Regulation of molecular thermal ablative resistance in hepatocellular carcinoma

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。局部热消融治疗是早中期HCC的重要治疗选择，可获得与手术相似的短期结果，且发病率较低。然而，较大肝癌治疗后的高肿瘤复发率（5年时高达75%）限制了其适用性，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的热消融可能诱导进一步的恶性进展。开发用于改善热消融疗效和最终患者预后的治疗策略将需要更好地理解调节热阻、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PI 3 K-AKT存活信号传导在HCC耐热性和进展中的关键作用，并且特别兴奋地观察到抑制PI 3 K-AKT-mTOR途径使HCC热敏化并加速热应激诱导的细胞杀伤。本研究的具体目的是：1）确定热应激诱导的MET/EGFR-PI 3 K-AKT信号转导调节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PI 3 K-AKT-mTOR抑制来调节HCC对热消融的敏感性。我们将结合细胞和分子生物学方法、新的成像技术以及体外、体内和基于患者的方法，系统地研究新的热应激诱导的MET/EGFR-PI 3 K-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抵抗和肿瘤进展的机制的理解，并为将基于机制的HCC联合消融治疗转化为早期临床试验提供强有力的科学框架。总的来说，由于缺乏有效的肝癌长期治疗方法，该建议可能具有很高的影响。这项研究的结果也可能推广到其他实体器官恶性肿瘤的热消融治疗，因为已知的RTK，PI 3 K-AKT通路和生长因子在其他肿瘤中的失调。

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.