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

三阴性乳腺癌介入治疗的联合疗法

基本信息

批准号：
9813371
负责人：
Eugene Kroll
金额：
$ 35.8万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-17 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9813371
关键词：
4T1 Adipose tissue Adjuvant Animal Cancer Model Animals Apoptosis Autopsy Behavioral Bilateral Biological Markers Blood Blood Glucose Brain Breast Epithelial Cells Caliber Cancer Etiology Carbohydrates Case Study Cells Citric Acid Cycle Clinic Combined Modality Therapy Consumption Control Groups Data Data Analyses Dependence Development Diagnosis Diet Dietary Carbohydrates Disease Dose Doxorubicin Enzymes Expression Profiling Fatty Liver Fatty acid glycerol esters Fermentation Freezing Gene Expression Genetic Glucose Glucose Transporter Goals Growth Guidelines Hepatic Histologic Histopathology Human Hypoxia Hypoxia Inducible Factor Immune Immunohistochemistry Implant Inbred BALB C Mice Incidence Infiltration Injections Intake Intervention Ketone Bodies Liver Lung Malignant Neoplasms Mammary Neoplasms Mammary gland Measurement Measures Metabolic Metabolism Metastatic Neoplasm to the Lung Metastatic to Metformin Monitor Morbidity - disease rate Mus Neoadjuvant Therapy Neoplasm Metastasis Normal Cell Normal tissue morphology Nutrient Outcome Oxygen Pathway interactions Patients Pattern Personal Satisfaction Pharmacologic Substance Polarography Proteins Radio Randomized Regimen Research Research Project Grants Resistance Serum Solid Neoplasm Students Supervision Survival Rate Techniques Testing Therapeutic Intervention Tissue Banks Tissue Sample Tissues Translating Treatment Protocols Tumor Debulking Tumor Tissue Ultrasonography Up-Regulation Vascular blood supply Vascularization Weight animal care animal tissue cancer cell cancer therapy chemotherapy clinically relevant computerized data processing conventional therapy design dietary restriction effective therapy efficacy testing experience experimental study glucose production ketogenic diet malignant breast neoplasm matrigel mortality mouse model neoplastic cell novel strategies triple-negative invasive breast carcinoma tumor tumor growth tumor hypoxia undergraduate student

项目摘要

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.

项目摘要和相关性摘要：侵袭性生长的肿瘤的一个共同特征是瘤内缺氧，这是由于血液供应不足。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，因此大大增加了它们的葡萄糖摄入量。缺氧肿瘤细胞的这种葡萄糖依赖性可以通过限制总葡萄糖来利用。可用葡萄糖。该提案的目的是测试葡萄糖限制是否会检查缺氧、糖酵解肿瘤的增殖。生酮饮食与临床相关的结合二甲双胍剂量显着降低 BALB/c 小鼠的血糖水平，且不会引起发病率。该提案将测试饮食/二甲双胍组合对生长和发育的功效。在已建立的小鼠体内原位植入、侵袭性生长的肿瘤的转移结果三阴性乳腺癌（TNBC）模型。以初步数据为指导，我们的目标是 1. 建立饮食/二甲双胍联合疗法在抑制乳腺肿瘤进展方面的功效转移，以及 2. 确定标准化疗与建议组合的疗效控制已发展的乳腺肿瘤的生长动态和转移进展的疗法。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会进化并适应治疗，成为众所周知且难以逃脱的代谢通过使用饮食/药物联合治疗方法来降低癌症的脆弱性。尽管碳水化合物饮食限制和二甲双胍是众所周知的干预措施，但尚未得到证实考虑联合用于癌症治疗。值得注意的是，低碳水化合物饮食和二甲双胍已被证明在癌症领域之外的人类中具有相容性。如果有效，这种治疗将扩展到 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。联合疗法也可能被证明是现有疗法的重要辅助手段。通过减少肿瘤的缺氧部分（通常具有化疗和放射抗性）来进行主线治疗。这 AREA 项目将为本科生提供实践研究的机会生物医学技术和数据分析经验。该项目专门设计用于对于医学预科本科生来说简单实用。相关性：TNBC 的治疗选择有限是尝试增加术后治疗的一个关键障碍。诊断患者的生存率。这个项目是一个众所周知的范式的合理延伸癌细胞的代谢重编程，如果成功，可以转化为主线癌症治疗或与现有治疗方案结合用作辅助剂。