A novel metabolic reprograming strategy for the treatment of diabetes-associated breast cancer

项目总结/摘要 糖尿病会增加女性患乳腺癌（BC）的风险和癌症患者的死亡率。非洲- 美国（AA）妇女不成比例地受到糖尿病及其并发症的影响。同时，这些 女性在BC省的结果最差。此外，许多女性在BC治疗后体重增加，最终 糖尿病AA和西班牙裔/拉丁裔妇女受此影响更大。存在一些重要的区别 糖尿病与非糖尿病BC患者在方案选择和癌症治疗结果方面的差异。 目前还没有针对糖尿病相关BC的特异性治疗方法。我们的长期目标是 了解糖尿病诱导的BC进展的基本机制，并制定个性化的 治疗糖尿病相关的BC。基于正常细胞和癌细胞之间的代谢差异， 我们首次提出了这种安全有效的治疗策略，靶向癌症代谢“毒”， BC细胞，对正常细胞相对无毒性。本项目的重点是针对乳酸代谢 和运输以诱导BC细胞死亡。这一策略的中心假设是，药物诱导 葡萄糖输入和糖酵解甚至更高的水平，同时阻止糖酵解产物进入 三羧酸（TCA）循环导致大量乳酸的产生。与此同时， 通过抑制单羧酸转运蛋白4（MCT 4）过量的乳酸导致代谢危机， 癌细胞内的酸化导致其死亡。我们的初步体外结果表明，这种代谢 重编程策略（MRS）可以成功地阻断癌细胞的增殖。此外，我们还发现， CB-2作为新型小分子MCT 4抑制剂（专利申请号：62/662，637）。CB-2显示了 对乳酸分泌有显著的抑制作用，对三阴性乳腺癌有显著的细胞毒活性 癌症（TNBC）细胞，其具有高糖酵解速率/MCT 4表达。在强有力的初步数据的指导下， 我们提出了三个具体目标来检验这一假设：（1）研究MRS对 不同BC细胞系的能量代谢途径以及对其敏感或抗性的可能原因 approach. (2)确定CB-2的作用机制和抗癌活性。(3)为了测试效果， 在携带人BC异种移植物的糖尿病小鼠模型中观察该MRS的安全性和潜在副作用。 总的来说，这些研究将使我们能够更深入地了解癌细胞代谢， 从长远来看，可能揭示了糖尿病相关BC和TNBC的有效治疗策略。的 复杂的生物学，有助于不平等的癌症负担需要调查，以增加我们的基本 了解癌症健康差异。因此，研究肿瘤细胞的糖代谢特征 将是揭示这种健康差异的重要一步。此外，寻找新的药物靶点， 在糖尿病相关BC中开发新的治疗方法有助于减少癌症健康差异。

PROJECT SUMMARY/ABSTRACT Diabetes increases the risk of breast cancer (BC) in women and mortality in patients with cancer. African- American (AA) women are disproportionately affected by diabetes and its complications. Concurrently, these women have worst outcome from BC. In addition, many women gain weight after BC treatment and end up with diabetes. AA and Hispanic/Latina women are even more affected by this. There exist some important distinctions between the BC patients with and without diabetes in the regimen selection and outcomes of cancer therapy. Currently there are no specific treatments to target diabetes-associated BC. Our long-term goals are to understand the fundamental mechanisms of diabetes-induced BC progression, and to develop personalized treatments for diabetes-associated BC. Based on the metabolic differences between normal and cancer cells, we for the first time propose this safe and effective therapeutic strategy targeting cancer metabolism to “poison” BC cells, with relatively non-toxicity to normal cells. The present project focuses on targeting lactate metabolism and transport to induce BC cell death. The central hypothesis of this strategy is that pharmaceutical induction of glucose import and glycolysis to even higher levels while blocking the products of glycolysis from entering the tricarboxylic acid (TCA) cycle, results in production of high amounts of lactate. Meanwhile, blocking the export of excessive lactate by inhibiting monocarboxylate transporter 4 (MCT4) leads to a metabolic crisis and acidification within the cancer cells, causing their death. Our preliminary in vitro results indicate that this metabolic reprogramming strategy (MRS) can successfully block cancer cells proliferation. Moreover, we have identified CB-2 as a novel small molecule MCT4 inhibitor (Patent Application Number: 62/662,637). CB-2 has shown a significantly inhibitory effect on lactate secretion and striking cytotoxic activity against triple-negative breast cancer (TNBC) cells, which have a high glycolytic rate/MCT4 expression. Guided by strong preliminary data, we propose to pursue three Specific Aims to test this hypothesis: (1) To investigate the effect of MRS on energy metabolic pathways of different BC cell lines and the possible reasons for sensitivity or resistance to this approach. (2) To confirm the mechanism of action and anticancer activity of CB-2. (3) To test the effectiveness, safety, and potential side effects of this MRS in diabetic mouse models bearing human BC xenografts. Collectively, these studies will allow us to gain a more in-depth understanding of cancer cell metabolism and may in the long term reveal an effective therapeutic strategy for diabetes-associated BC and TNBCs. The complex biology that contributes to the unequal cancer burdens needs to be investigated to increase our basic understanding of cancer health disparities. Hence, investigating glucose metabolism features in tumor cells would be a significant step in shedding light on this health disparity. Moreover, searching new drug targets and developing new treatment methods in diabetes-associated BC contribute to decreasing cancer health disparities.