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

项目摘要/摘要 糖尿病会增加女性患乳腺癌的风险，增加癌症患者的死亡率。非洲-- 美国(AA)女性受糖尿病及其并发症的影响不成比例。同时，这些 从公元前开始，女性的结局最差。此外，许多女性在接受BC治疗后体重增加，最终患上 糖尿病。戒酒协会和西班牙裔/拉丁裔女性更受此影响。它们之间存在着一些重要的区别 比较合并糖尿病和不合并糖尿病的BC患者在方案选择和肿瘤治疗效果方面的差异。 目前还没有针对糖尿病相关BC的特定治疗方法。我们的长期目标是 了解糖尿病引起BC进展的基本机制，并制定个性化的 糖尿病相关BC的治疗。根据正常细胞和癌细胞之间的代谢差异， 我们首次提出了这一安全有效的针对癌症新陈代谢的治疗策略。 BC细胞，对正常细胞相对无毒。本项目的重点是以乳酸代谢为目标 和运输来诱导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达到更高水平，同时阻止糖酵解产物进入 三羧酸(TCA)循环会导致大量乳酸的产生。同时，阻止出口 通过抑制单羧酸转运体4(MCT4)来抑制过量乳酸会导致代谢危机和 癌细胞内的酸化，导致它们死亡。我们的初步体外结果表明，这种代谢 重编程策略(MRS)可以成功地阻止癌细胞的增殖。此外，我们已经确定了 CB-2作为新型小分子MCT4抑制剂(专利申请号：62/662,637)。CB-2已经显示出 对三阴性乳腺具有显著的乳酸分泌抑制作用和显著的细胞毒作用 肿瘤(TNBC)细胞，具有高糖酵解率/MCT4表达。在强劲的初步数据的指引下， 我们建议追求三个具体目标来检验这一假说：(1)研究MRS对 不同BC细胞系的能量代谢途径及其敏感或耐药的可能原因 接近。(2)确定CB-2的作用机制和抗癌活性。(3)检验效果； 该MRS在人BC移植的糖尿病小鼠模型中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的新陈代谢和 从长远来看，可能会揭示一种有效的治疗糖尿病相关BC和TNBCs的策略。这个 导致癌症负担不平等的复杂生物学需要进行研究，以增加我们的基础 了解癌症健康差异。因此，研究肿瘤细胞的葡萄糖代谢特征 将是揭示这种健康差距的重要一步。此外，寻找新的药物靶点和 开发与糖尿病相关的BC的新治疗方法有助于减少癌症健康差距。

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.