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

阐明 PIM 激酶在乳腺癌生长和转移中的代谢功能

• 批准号: 9974996
• 负责人: Joyce Vivian Lee
• 金额: $ 6.53万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9974996
• 关键词: Address; Affect; Animals; Back; Biological Markers; Breast Cancer Cell; Breast Cancer Patient; Cancer Biology; Cell Survival; Cells; Clinic; Clinical Trials; DNA Damage; DNA Repair; DNA biosynthesis; Data; Development; Disease; Distant Metastasis; Drug usage; Embryo; Environment; Enzymes; Epidermal Growth Factor Receptor; Estrogen Receptors; Fellowship; Fibroblasts; Genes; Genetically Engineered Mouse; Goals; Growth; Human; In Vitro; Institution; Knock-out; Knowledge; Lead; Lung; MYC gene; Malignant Neoplasms; Mammary Neoplasms; Messenger RNA; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Molecular; Moloney Leukemia Virus; Mus; Mutagens; Neoplasm Metastasis; Nucleotide Biosynthesis; Nucleotides; Oncogenic; Operative Surgical Procedures; Outcome; Oxidative Phosphorylation; Oxidative Stress; PIM1 gene; Pathway interactions; Patient-Focused Outcomes; Patient-derived xenograft models of breast cancer; Patients; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Positioning Attribute; Pre-Clinical Model; Predisposition; Primary Neoplasm; Process; Production; Progesterone Receptors; Purines; Pyrimidine; Reactive Oxygen Species; Regulation; Research; Research Personnel; Risk; Role; Sampling; Testing; The Cancer Genome Atlas; Up-Regulation; Work; Xenograft Model; Xenograft procedure; breast cancer progression; cancer subtypes; cancer type; cell growth; chemotherapy; clinically relevant; contextual factors; genotoxicity; in vivo; inhibitor/antagonist; integration site; interest; kinase inhibitor; malignant breast neoplasm; metastatic process; mortality; novel; nucleotide metabolism; overexpression; programs; proto-oncogene protein pim; receptor; skills; targeted agent; targeted treatment; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor DNA; tumor growth; tumor metabolism; tumor progression; tumor xenograft

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.

项目摘要/摘要 三重阴性乳腺癌(TNBC)是一种缺乏HER2表达的乳腺癌亚型， 雌激素和孕激素受体代表着预后最差的肿瘤类型，因为它的高度 增殖表型，早期转移，仍然没有靶向药物。因此，这种癌症类型仍然 代表着在诊所治疗的关键挑战。同时参与多机构i-spy乳腺癌 Goga实验室的试验发现，癌基因myc在TNBC中不成比例地高表达 亚型，2)与患者预后不佳有关，3)可以作为靶向治疗的基础。使用 无偏筛选，我们最近发现了一种被低估的激酶，PIM1 a激酶，它选择性地抑制 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小鼠白血病病毒(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生长的机制是非常有兴趣的。我们有耐人寻味的 初步数据表明，PIM调节原发肿瘤生长所需的代谢途径 转移。这个提议的中心假设是PIM支持所需的代谢程序 TNBC及其抑制作用失调原发肿瘤生长和生长所需的代谢过程 转移性细胞存活。我们寻求使用我们的临床前TNBC模型来发现代谢途径 并确定靶向这些通路是否能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原发肿瘤的生长中上调。在目标1中： 研究依赖于PIM的核苷酸可用性变化对TNBC进展的影响，我建议研究 PIM对嘧啶和嘌呤合成和/或挽救途径的调节及PIM是否抑制 与需要核苷酸代谢的现有疗法协同作用。此外，PIM1在患者体内的表达 样本与TNBC的远处转移呈正相关。我的初步数据建议废除PIM 活跃性可减少转移。我预测PIM在转移过程中调节重要的代谢过程。在目标2中： 阐明PIM对转移性TNBC代谢途径的调节，我将确定PIM是否调节 转移性细胞生长和存活所必需的重要代谢过程。 我这次研究的目标是发现TNBC对PIM的要求背后的新的分子机制， 这将支持临床试验，以优化PIM抑制剂与其他靶向药物的结合。另外， 完成拟议的工作将帮助我培养必要的技能，以便采取步骤申请 在一家学术机构担任独立研究员的职位，继续癌症生物学和 新陈代谢。