Targeting Slc16a/Mct Lactate Transporters in Cancer Therapeutics

描述(申请人提供)：癌症的一个标志是通过有氧糖酵解(Warburg效应)进行的葡萄糖分解代谢。这种表型包括显著增加葡萄糖和氨基酸转运蛋白的表达，以及将线粒体的功能切换到合成代谢细胞器。综合作用是丙酮酸显著(~95%)转向乳酸，乳酸通过专门的12次跨膜单羧酸转运蛋白MCT1和MCT4从癌细胞输出，我们已经证明这两种转运蛋白在几种肿瘤类型中过度表达和反向调节。在近70%的人类癌症中，MYC癌蛋白被激活，它们协调推动肿瘤发生的基因转录的大规模变化，包括一系列代谢酶。我们已经证明，大多数糖酵解酶和氨基酸转运体在表达Myc的癌前B细胞中升高，并且这种反应在Myc驱动的淋巴瘤中被放大。因此，癌前和肿瘤性表达Myc的B细胞会产生过量的乳酸。值得注意的是，我们已经证明，Myc通过直接诱导MCT1的转录来协调细胞中的乳酸稳态，并且MCT1的升高是MYC参与的人类恶性肿瘤的一个标志。重要的是，我们的多PI研究团队结合了癌症遗传学和治疗学方面的专业知识(Pi John Cveland博士)和合成有机化学及新疗法派生方面的世界领先企业(Pi Dr.William Roush)，他们已经证明，现有的和新型的内部抑制MCT1药物可以抑制人类淋巴瘤和乳腺癌细胞的代谢和增殖，并在没有副作用的情况下阻碍肿瘤的形成。因此，我们假设阻断MCT1和/或MCT4导向的乳酸转运是一种创新的、广泛适用于抗癌治疗的策略。使用小鼠和人类肿瘤模型，在目标1中，我们检验了MCT1对Myc驱动的淋巴瘤的发生和维持都是必需的假设，在目标2中，我们检验了MCT1和MCT4在乳腺癌的发生和维持中的作用。在目标3中，我们将使用重复疗效、药物化学和DMPK筛选来优化我们的主要MCT1抑制剂的药物相似性。我们还将开发、验证和提纯MCT4抑制剂，并开发泛-MCT1/MCT4抑制剂。这些新的药物将使用我们的小鼠和人类淋巴瘤和乳腺癌模型来测试其有效性、安全性和选择性。在目标4中，我们将利用人类恶性肿瘤中谷氨酰胺(例如Asct2)和大的中性氨基酸转运体(例如LAT1)表达的增加。具体地说，我们将把我们的抗MCT抑制剂化学地拴在这些转运蛋白的配体上，我们已经证明，这可以增强它们的肿瘤细胞输送和效力。这些新型结合物的有效性、有效性、选择性和安全性将通过淋巴瘤和乳腺癌模型进行测试。我们认为，集合起来的研究团队将产生一系列新的、有效和安全的抗癌药物，这些药物将在化学预防和广谱治疗中应用。

DESCRIPTION (provided by applicant): A hallmark of cancer is glucose catabolism via aerobic glycolysis (the Warburg effect). This phenotype includes marked increases in the expression of glucose and amino acid transporters and a switch in the functions of mitochondria to an anabolic organelle. The combined effect is a marked diversion (~95%) of pyruvate towards lactate, which is exported out of the cancer cell via dedicated 12-transmembrane-pass monocarboxylic acid transporters coined Mct1 and Mct4, which we have shown are overexpressed and inversely regulated in several tumor types. Myc oncoproteins are activated in nearly 70% of human cancers, where they orchestrate wholesale changes in gene transcription that drive tumorigenesis, including a cast of metabolic enzymes. We have shown that most glycolytic enzymes and amino acid transporters are elevated in premalignant Myc-expressing B cells, and that this response is amplified in Myc-driven lymphoma. Accordingly, premalignant and neoplastic Myc-expressing B cells produce excess levels of lactate. Notably, we have shown that Myc coordinates lactate homeostasis in the cell by directly inducing the transcription of Mct1, and that elevated MCT1 is a hallmark of human malignancies with MYC involvement. Importantly, our Multi-PI research team, which combines expertise in cancer genetics and therapeutics (PI Dr. John Cleveland) with a world leader in synthetic organic chemistry and the derivation of novel therapeutics (PI Dr. William Roush), has demonstrated that established and new in-house agents that inhibit Mct1 disable human lymphoma and breast cancer cell metabolism and proliferation, and impair tumorigenesis without side effects. Thus, we hypothesize that blocking Mct1- and/or Mct4-directed lactate transport is an innovative, widely applicable strategy for anti-cancer therapy. Using both mouse and human tumor models, in Aim 1 we test the hypothesis that Mct1 is necessary for both the development and maintenance of Myc-driven lymphoma, and in Aim 2 we test the contribution of both Mct1 and Mct4 to the development and maintenance of breast cancer. In Aim 3 the drug-likeness of our lead Mct1 inhibitors will be optimized using reiterative efficacy, medicinal chemistry and DMPK screens. We will also develop, validate and refine Mct4 inhibitors and develop pan-Mct1/Mct4 inhibitors. These new agents will be tested for efficacy, safety, and selectivity using our mouse and human lymphoma and breast cancer models. In Aim 4 we will exploit the increased expression of the glutamine (e.g., Asct2) and large neutral amino acid transporters (e.g., LAT1) manifest in human malignancies. Specifically, we will chemically tether our anti-Mct inhibitors to ligands for these transporters, which we have shown augments their tumor cell delivery and potency. The efficacy, potency, selectivity and safety of these novel conjugates will be tested using lymphoma and breast cancer models. We submit that the assembled research team will generate a cast of new, efficacious and safe anti-cancer agents that will have applications in chemoprevention and as broad-spectrum therapeutics.