Sex-Dependent PTHrP Processing and Lung Cancer Survival

性别依赖性 PTHrP 加工和肺癌生存

• 批准号: 8331170
• 负责人: RANDOLPH H HASTINGS
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331170
• 关键词: Address; Affect; Androgen Antagonists; Androgens; Basic Science; Biological Assay; Cancer Cell Growth; Cancer Model; Cancer Patient; Cancer cell line; Carcinoma; Cells; Data; Development; Disease; Drug Delivery Systems; Epitopes; Equilibrium; Female; Functional disorder; Gender; Goals; Gonadal Steroid Hormones; Growth; Guanidines; High Prevalence; Histology; Hormonal; Hormones; Human; Immunoassay; Immunocompromised Host; In Vitro; Individual; Knowledge; Lead; Learning; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Mediating; Molecular; Mus; Non-Small-Cell Lung Carcinoma; Oncogene Proteins; Outcome; Pathway interactions; Patient Care; Patients; Peptide Hydrolases; Peptides; Process; Processed Genes; Proteins; Proteolysis; Proteolytic Processing; Regulatory Pathway; Relative (related person); Resistance; Resources; Role; Serine Protease; Sex Characteristics; Smoking; Smoking History; Tertiary Protein Structure; Testing; Testosterone; Therapeutic Intervention; Time; Veterans; Woman; Work; amino-terminal parathyroid hormone; anticancer research; authority; base; cancer therapy; clinically significant; experience; hormone therapy; improved; lung Carcinoma; male; mouse model; mutant; novel; novel marker; outcome forecast; parathyroid hormone-related protein; prognostic indicator; prohormone; protein expression; research study; sex; small molecule; tumor; tumor progression

DESCRIPTION (provided by applicant): Parathyroid hormone-related protein (PTHrP), an oncoprotein expressed in 50-75% of human lung carcinomas, is a multifunctional molecule that undergoes post-translational processing. Processing has significant implications for patient outcome. From our previous work, we know that tumor expression of carboxyl-terminal PTHrP by itself is a positive prognostic indicator in women with non-small cell lung carcinoma (NSCLC), while processing to solely amino-terminal PTHrP is associated with shorter patient survival. Interestingly, lung carcinomas in females are likely to express carboxyl PTHrP alone and only female patients demonstrate a survival benefit from when expressing this domain. In contrast, carcinomas in males usually contain both PTHrP epitopes and do not show a survival benefit. Thus, a sex-based difference in relative expression of amino and carboxyl-terminal PTHrP contributes to a sex-dependent difference in outcome. Preliminary data from a mouse lung cancer model suggest that testosterone controls the sex difference in amino and carboxyl PTHrP. As a hypothesis, we propose that the relative expression of amino- and carboxyl-terminal PTHrP is a function of processing that varies between male and female carcinomas because of sex steroids. Furthermore, amino and carboxyl PTHrP regulate tumor progression directly through stimulatory and inhibitory effects, respectively, on lung cancer cell growth, survival and invasiveness. Aim 1 will establish the effects of androgens on processing of PTHrP in lung carcinoma in over 14 different lung cancer cell lines, in orthotopic lung carcinomas in syngeneic or immunocompromised mice, and in fresh human lung carcinomas. The studies will consider interactions with histology, sex, smoking history, mutational status in common, important molecular drivers and other covariates. Processing will be assessed by region-specific immunoassay, in vitro PTHrP proteolysis assays and mass spectrometry. Aim 2 will define the regulatory effects of PTHrP processing on lung carcinoma progression in the mouse models. Experiments will study PTHrP forms that have been processed by gene truncation to lack amino or carboxyl PTHrP domains. Additional experiments will study PTHrP mutants resistant to key processing steps. Aim 3 will identify proteases that regulate androgen-dependent PTHrP processing and the associated effects on tumor progression. The experiments will use activity-based probes to isolate and sequence proteases regulated by androgens. Subsequent experiments will confirm the role of these proteases in PTHrP processing. The translational benefit of this project will result from learning how hormonal pathways affect the balance between amino PTHrP and carboxyl PTHrP in lung cancer and identifying the proteases mediating those effects. Novel, improved treatments could be sought in drugs that targeted the androgen regulatory pathway or the proteases to augment carboxyl PTHrP relative to amino PTHrP and prolong survival. This goal may be close to fruition because we have found individual cyclic guanidine compounds , a class of molecule with known effects on serine protease activity, that reduce amino PTHrP in lung cancer.

描述（由申请人提供）： 甲状旁腺激素相关蛋白 (PTHrP) 是一种在 50-75% 的人类肺癌中表达的癌蛋白，是一种进行翻译后加工的多功能分子。处理对患者的治疗结果具有重大影响。从我们之前的工作中，我们知道，羧基末端 PTHrP 的肿瘤表达本身是女性非小细胞肺癌 (NSCLC) 的积极预后指标，而仅加工为氨基末端 PTHrP 与患者生存期较短有关。有趣的是，女性肺癌可能单独表达羧基 PTHrP，并且只有女性患者在表达该结构域时才表现出生存获益。相比之下，男性癌症通常含有两种 PTHrP 表位，并且不会显示出生存获益。因此，氨基和羧基末端 PTHrP 相对表达的性别差异导致了结果的性别依赖性差异。小鼠肺癌模型的初步数据表明，睾酮控制氨基和羧基 PTHrP 的性别差异。作为一个假设，我们提出，氨基末端和羧基末端 PTHrP 的相对表达是一种加工函数，由于性类固醇的原因，男性和女性癌症之间的差异是不同的。此外，氨基和羧基 PTHrP 分别通过对肺癌细胞生长、存活和侵袭的刺激和抑制作用直接调节肿瘤进展。目标 1 将确定雄激素对超过 14 种不同肺癌细胞系的肺癌、同基因或免疫功能低下小鼠的原位肺癌以及新鲜人肺癌中 PTHrP 加工的影响。这些研究将考虑与组织学、性别、吸烟史、常见突变状态、重要分子驱动因素和其他协变量的相互作用。处理过程将通过区域特异性免疫测定、体外 PTHrP 蛋白水解测定和质谱法进行评估。目标 2 将定义 PTHrP 加工对小鼠模型肺癌进展的调节作用。实验将研究通过基因截短处理以缺少氨基或羧基 PTHrP 结构域的 PTHrP 形式。其他实验将研究 PTHrP 突变体对关键加工步骤的抵抗力。目标 3 将鉴定调节雄激素依赖性 PTHrP 加工的蛋白酶及其对肿瘤进展的相关影响。实验将使用基于活性的探针来分离和测序受雄激素调节的蛋白酶。后续实验将证实这些蛋白酶在 PTHrP 加工中的作用。该项目的转化效益将来自于了解激素途径如何影响肺癌中氨基 PTHrP 和羧基 PTHrP 之间的平衡，并鉴定介导这些影响的蛋白酶。可以在针对雄激素调节途径或蛋白酶的药物中寻求新颖、改进的治疗方法，以相对于氨基 PTHrP 增强羧基 PTHrP 并延长生存期。这个目标可能已经接近实现，因为我们已经发现了单独的环胍化合物，这是一类已知对丝氨酸蛋白酶活性有影响的分子，可以减少肺癌中的氨基 PTHrP。