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景的新型血管干扰剂(VDA)与 领先的治疗方法，以加强肾癌的治疗。肾细胞癌(RCC)通常表现为 通过使von Hippel Lindau(VHL)肿瘤抑制蛋白失活，促进缺氧积累 诱导因子(HIF)与广泛血管系统的发展正常人血管内皮细胞 血管基本上是静止的，但肿瘤的侵袭性新生血管不成熟，缺乏周细胞。 支持，并表现出更高的渗透性，为癌症治疗提供了一个选择性的靶点。治疗性 VDAS的目标是导致已建立的肿瘤血管迅速广泛中断，从而导致局部 缺血、缺氧和肿瘤坏死的诱导。我们已经确定Oxi8007是一种新的高效、水溶性的 VDA前药导致血管长时间中断，剂量依赖性肿瘤生长延迟，无明显 全身毒性。然而，VDA单一疗法通常会导致肿瘤周围和 Oxi8007可能在基于以下补充模式的现有铅疗法方面最有效 行动。我们将研究由贝洛通治疗公司开发的小分子HIF-2拮抗剂PT2977， 这代表了早期临床试验中的一种新的化疗药物。与此同时，卡波赞蒂尼，小型- 针对c-met受体ax1和VEGFR-2的分子激酶抑制剂最近被批准为第一个 转移性肾癌患者的直线治疗选择。我们也认识到正在出现的 免疫治疗，并预计Oxi8007诱导的坏死将增强抗原提呈促进 回应。我们最重要的假设是，将这些治疗方法结合起来将实现强健的长期 碾压混凝土的期限控制。 调查将受益于德克萨斯大学西南肾癌孢子的资源，该资源已 开发了一些新的患者来源的肿瘤株，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机 侵袭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荧光素酶转基因的RencA细胞。在……里面 此外，最近可用的多光谱光声断层扫描(MSOT)非侵入性地显示血管 范围和局部氧合，不需要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讨Oxi8007的作用机制。有效地 联合靶向治疗应该会提高肾癌患者的治疗水平和最终存活率。 这些研究的目标是证明有效的联合疗法是治疗 在大型动物中的调查和翻译到临床。

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

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

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

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