Targeting Slc16a/Mct Lactate Transporters in Cancer Therapeutics

描述（由申请人提供）：癌症的一个标志是通过有氧糖酵解进行葡萄糖分解代谢（Warburg效应）。这种表型包括葡萄糖和氨基酸转运蛋白表达的显著增加以及线粒体功能向合成代谢细胞器的转换。综合效应是丙酮酸向乳酸的显著转移（约95%），乳酸通过专用的12跨膜通道单羧酸转运体Mct1和Mct4输出出癌细胞，我们已经证明在几种肿瘤类型中过度表达和反向调节。Myc癌蛋白在近70%的人类癌症中被激活，它们协调了驱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蛋白在癌前表达myc的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，癌前和肿瘤中表达myc的B细胞产生过量的乳酸。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，并且升高的Mct1是Myc参与的人类恶性肿瘤的标志。重要的是，我们的Multi-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 Dr. John Cleveland）和合成有机化学领域的世界领导者以及新疗法的衍生（PI Dr. William Roush），已经证明了现有的和新的内部抑制Mct1的药物可以使人类淋巴瘤和乳腺癌细胞代谢和增殖丧失能力，并且在没有副作用的情况下损害肿瘤发生。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、广泛适用的抗癌治疗策略。使用小鼠和人类肿瘤模型，在Aim 1中，我们测试了Mct1对于myc驱动淋巴瘤的发展和维持都是必要的假设，在Aim 2中，我们测试了Mct1和Mct4对乳腺癌的发展和维持的贡献。在Aim 3中，我们的先导Mct1抑制剂的药物相似性将通过重复功效、药物化学和DMPK筛选来优化。我们还将开发、验证和完善Mct4抑制剂，并开发泛mct1 /Mct4抑制剂。这些新药将在我们的小鼠和人类淋巴瘤和乳腺癌模型上进行有效性、安全性和选择性测试。在Aim 4中，我们将利用谷氨酰胺（如Asct2）和大中性氨基酸转运体（如LAT1）在人类恶性肿瘤中的表达增加。具体来说，我们将用化学方法将我们的抗mct抑制剂与这些转运体的配体捆绑在一起，我们已经证明这可以增强它们的肿瘤细胞传递和效力。这些新型缀合物的功效、效力、选择性和安全性将在淋巴瘤和乳腺癌模型中进行测试。我们认为，组建的研究团队将产生一系列新的、有效的、安全的抗癌药物，这些药物将在化学预防和广谱治疗中得到应用。

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.