Elucidating metabolic functions of PIM Kinase in breast cancer growth and metastasis

项目概要/摘要 三阴性乳腺癌（TNBC），缺乏HER2表达的乳腺癌亚型， 雌激素和孕激素受体，代表了肿瘤类型与最差的结果，由于其高度 增殖表型，早期转移，并且仍然没有靶向药物。因此，这种癌症类型仍然 这是临床治疗的一个关键挑战。在参与多机构I-SPY乳腺癌 Goga实验室发现，癌基因MYC：1）在TNBC中异常高表达， 亚型，2）与不良患者结局相关，以及3）可能是靶向治疗的基础。使用 无偏筛选，我们最近发现了一种未被重视的激酶，PIM 1激酶，其抑制选择性 阻止显示高MYC的乳腺肿瘤细胞的生长，如TNBC。值得注意的是，前病毒的抑制剂 Moloney鼠白血病病毒（PIM）激酶的整合位点目前正在临床上进行测试。那里 更好地描述PIM抑制如何阻止TNBC生长的机制是很有意义的。我们有一个有趣的 初步数据表明PIM调节原发性肿瘤生长所需的代谢途径， 转移该建议的中心假设是PIM支持代谢程序， TNBC及其抑制使原发性肿瘤生长所必需的代谢过程失调， 转移细胞存活率。我们寻求使用我们的TNBC临床前模型来发现代谢途径 并确定靶向这些途径是否会阻止肿瘤的生长和进展。 我的初步数据表明核苷酸合成在TNBC原发性肿瘤生长中上调。目标1： 研究核苷酸可用性的PIM依赖性变化对TNBC进展的影响，我建议研究 通过PIM调节嘧啶和嘌呤合成和/或补救途径，并测试PIM抑制是否 与需要核苷酸代谢的现有疗法是协同的。此外，患者中的PIM 1表达 样本中TNBC的远处转移呈正相关。我的初步数据显示废除PIM 活动减少转移。我预测PIM调节转移中重要的代谢过程。目标2： 阐明PIM在转移性TNBC中对代谢途径的调节，我将确定PIM是否调节 重要的代谢过程是转移性细胞生长和存活所必需的。 我的目标是这个奖学金是揭示背后的PIM TNBC要求新的分子机制， 这将支持临床试验，以优化PIM抑制剂与其他靶向药物的组合。此外，本发明还 完成拟议的工作将帮助我发展必要的技能，采取步骤申请一个 在学术机构担任独立研究员，继续进行癌症生物学研究， 新陈代谢.

PROJECT SUMMARY / ABSTRACT Triple negative breast cancers (TNBC), the breast cancer subtype that lacks expression of the HER2, estrogen, and progesterone receptors, represent the tumor type with the poorest outcome due to its highly proliferative phenotype, early metastasis, and remains without targeted agents. Thus, this cancer type still represents a critical challenge to treat in the clinic. While involved in the multi-institutional I-SPY breast cancer trials, the Goga Lab discovered that the oncogene MYC is: 1) disproportionally highly-expressed in the TNBC subtype, 2) associated with poor patient outcome, and 3) can be the basis of targeted therapies. Using an unbiased screen, we recently identified an under-appreciated kinase, PIM1 a kinase whose inhibition selectively stops the growth of breast tumor cells that display high MYC, such as TNBC. Notably, inhibitors of the Proviral integration site for Moloney Murine leukemic virus (PIM) kinases are currently being tested in the clinic. There is great interest to better delineate mechanisms for how PIM inhibition stops TNBC growth. We have intriguing preliminary data that suggests PIM regulates metabolic pathways required for primary tumor growth and metastasis. The central hypothesis of this proposal is that PIM supports metabolic programs required for TNBC and its inhibition dysregulates metabolic processes necessary for primary tumor growth and metastatic cell survival. We seek to use our pre-clinical models of TNBC to discover metabolic pathways regulated by PIM and determine if targeting these pathways stops tumor growth and progression. My preliminary data suggests nucleotide synthesis is upregulated in TNBC primary tumor growth. In Aim 1: Investigate effects of PIM-dependent changes in nucleotide availability on TNBC progression, I propose to study the regulation of pyrimidine and purine synthesis and/or salvage pathways by PIM and test whether PIM inhibition is synergistic with existing therapies that require nucleotide metabolism. Additionally, PIM1 expression in patient samples is positively associated with distant-metastasis in TNBC. My preliminary data suggests abrogating PIM activity decreases metastasis. I predict PIM regulates important metabolic processes in metastasis. In Aim 2: Elucidate PIM’s regulation of metabolic pathways in metastatic TNBC, I will determine whether PIM regulates important metabolic processes that are necessary for metastatic cell growth and survival. My goal for this fellowship is to uncover new molecular mechanisms behind TNBC requirement for PIM, which will support clinical trials to optimize combining PIM inhibitor with other targeted agents. Additionally, completion of the proposed work will help me develop the skills necessary to take steps towards applying for an independent investigator position at an academic institution to continue research in cancer biology and metabolism.