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给肿瘤的有效剂量来降低放射疗法的有效性。 严重缺氧需要大2.8倍的细胞才能达到与完全相同的细胞杀死 充氧。因此，许多小组试图将更多的氧气供应肿瘤，以减少 缺氧并增加放射性敏感性。这些策略确实有效地使啮齿动物中的模型肿瘤有效地放射敏， 但没有证明在人类试验中取得成功。我们对肿瘤氧合的看法与生物学不同 观点和对成功观点的评估。在生物学方面，如果我们可以临床减少氧气 需求而不是增加供应，我们可以有效地减少缺氧并产生肿瘤 放射敏化。我们已经确定了磷灰石为FDA批准的分子，具有抑制能力 临床剂量下的线粒体功能。小鼠肿瘤的研究支持了蒲公会可以的想法 通过调节氧气消耗，产生“代谢放射敏化”，可以放射敏感。按照 评估木瓜仪，我们建议在异质中测试其作为临床放射敏剂的潜力 OSU兽医医学院接受了赞助犬软组织肉瘤的种群。这 异构宿主和肿瘤遗传学产生了我们假设的临床试验，这将更具预测性 人类的成功比啮齿动物的研究。磷灰碱不是针对特定癌症突变的，应是 在存在缺氧的任何实体瘤中作为放射增敏剂有效。拟议的研究将是阶段0 药效学研究将确定木偶爸爸是否会增加犬类软组织中的氧合 通过实时通过近红外光谱（FD-NIRS）技术测量的肉瘤。我们建议测试10 具有1 mg/kg和10只动物的动物，有2 mg/kg的木瓜。相关生物学研究将确定是否是否 基线肿瘤缺氧或其他生物学变量可以预测对木偶护的反应。这些研究会 确定犬软组织肉瘤是否是测试新的低氧肿瘤放射敏剂的可行系统，以及是否是否 在将来的介入试验中，应将罂粟碱视为潜在的放射性敏感剂。