效地增强当前基于互补模式的先导疗法行动。我们将研究由 Peloton Therapeutics 开发的小分子 HIF-2 拮抗剂 PT2977，它代表了早期临床试验中的一类新型化疗药物。与此同时，卡博替尼（cabozantinib），一种小靶向 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肾细胞癌患者的一线治疗选择。我们还认识到正在取得的成功免疫疗法并预计 OXi8007 诱导的坏死将增强抗原呈递，促进回复。我们的首要假设是，结合这些治疗方法将实现稳健的长期治疗 RCC 的期限控制。调查将受益于 UT 西南肾癌 SPORE 的资源，该资源已开发了许多新的患者来源的肿瘤系，这些肿瘤系对 HIF-2 拮抗剂表现出不同的敏感性。有效的治疗组合可能取决于各自药物和非药物的给药时间。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) 将有效地检测免疫活性小鼠体内转染荧光素酶的 RENCA 细胞。在此外，最近可用的多光谱光声断层扫描（MSOT）可非侵入性地揭示血管程度和区域氧合，无需外源报告分子或细胞转染。基于细胞的补充研究旨在进一步探索 OXi8007 的作用机制。有效地结合靶向治疗应该可以增强肾癌患者的治疗并最终提高其生存率。这些研究的目的是证明有效的联合疗法作为基础对大型动物的研究并转化为临床。