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:10646312
- 负责人:
- 金额:$ 48.08万
- 依托单位:
- 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:
- 关键词:AcuteAnimalsAntibodiesAntigen PresentationBlood VesselsCTLA4 geneCancer PatientCell Cycle ArrestCellsClinicClinical TrialsCombined Modality TherapyComplementDevelopmentDisputesDisseminated Malignant NeoplasmDoseDrug CombinationsEndotheliumExhibitsFoundationsGoalsGrowthHistologyHumanHypoxiaHypoxia Inducible FactorImmune checkpoint inhibitorImmune responseImmunocompetentImmunologic StimulationImmunotherapyInfiltrationInvestigationIschemiaKDR geneKidney NeoplasmsLeadLuciferasesMacrophageMetastatic Renal Cell CancerModelingMusNecrosisNecrosis InductionPatientsPericytesPermeabilityPharmacodynamicsProdrugsRefractoryRenal Cell CarcinomaRenal carcinomaReporterReportingResistanceResourcesTherapeuticThymidine KinaseToxic effectTransfectionTranslationsTreatment EfficacyTumor-Associated VasculatureTyrosine Kinase InhibitorUp-RegulationVascular PermeabilitiesVon Hippel-Lindau Tumor Suppressor ProteinWaterantagonistanti-CTLA4anti-PD-1bHLH-PAS factor HLFbioluminescence imagingcancer therapychemotherapycohortdesignearly phase clinical trialeffective therapyimage guidedimmune activationimmunoreactivityimprovedin vivoinnovationinventionkinase inhibitorlight emissionneovasculaturenon-invasive imagingnoveloptoacoustic tomographypatient derived xenograft modelpharmacokinetics and pharmacodynamicsreceptorresponsesmall moleculesuccesssurvivorshipsystemic toxicitytargeted cancer therapytargeted treatmenttherapeutic targettherapy resistanttreatment responsetumortumor growthtumor 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途的新型血管破坏剂(VDA)与
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 影响因子:11.2
- 作者:
- 通讯作者:
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:
- 影响因子:5.2
- 作者:
- 通讯作者:
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:
- 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:
- 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
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{{ truncateString('RALPH P. MASON', 18)}}的其他基金
Novel nanoparticles to stimulate therapeutic angiogenesis in peripheral arterial disease
刺激外周动脉疾病治疗性血管生成的新型纳米颗粒
- 批准号:
10462909 - 财政年份:2022
- 资助金额:
$ 48.08万 - 项目类别:
Novel nanoparticles to stimulate therapeutic angiogenesis in peripheral arterial disease
刺激外周动脉疾病治疗性血管生成的新型纳米颗粒
- 批准号:
10756875 - 财政年份:2022
- 资助金额:
$ 48.08万 - 项目类别:
Novel nanoparticles to stimulate therapeutic angiogenesis in peripheral arterial disease
刺激外周动脉疾病治疗性血管生成的新型纳米颗粒
- 批准号:
10616740 - 财政年份:2022
- 资助金额:
$ 48.08万 - 项目类别:
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:
10442463 - 财政年份:2020
- 资助金额:
$ 48.08万 - 项目类别:
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:
10058644 - 财政年份:2020
- 资助金额:
$ 48.08万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 48.08万 - 项目类别:
PROGNOSTIC RADIOLOGY AND THE PATHOPHYSIOLOGY OF TUMORS
预后放射学和肿瘤病理生理学
- 批准号:
8363897 - 财政年份:2011
- 资助金额:
$ 48.08万 - 项目类别:
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