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: 9126407
• 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/9126407
• 关键词: Ablation; Aftercare; Animal Model; Apoptosis; Cause of Death; Cell Death; Cell Survival; Combined Modality Therapy; Epidermal Growth Factor Receptor; FRAP1 gene; Goals; Growth; Health; 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; improved; in vivo; mTOR Inhibitor; mTOR inhibition; mortality; novel; outcome forecast; prevent; release factor; therapeutic development; therapeutic target; tumor; tumor ablation; 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，远程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重大负担，在过去30年中，美国在美国的发病率增加了两倍。局部热烧蚀疗法是早期阶段HCC的重要治疗选择，达到了类似于手术的短期结局，发病率较小。但是，治疗较大的HCC（在5年时最多75％）后，肿瘤复发率很高，这些患者的总生存率仍然很差。值得关注的是，有证据表明，HCC的热消融可能会导致进一步的恶性进展。开发用于提高热消融和最终患者预后功效的治疗策略，将需要对调节热耐药性，复发性和肿瘤进展的分子机制有更深入的了解。我们已经确定了HCC热耐药性和进展中介导的PI3K-AKT存活信号传导的热应力诱导的MET和EGFR受体酪氨酸激酶（RTK）的关键作用，并且特别兴奋，并且对抑制PI3K-AKT-MTOR途径的观察值特别兴奋。该提案的具体目的是：1）确定热应力诱导的MET的机制/EGFR-PI3K-AKT信号传导调节HCC分子热度调节； 2）确定热消融诱导肿瘤进展的机制； 3）通过PI3K-AKT-MTOR抑制调节HCC对热消融的敏感性。我们将结合细胞和分子方法，新型成像技术以及体外和基于患者的方法，用于系统地研究新型热应激诱导的MET/EGFR-PI3K-AKT轴在HCC热度和肿瘤进展中的机械作用。这些研究的成功完成将提高我们对分子热消融机制的理解，诱导的耐药性和肿瘤进展，并为将基于机制的HCC的基于机制的HCC疗法转化为早期阶段临床试验提供了强大的科学框架。总体而言，鉴于缺乏有效的HCC长期治疗，该提案可能是高IMPAC的。这项研究的发现可能也可能是由于已知的RTK，PI3K-AKT途径和其他肿瘤中的其他固体器官恶性肿瘤而被热消融治疗的其他固体器官恶性肿瘤。