Targeting Signaling Vulnerabilities for Oral Cancer Prevention

摘要 迫切需要制定预防策略来阻止口腔癌前病变(OPL)的进展。 转化为头颈部鳞状细胞癌(HNSCC)，这种疾病每年导致30多万人死亡 全世界。我们的团队发现，PI3K/mTOR信号网络的激活是最频繁的 HNSCC和OPLS中异常的致癌信号机制及其PI3K/mTOR抑制 在实验性OPL和HNSCC模型中表现出强大的抗肿瘤活性。这些发现提供了基础 对于我们的第二阶段临床试验(NCT01195922)，探索HNSCC患者的抗肿瘤活性mTOR阻断。 最近，我们发现重新调整二甲双胍的用途，这是一种数百万2型糖尿病(T2 DM)安全使用的药物 在实验性OPL模型中，可减少mTOR信号转导，并显示出有效的化学预防活性。 基于这些发现，流行病学数据显示T2 DM的HNSCC发病率显著较低 在服用二甲双胍的患者中，我们在OPL患者中进行了IIa期试验，以探索二甲双胍的潜力。 预防口腔癌(M4OC-预防试验；NCT02581137)。这是第一项评估 二甲双胍在OPL中的化学预防作用。组织学有效率为60%，我们发现 OPL的组织学反应与mTOR抑制显著相关。这些结果提供了 发起由NCI资助的多机构癌症预防临床试验基金会(M4OC-预防2.0)， 一项IIb期随机、双盲、安慰剂对照试验，对患有OPL的现有和既往吸烟者进行研究 二甲双胍预防口腔癌的潜力。然而，我们对此仍有不完全的认识。 在OPL或任何其他癌前病变中，二甲双胍治疗反应的分子决定因素。 本项目的总体目标是阐明二甲双胍作用于OPL的分子机制。 和HNSCC以(A)确定用于预测和监测临床反应的生物标记物，(B)为 基于机制的多模式精确化学预防战略，以及(C)预防和克服毒品 抵抗。利用来自我们的M4OC-预防的临床、遗传和组织样本的丰富数据 凭借我们团队在解码癌症促进途径方面的专业知识进行试验，我们项目的长期目标是 定义(1)预测对二甲双胍的反应的机械性生物标志物和(2)合适的多模式治疗 克服抗药性的选择。我们计划中的研究将揭示新的机制和基因 在未来的精确预防试验中，二甲双胍敏感性的决定因素将为患者选择提供信息，推出新的 二甲双胍同时抑制mTOR诱导OPL组织学反应的机制 和YAP1信号转导，为新的二甲双胍精确免疫预防策略提供了新的见解。 耐药的OPL病变。通过聚焦于一种具有公认的癌前状态并易于获得的癌症 对于组织学和分子学评估，我们的发现将产生广泛的影响，因为它们将使 二甲双胍作为一种有效、安全、低成本的多种恶性肿瘤预防药物的开发。

Abstract There is an urgent need to develop prevention strategies to halt progression of oral premalignant lesions (OPL) into head and neck squamous cell carcinoma (HNSCC), a disease that results in over 300,000 deaths each year worldwide. Our team discovered that activation of the PI3K/mTOR signaling network is the most frequently dysregulated cancer-driving signaling mechanism in HNSCC and OPLs and that, in turn, PI3K/mTOR inhibition exerts potent antitumor activity in experimental OPL and HNSCC models. These findings provided the foundation for our Phase II clinical trial (NCT01195922) exploring the antitumor activity mTOR blockade in HNSCC patients. More recently, we showed that repurposing metformin, a drug safely used by millions of type 2 diabetes (T2DM) patients, decreases mTOR signaling and displays potent chemopreventive activity in experimental OPL models. Based on these findings, and epidemiological data showing a significantly lower HNSCC incidence in T2DM patients on metformin, we conducted a Phase IIa trial in individuals with OPL to explore the potential of metformin to prevent oral cancer (M4OC-Prevent trial; NCT02581137). This represented the first study evaluating the chemopreventive potential of metformin in OPL. The histologic response rate was 60%, and we found a significant correlation between histological response and mTOR inhibition in OPL. These results provided the foundation for launching a multi-institutional NCI-funded Cancer Prevention Clinical Trial (M4OC-Prevent 2.0), a Phase IIb randomized, double-blind, placebo-controlled trial in current and former smokers with OPL to explore the potential of metformin for oral cancer prevention. However, we still have an incomplete understanding of the molecular determinants of the therapeutic response to metformin in OPL or in any other precancerous lesions. The overall objective of this project is to elucidate the molecular mechanisms by which metformin acts on OPL and HNSCC to (a) identify biomarkers for predicting and monitoring clinical response, (b) provide a rationale for mechanism-based multimodal precision chemoprevention strategies, and (c) prevent and overcome drug resistance. Leveraging the wealth of data from clinical, genetic, and tissue specimens from our M4OC-Prevent trial with our team’s expertise in decoding cancer promoting pathways, the long-term goal of our project is to define (1) mechanistic biomarkers predicting a response to metformin and (2) suitable multimodal therapeutic options to overcome drug resistance. Our planned studies will uncover new mechanistic and genetic determinants of metformin sensitivity to inform patient selection in future precision prevention trials, unveil novel mechanisms by which metformin induces histological response in OPL by the concomitant inhibition of mTOR and YAP1 signaling, and provide insights into novel a precision immune prevention strategy for metformin- resistant OPL lesions. By focusing on a cancer with a well-recognized premalignant state and readily accessible lesions for histological and molecular evaluation, our findings will have a broad impact, as they will enable the development of metformin as an effective, safe, and low-cost preventive agent for multiple malignancies.