A phase 0 pilot study to determine if papaverine increases oxygenation in spontaneous canine soft tissue sarcoma

一项 0 期试点研究，以确定罂粟碱是否会增加自发性犬软组织肉瘤的氧合

• 批准号: 9985010
• 负责人: Nicholas C. Denko
• 金额: $ 16.97万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9985010
• 关键词: Acute; Affect; Animals; Binding; Biological; Biology; Biopsy; Blood Circulation; Canis familiaris; Cells; Client; Clinical; Clinical Trials; Complex; Data; Dose; Effectiveness; Elements; Enrollment; Evaluation; FDA approved; Frequencies; Future; Genes; Genetic; Glucose; Human; Hypoxia; IACUC; Intervention Trial; Learning; Malignant Neoplasms; Measurement; Measures; Metabolic; Mitochondria; Modeling; Mus; Mutation; Near-Infrared Spectroscopy; Neoadjuvant Therapy; Normal tissue morphology; Ohio; Optics; Oxygen; Oxygen Consumption; Papaverine; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase 0 Clinical Trial; Phase 0 Trial; Phosphoserine; Pilot Projects; Pimonidazole; Population; Population Heterogeneity; Preclinical Testing; Radiation; Radiation Tolerance; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Regulation; Rodent; Rodent Model; Scheme; Series; Serum Markers; Side; Soft tissue sarcoma; Solid Neoplasm; Stains; System; Technology; Testing; Time; Transplantation; Tumor Oxygenation; Universities; Validation; Veterinary Medicine; Veterinary Schools; Work; base; cell killing; cohort; exosome; glucose metabolism; medical schools; neoplastic cell; novel; oxidation; pet animal; pre-clinical; predicting response; programs; radiation response; relative effectiveness; research clinical testing; response; sarcoma; success; tumor; tumor hypoxia

ABSTRACT Tumor hypoxia reduces the effectiveness of radiotherapy by reducing the effective dose delivered to the tumor. Cells that are severely hypoxic require 2.8-fold greater dose to achieve the same cell kill as those that are fully oxygenated. For this reason, many groups have tried to deliver more oxygen to tumors as a therapy to reduce hypoxia and increase radiosensitivity. These strategies did effectively radiosensitize model tumors in rodents, but did not prove successful in human trials. We have looked at tumor oxygenation differently from the biological perspective and the evaluation of success perspective. In terms of biology, if we could clinically reduce oxygen demand rather than increase its supply, we could effectively reduce hypoxia and produce tumor radiosensitization. We have identified papaverine as an FDA-approved molecule with the ability to inhibit mitochondrial function at clinical doses. Studies in mouse tumors support the idea that papaverine can radiosensitize through regulation of oxygen consumption, producing “Metabolic Radiosensitization”. In terms of the evaluation of papaverine, we propose to test its potential as a clinical radiosensitizer in a heterogeneous population of spontaneous canine soft tissue sarcomas being treated at OSU Veterinary Medical School. The heterogeneous host- and tumor genetics generate a clinical trial that we hypothesize will be much more predictive of human success than a rodent study. Papaverine is not targeted to a specific cancer mutation, and should be effective as a radiosensitizer in any solid tumor where hypoxia exists. The proposed study will be a phase 0 pharmacodynamics study that will determine if papaverine can increase oxygenation in canine soft tissue sarcoma as measured by near infrared spectroscopy (FD-NIRS) technology in real time. We propose to test 10 animals with 1 mg/kg and 10 animals with 2 mg/kg papaverine. Correlative biological studies will determine if baseline tumor hypoxia or other biological variables can predict response to papaverine. These studies will determine if canine soft tissue sarcoma is a feasible system to test new hypoxic tumor radiosensitizers, and if papaverine should be considered as a potential radiosensitizer in future interventional trials.

抽象的 肿瘤缺氧通过减少递送至肿瘤的有效剂量来降低放射治疗的有效性。 严重缺氧的细胞需要 2.8 倍的剂量才能达到与完全缺氧的细胞相同的细胞杀灭效果。 出于这个原因，许多研究小组尝试向肿瘤输送更多的氧气作为减少肿瘤的治疗方法。 缺氧和增加放射敏感性这些策略确实有效地提高了啮齿动物模型肿瘤的放射敏感性。 但在人体试验中并未取得成功，我们对肿瘤氧合的研究与生物学不同。 从生物学的角度和评估成功的角度来看，如果我们能够在临床上减少氧气。 需求而不是增加供应，我们可以有效减少缺氧并产生肿瘤 我们已确定罂粟碱是 FDA 批准的具有抑制作用的分子。 临床剂量下的线粒体功能对小鼠肿瘤的研究支持了罂粟碱可以发挥作用的观点。 通过调节耗氧量实现放射增敏，产生“代谢放射增敏”。 在对罂粟碱进行评估时，我们建议在异质性中测试其作为临床放射增敏剂的潜力 俄勒冈州立大学兽医医学院正在治疗自发性犬软组织肉瘤群体。 异质宿主和肿瘤遗传学产生的临床试验将更具预测性 罂粟碱并不针对特定的癌症突变，因此应该针对人类的成功进行研究。 作为放射增敏剂，对任何存在缺氧的实体瘤都有效。拟议的研究将处于 0 期。 药效学研究将确定罂粟碱是否可以增加犬软组织的氧合作用 通过近红外光谱 (FD-NIRS) 技术实时测量肉瘤 我们建议测试 10 个。 1 mg/kg 的动物和 2 mg/kg 10 只动物的相关生物学研究将确定是否。 基线肿瘤缺氧或其他生物变量可以预测对罂粟碱的反应。 确定犬软组织肉瘤是否是测试新的缺氧肿瘤放射增敏剂的可行系统，以及是否 在未来的介入试验中，罂粟碱应被视为潜在的放射增敏剂。