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破坏剂（VDA）与

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