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 头颈部鳞状细胞癌（HNSCC），一种每年导致30多万人死亡的疾病 国际吧我们的团队发现PI 3 K/mTOR信号网络的激活是最常见的。 HNSCC和OPL中的癌症驱动信号机制失调，反过来，PI 3 K/mTOR抑制 在实验性OPL和HNSCC模型中发挥有效的抗肿瘤活性。这些发现为 用于我们的II期临床试验（NCT 01195922），探索HNSCC患者中的抗肿瘤活性mTOR阻断。 最近，我们发现，重新利用二甲双胍，一种被数百万2型糖尿病（T2 DM）患者安全使用的药物， 患者，减少mTOR信号传导，并在实验OPL模型中显示出有效的化学预防活性。 基于这些发现，以及流行病学数据显示T2 DM患者HNSCC发病率显著较低 我们在OPL患者中进行了一项IIa期试验，以探索二甲双胍的潜力 预防口腔癌（M4 OC-预防试验; NCT 02581137）。这是第一项评估 二甲双胍在OPL中的化学预防潜力。组织学反应率为60%，我们发现 OPL中组织学反应与mTOR抑制之间存在显著相关性。这些结果提供了 基金会发起了一项由多机构NCI资助的癌症预防临床试验（M4 OC预防2.0）， 一项在当前和既往吸烟的OPL患者中进行的IIb期随机、双盲、安慰剂对照试验，以探索 二甲双胍预防口腔癌的潜力。然而，我们对这一问题的认识仍然不够全面。 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）鉴定用于预测和监测临床应答的生物标志物，（B）提供以下依据 基于机制的多模式精确化学预防策略，以及（c）预防和克服药物 阻力利用来自M4 OC-Prevent的临床、遗传和组织标本的丰富数据， 利用我们团队解码癌症促进途径的专业知识，我们项目的长期目标是 定义（1）预测二甲双胍应答的机制生物标志物和（2）合适的多模式治疗 克服耐药性的选择。我们计划的研究将揭示新的机制和遗传 二甲双胍敏感性的决定因素，以告知未来精确预防试验中的患者选择， 二甲双胍通过同时抑制mTOR诱导OPL组织学反应的机制 和YAP 1信号传导，并为二甲双胍的新的精确免疫预防策略提供见解- 耐药OPL病变。通过关注具有公认的癌前状态且易于获得的癌症， 我们的研究结果将产生广泛的影响，因为它们将使 开发二甲双胍作为一种有效、安全、低成本的预防多种恶性肿瘤的药物。

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.