Regulation of molecular thermal ablative resistance in hepatocellular carcinoma

肝细胞癌分子热烧蚀抗性的调节

• 批准号: 8555135
• 负责人: David A Woodrum
• 金额: $ 32.99万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555135
• 关键词: Ablation; Aftercare; Animal Model; Apoptosis; Cause of Death; Cell Death; Cell Survival; Combined Modality Therapy; Epidermal Growth Factor Receptor; Goals; Growth; Growth Factor; Heat Stress Disorders; Heating; Imaging Techniques; In Vitro; Incidence; Individual; Ligands; Liver neoplasms; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Methods; Molecular; Morbidity - disease rate; Neoplasm Metastasis; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phenotype; Primary carcinoma of the liver cells; Prognostic Factor; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases; Recurrence; Regulation; Research; Resistance; Role; Serum; Signal Transduction; Solid; Staging; Stimulus; Therapeutic; Thermal Ablation Therapy; Time; Translating; Treatment Failure; base; cancer therapy; cell killing; human FRAP1 protein; improved; in vivo; mTOR Inhibitor; mTOR inhibition; mortality; novel; outcome forecast; prevent; public health relevance; therapeutic development; therapeutic target; tumor; tumor growth; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): The broad, long-range objective of this proposal is to improve the prognosis for patients with hepatocellular carcinoma (HCC). HCC is a major global burden of morbidity and mortality and its incidence in the US has tripled over the past 30 years. Locoregional thermal ablative therapies are important treatment options for early-mid stage HCC, achieving short-term outcomes similar to surgery with less morbidity. However, high tumor recurrence rates after treatment of larger HCCs (up to 75% at 5 years) limit their applicability and overall survival remains poor for these patients. Of significant concern, there is evidence that thermal ablation of HCC may induce further malignant progression. Development of therapeutic strategies for improving the efficacy of thermal ablation and ultimately patient prognosis will require a greater understanding of the molecular mechanisms regulating thermal resistance, recurrence and tumor progression. We have identified a critical role for heat stress induced MET and EGFR receptor tyrosine kinase (RTK) mediated PI3K-AKT survival signaling in HCC thermal resistance and progression and are especially excited about the observation that inhibition of the PI3K-AKT-mTOR pathway thermosensitizes HCC and accelerates heat stress induced cell killing. The specific aims of this proposal are: 1) To determine mechanisms of heat stress induced MET/EGFR-PI3K-AKT signaling regulating HCC molecular thermoresistance; 2) To determine mechanisms of thermal ablation induced tumor progression; 3) To modulate HCC sensitivity to thermal ablation by PI3K-AKT-mTOR inhibition. We will use a combination of cellular and molecular methods, novel imaging techniques and in vitro, in vivo and patient-based approaches to systematically investigative the mechanistic role of the novel heat stress induced MET/EGFR-PI3K-AKT axis in HCC thermoresistance and tumor progression. Successful completion of these studies will increase our understanding of the mechanisms of molecular thermal ablation induced resistance and tumor progression and provide a strong scientific framework for translating a mechanism- based combination ablative therapy for HCC to early stage clinical trials. Overall, this proposal is potentially of high impac given lack of effective long-term treatments for HCC. The findings from this research will also likely be generalizable to other solid organ malignancies treated with thermal ablation because of the known dysregulation of RTKs, PI3K-AKT pathway, and growth factors in other tumors.

描述（由申请人提供）：该提案的广泛、长期目标是改善肝细胞癌（HCC）患者的预后。 HCC 是全球发病率和死亡率的主要负担，其在美国的发病率在过去 30 年中增加了两倍。局部热消融疗法是早中期 HCC 的重要治疗选择，可实现与手术相似的短期结果，但发病率较低。然而，较大的 HCC 治疗后的高肿瘤复发率（5 年高达 75%）限制了它们的适用性，并且这些患者的总生存率仍然很差。值得注意的是，有证据表明 HCC 热消融可能会导致进一步的恶性进展。开发提高热消融疗效和最终患者预后的治疗策略需要更好地了解调节热阻、复发和肿瘤进展的分子机制。我们已经确定了热应激诱导的 MET 和 EGFR 受体酪氨酸激酶 (RTK) 介导的 PI3K-AKT 存活信号在 HCC 耐热性和进展中的关键作用，并且对抑制 PI3K-AKT-mTOR 通路使 HCC 热敏化并加速热应激诱导的细胞杀伤这一观察结果感到特别兴奋。该提案的具体目标是： 1) 确定热应激诱导的 MET/EGFR-PI3K-AKT 信号调节 HCC 分子耐热性的机制； 2) 确定热消融诱导肿瘤进展的机制； 3) 通过抑制 PI3K-AKT-mTOR 来调节 HCC 对热消融的敏感性。我们将结合细胞和分子方法、新颖的成像技术以及体外、体内和基于患者的方法，系统地研究新型热应激诱导的 MET/EGFR-PI3K-AKT 轴在 HCC 耐热性和肿瘤进展中的机制作用。这些研究的成功完成将增加我们对分子热消融诱导耐药和肿瘤进展机制的理解，并为将基于机制的肝癌联合消融疗法转化为早期临床试验提供强有力的科学框架。总体而言，鉴于 HCC 缺乏有效的长期治疗方法，该提案可能具有很高的影响力。由于其他肿瘤中已知的 RTK、PI3K-AKT 通路和生长因子的失调，这项研究的结果也可能推广到采用热消融治疗的其他实体器官恶性肿瘤。