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: 10646312
• 负责人: RALPH P. MASON
• 金额: $ 48.08万
• 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/10646312
• 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; Hypoxia Inducible Factor; Immune checkpoint inhibitor; Immune response; Immunocompetent; Immunologic Stimulation; Immunotherapy; Infiltration; Investigation; Ischemia; KDR gene; Kidney Neoplasms; Lead; Luciferases; Macrophage; Metastatic Renal Cell Cancer; Modeling; Mus; Necrosis; Necrosis Induction; Patients; Pericytes; Permeability; Pharmacodynamics; Prodrugs; Refractory; Renal Cell Carcinoma; Renal carcinoma; Reporter; Reporting; Resistance; Resources; Therapeutic; Thymidine Kinase; Toxic effect; Transfection; Translations; Treatment Efficacy; Tumor-Associated Vasculature; Tyrosine Kinase Inhibitor; Up-Regulation; Vascular Permeabilities; Von Hippel-Lindau Tumor Suppressor Protein; Water; antagonist; anti-CTLA4; anti-PD-1; bHLH-PAS factor HLF; bioluminescence imaging; cancer therapy; chemotherapy; cohort; design; early phase clinical trial; effective therapy; image guided; immune activation; immunoreactivity; improved; in vivo; innovation; invention; kinase inhibitor; light emission; 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; treatment response; tumor; tumor growth; 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.

我们将开发一种有前途的新型血管阻断剂（VDA）与 领导疗法以增强肾癌的治疗。肾细胞癌（RCC）通常以 通过灭活von Hippel Lindau（vHL）肿瘤抑制蛋白，促进缺氧累积 诱导因子（HIF）和随之而来的发展广泛的脉管系统。正常人的内皮细胞 血管基本上是静止的，但肿瘤的侵袭性新生血管是不成熟的，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 VDA的目标是引起已建立的肿瘤血管系统的快速广泛破坏，导致局部 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前药产生延长的血管破坏，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单一疗法通常导致肿瘤外周的再生长， OXi8007可能是最有效的，在增强目前的电极导线治疗的基础上的互补模式， 行动上我们将研究由Peloton Therapeutics开发的小分子HIF-2拮抗剂PT 2977， 其代表了早期临床试验中的一类新的化疗药物。与此同时，卡博替尼，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RCC患者的一线治疗选择。我们还认识到， 预期OXi8007诱导坏死将增强抗原呈递促进 反应我们的总体假设是，结合这些治疗方法将实现强大的长期 RCC的长期控制。 调查将受益于UT西南肾癌孢子的资源， 开发了许多对HIF-2拮抗剂表现出不同敏感性的新的患者来源的肿瘤系。 有效的治疗组合将可能取决于各药剂的施用时机和非施用时机。 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）将有效地询问免疫活性小鼠中的经酶转染的RENCA细胞。在 此外，最近可用的多光谱光声断层扫描（MSOT）非侵入性地揭示了血管 范围和区域氧合，而不需要外源报告分子或细胞转染。 补充的基于细胞的研究旨在进一步探索OXi8007的作用机制。有效 联合靶向治疗应能提高肾癌患者的治疗效果和最终生存率。 这些研究的目的是证明有效的联合治疗作为基础， 在大型动物中进行研究并将其转化为临床。

项目成果

Intratumoral Resolution of Driver Gene Mutation Heterogeneity in Renal Cancer Using Deep Learning.

• DOI: 10.1158/0008-5472.can-21-2318
• 发表时间: 2022-08-03
• 期刊: Cancer research
• 影响因子: 11.2

Demonstrating Tumor Vascular Disrupting Activity of the Small-Molecule Dihydronaphthalene Tubulin-Binding Agent OXi6196 as a Potential Therapeutic for Cancer Treatment.

• DOI: 10.3390/cancers14174208
• 发表时间: 2022-08-30
• 期刊: Cancers
• 影响因子: 5.2

The Evolution of Angiogenic and Inflamed Tumors: The Renal Cancer Paradigm.

• DOI: 10.1016/j.ccell.2020.10.021
• 发表时间: 2020-12-14
• 期刊: CANCER CELL
• 影响因子: 50.3
• 作者: Brugarolas, James;Rajaram, Satwik;Christie, Alana;Kapur, Payal
• 通讯作者: Kapur, Payal

Synthesis of the Hypoxia-Inducible Factor-2α (HIF-2α) Inhibitor, 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977, Belzutifan); Efficient Replication of Established Approaches.

缺氧诱导因子-2α (HIF-2α) 抑制剂的合成，3-[(1S,2S,3R)-2,3-二氟-1-羟基-7-甲基磺酰基林丹-4-基]氧基-5

• DOI: 10.1016/j.tetlet.2023.154691
• 发表时间: 2023
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Hamal,KhagendraB;Pavlich,CyprianI;Carlson,GrahamJ;Wong,YuChing;Zhao,Fangzhou;Zhang,Qing;Klausmeyer,KevinK;Pinney,KevinG
• 通讯作者: Pinney,KevinG