Regulation of molecular thermal ablative resistance in hepatocellular carcinoma

描述(由申请人提供)：这项建议的广泛、长期目标是改善肝细胞癌(HCC)患者的预后。肝癌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、中期肝细胞癌的重要治疗选择，可获得与手术相似的短期疗效，且发病率较低。然而，较大的肝癌治疗后较高的肿瘤复发率(5年时高达75%)限制了它们的适用性，这些患者的总体存活率仍然很低。值得关注的是，有证据表明，肝细胞癌的热消融可能会导致进一步的恶性进展。为了提高热消融的疗效和最终患者的预后，制定治疗策略将需要更多地了解调节热耐受、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生存信号在肝癌的热耐受和进展中起着关键作用，尤其令人兴奋的是，抑制PI3K-AKT-mTOR通路可以使肝癌变得热敏感，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-PI3K-AKT信号调节肝癌分子热抗性的机制；2)确定热消融诱导肿瘤进展的机制；3)通过抑制PI3K-AKT-mTOR来调节肝细胞癌对热消融的敏感性。我们将结合细胞和分子方法、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-PI3K-AKT轴在肝癌耐热性和肿瘤进展中的机制作用。这些研究的成功完成将加深我们对分子热消融诱导耐药和肿瘤进展机制的理解，并为将基于机制的联合消融治疗肝癌转化为早期临床试验提供强有力的科学框架。总体而言，考虑到缺乏对肝癌的有效长期治疗，这一建议可能具有高度的影响。由于RTK、PI3K-AKT通路和生长因子在其他肿瘤中的调节失调，这项研究的发现也可能推广到其他接受热消融治疗的实体器官恶性肿瘤。

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.