A combination therapy for interventional treatment of triple-negative breast cancer

项目概要和相关性 摘要：侵袭性生长肿瘤的一个共同特征是由于肿瘤细胞的增殖而导致的肿瘤内缺氧。 血液供应不足。肿瘤细胞通过重新编程其代谢来适应缺氧， 葡萄糖发酵作为主要的能量途径，因此， 葡萄糖摄入量缺氧肿瘤细胞的这种葡萄糖依赖性可以通过限制总的 可用葡萄糖。该提案的目的是测试葡萄糖限制是否可以检查 缺氧糖酵解肿瘤的增殖。生酮饮食与临床相关 剂量的二甲双胍显著降低了BALB/c小鼠的血糖水平， 发病率该提案将测试饮食/二甲双胍组合对生长的功效， 在已建立的小鼠中原位植入的、侵袭性生长的肿瘤的转移结果 三阴性乳腺癌（TNBC）模型。在初步数据的指导下，我们的目标是1。建立 饮食/二甲双胍联合治疗在抑制乳腺肿瘤进展至 转移，和2.确定标准化疗与拟定联合用药的疗效 治疗以控制已发展的乳腺肿瘤的生长动力学和向转移的进展。 这种方法将癌症治疗发现的重点从遗传途径或蛋白质转移 目标，往往演变和适应治疗，以一个众所周知的和难以逃脱的代谢 通过使用饮食/药物治疗方法的组合来降低癌症的脆弱性。而 碳水化合物饮食限制和二甲双胍是众所周知的干预措施，但它们还有待于 被认为是用于癌症治疗的组合。值得注意的是，低碳水化合物饮食和二甲双胍 已经被证明在癌症领域之外的人类中是相容的。如果有效，这种治疗方法将 可以扩展到TNBC以外的其他缺氧和糖酵解肿瘤，特别是那些 折射到传统疗法，最终目标是将这种治疗方案转化为 人类癌症治疗联合治疗也可以证明是现有的免疫抑制剂的重要辅助治疗。 通过减少肿瘤的缺氧（通常是化疗和放射抗性）部分来进行主线治疗。这 AREA项目将为本科生提供研究机会， 生物医学技术和数据分析经验。该项目是专门为 对医学预科本科生来说简单实用。 相关性：TNBC的治疗选择有限，这是试图增加TNBC治疗后死亡率的关键障碍。 诊断患者生存率。这个项目是一个著名的范例的合理延伸， 代谢重编程的癌细胞，如果成功，可以转化为主线癌症 治疗或用作与现有治疗方案组合的辅助剂。

PROJECT SUMMARY AND RELEVANCE Summary: A common feature of aggressively growing tumors is intratumoral hypoxia due to the insufficient blood supply. Tumor cells adapt to hypoxia by reprogramming their metabolism to rely on glucose fermentation as the main energetic pathway and, consequently, drastically increase their glucose intake. This glucose dependence of hypoxic tumor cells can be exploited by limiting total available glucose. The objective of the proposal is to test whether glucose limitation checks the proliferation of hypoxic, glycolytic tumors. A combination of a ketogenic diet with clinically relevant doses of metformin significantly reduced blood glucose levels in BALB/c mice without causing morbidity. This proposal will test the efficacy of the diet/metformin combination on the growth and metastatic outcome of orthotopically implanted, aggressively growing tumors in an established murine model of triple-negative breast cancer (TNBC). Guided by preliminary data, we aim to 1. Establish the efficacy of the diet/metformin combination therapy in inhibiting the progression of mammary tumors to metastasis, and 2. Determine the efficacy of standard chemotherapy with the proposed combination therapy to control the growth dynamics and progression to metastasis of developed mammary tumors. This approach shifts the emphasis of cancer treatment discovery from genetic pathway or protein targets, which tend to evolve and adapt to therapy, to a well-known and hard to escape metabolic vulnerability of cancer by using a combination diet/pharmaceutical therapy approach. While carbohydrate dietary restriction and metformin are well-known interventions, they have yet to be considered in combination for cancer treatment. Significantly, low carbohydrate diets and metformin have been shown to be compatible in humans outside of the cancer field. If effective, this treatment will be expanded to other hypoxic and glycolytic tumors beyond TNBC, particularly those tumors that are refractive to conventional therapies, with the ultimate goal of translating this treatment protocol into a human cancer therapy. The combination therapy may also prove to be a significant adjuvant to existing mainline treatments by debulking the hypoxic, typically chemo- and radio-resistant, part of a tumor. This AREA project will provide research opportunities for undergraduate students to gain hands-on experience in biomedical techniques and data analysis. The project is specifically designed to be straightforward and practical for pre-med undergraduate students. Relevance: Limited treatment options for TNBC represent a critical barrier in attempts to increase post- diagnosis patient survival rates. This project is a rational extension of a well-known paradigm of metabolic reprogramming of cancer cells and, if successful, can be translated into a mainline cancer treatment or used as an adjuvant in combination with existing treatment options.