Breaking the Obesity-Cancer Link: New Targets and Strategies

 描述（由申请人提供）：流行病学和实验研究已经确定，肥胖是大多数癌症类型的重要风险和/或预后因素，但肥胖-癌症联系的潜在机制尚未明确阐明。这种知识差距阻碍了制定基于机制的策略，以更精确地干预预防和控制肥胖相关癌症的努力。考虑到全球肥胖和癌症发病率的上升，以及许多人减肥的挑战，我提出了一种综合的多层次方法来解决四个关键问题，这些问题将导致新的，有效的基于机制的干预措施，以抵消肥胖相关的癌症负担增加：i）单独适度减肥，或与其他基于机制的干预措施相结合，逆转肥胖的促癌效应？ii）肥胖诱导化疗耐药的机制（和解决方案）是什么？iii）抵消肥胖的促转移效应的目标和策略是什么？iv）通过去卷积（并最终破坏）脂肪细胞、巨噬细胞和上皮细胞之间的相互串扰，可以确定哪些抵消肥胖影响的新靶点？总体目标是利用我们在能量平衡和癌症研究方面的专业知识（包括乳腺癌、结肠癌和胰腺癌的充分表征的临床前模型，以及跨越临床试验和流行病学研究的分子/细胞生物学方法的成熟合作），以阐明机制靶点，鉴定可用于平行人类和动物研究的新生物标志物，并制定有效的干预措施，打破肥胖与癌症的联系，减轻肥胖人群的癌症负担。

 DESCRIPTION (provided by applicant): Epidemiologic and experimental studies have established that obesity is an important risk and/or prognostic factor for most cancer types, but the mechanisms underlying the obesity-cancer link have not been clearly elucidated. This knowledge gap is hampering efforts to develop mechanism-based strategies to more precisely intervene to prevent and control obesity-related cancers. Given the rising rates of obesity and cancer worldwide, and the challenges for many people to lose excess weight, I propose an integrated multilevel approach to address four critical questions that will lead to new, effective mechanism-based interventions to offset obesity-associated increases in cancer burden: i) Does moderate weight loss alone, or in combination with other mechanism-based interventions, reverse the procancer effects of obesity? ii) What are the mechanisms of (and solutions to) obesity-induced chemotherapeutic resistance? iii) What are the targets and strategies for offsetting the pro-metastatic effects of obesity? iv) What new targets for offsetting the effects o obesity can be identified by deconvoluting (and ultimately disrupting) the reciprocal crosstalk between adipocytes, macrophages and epithelial cells? The overarching goal is to capitalize on our expertise in energy balance and cancer research (including well-characterized preclinical models of breast, colon and pancreatic cancer and well-established collaborations spanning molecular/cellular biologic approaches to clinical trials and epidemiologic studies) to elucidate mechanistic targets, identify new biomarkers that can be used in parallel human and animal studies, and develop effective interventions to break obesity-cancer links and reduce the burden of cancer in obese people.