(PQD2) Molecular Basis for the Chemosensitivity of Testicular Germ Cell Cancers

(PQD2) 睾丸生殖细胞癌化学敏感性的分子基础

• 批准号: 8687336
• 负责人: Robert S Weiss
• 金额: $ 16.86万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687336
• 关键词: Advanced Malignant Neoplasm; Animals; Antineoplastic Agents; Apoptosis; Biological Assay; Biological Markers; Bypass; Candidate Disease Gene; Cells; Characteristics; Cisplatin; Common Neoplasm; DNA; DNA Damage; DNA biosynthesis; DNA lesion; Data; Distant; Elements; Embryonal Carcinoma; Embryonal Carcinoma Cell; Employee Strikes; Event; Fiber; Gene Mutation; Genes; Genetic Determinism; Genetically Engineered Mouse; Genome; Germ Cell Cancers; Germ Cells; Germ cell tumor; Human; Hypersensitivity; Knowledge; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of testis; Measures; Mediating; Modeling; Molecular; Molecular Target; Mus; Mutagens; Mutation; Nature; Neoplasm Metastasis; Neoplasms; Oncogene Activation; Oncogenes; Oncogenic; Penetrance; Pluripotent Stem Cells; Predisposition; Property; RNA Sequences; Relapse; Resistance; Signal Transduction; Site; Solid; Solid Neoplasm; Somatic Cell; Spermatogonia; Staging; Stem cells; Stress; Structure of primordial sex cell; System; Teratocarcinoma; Teratoma; Testicular Germ Cell Tumor; Testicular Neoplasms; Testicular malignant germ cell tumor; Testing; Therapeutic; Toxic effect; Undifferentiated; Work; base; cancer stem cell; cancer therapy; cell transformation; cell type; chemotherapy; design; effective therapy; embryonic stem cell; improved; in vivo; induced pluripotent stem cell; mouse model; novel; novel therapeutics; pluripotency; precursor cell; pressure; prevent; public health relevance; reconstitution; research study; response; senescence; stem cell population; theories; therapy resistant; treatment strategy; tumor progression; tumorigenesis; young man

DESCRIPTION (provided by applicant): Unlike most solid cancers, Testicular Germ Cell Tumors (TGCTs) typically are highly responsive to conventional chemotherapeutics. The long-term objectives of the proposed studies are to elucidate the molecular basis for TGCT chemosensitivity and to determine whether knowledge of the underlying mechanisms can be used to sensitize other cancers that are resistant to the same therapies. We hypothesize that the sensitivity of TGCTs to conventional chemotherapy derives from unique features of the cellular DNA damage response (DDR) in germ cells, the cells from which TGCTs arise. The DDR protects cells against genome damage and in many cell types becomes activated in response to oncogenic events. This provides a barrier to tumor progression, but also creates selective pressure for DDR gene mutations, resulting in advanced cancers that harbor a dysfunctional DDR and therefore are unable to respond to genotoxic chemotherapeutics. By contrast, DDR activation is not observed in early-stage TGCTs, and testicular cancers rarely contain DDR gene mutations. We will test the hypothesis that these unique DDR features underlie the chemosensitivity of TGCTs using a novel mouse TGCT model in which the animals develop metastatic teratocarcinoma, a mixed germ cell tumor composed of teratoma and embryonal carcinoma, the latter consisting of malignant pluripotent stem cells that are similar to embryonic stem cells. While current dogma suggests that many cancers contain a stem cell population that can survive chemotherapy, resulting in relapse, we propose that TGCTs can be completely cured by chemotherapy due to the DDR-mediated hypersensitivity of the pluripotent germ cells within these cancers. In Aim 1, we will use our novel mouse TGCT model to elucidate the cellular and molecular effects of conventional chemotherapeutics on embryonal carcinoma cells in vivo and will identify genetic determinants of chemosensitivity in these cancers. In Aim 2, we will directly test whether the pluripotent stem cells in TGCTs are unique in terms of the occurrence of DNA damage following oncogenic events or in the mechanisms of DDR activation in response to oncogene-induced DNA lesions. Together, these experiments will reveal how the DDR properties of TGCTs influence oncogenic transformation as well as the degree of treatment sensitivity in advanced cancers. Understanding the molecular basis for TGCT chemosensitivity will likely provide new biomarkers for predicting therapeutic responses in a variety of cancers and yield new molecular targets for enhancing the efficacy of conventional chemotherapeutics.

描述（由申请人提供）：与大多数实体癌不同，睾丸生殖细胞肿瘤（TGCT）通常对常规化疗药物高度敏感。拟议研究的长期目标是阐明TGCT化疗敏感性的分子基础，并确定潜在机制的知识是否可用于使对相同疗法具有抗性的其他癌症敏感。我们假设TGCT对常规化疗的敏感性来自生殖细胞中细胞DNA损伤反应（DDR）的独特特征，生殖细胞是TGCT产生的细胞。DDR保护细胞免受基因组损伤，并且在许多细胞类型中响应致癌事件而被激活。这为肿瘤进展提供了障碍，但也为DDR基因突变创造了选择性压力，导致晚期癌症具有功能失调的DDR，因此无法对遗传毒性化疗药物作出反应。相比之下，在早期TGCT中未观察到DDR激活，睾丸癌很少包含DDR基因突变。我们将测试的假设，这些独特的DDR功能的基础上的TGCT的化疗敏感性，使用一种新的小鼠TGCT模型，其中的动物发展转移性畸胎瘤，混合生殖细胞肿瘤组成的畸胎瘤和胚胎癌，后者组成的恶性多能干细胞，是类似于胚胎干细胞。虽然目前的教条表明，许多癌症含有可以在化疗中存活的干细胞群体，导致复发，但我们提出，由于这些癌症中多能生殖细胞的DDR介导的超敏反应，TGCT可以通过化疗完全治愈。在目标1中，我们将使用我们的新的小鼠TGCT模型来阐明常规化疗药物对体内胚胎癌细胞的细胞和分子效应，并将确定这些癌症中化疗敏感性的遗传决定因素。在目标2中，我们将直接测试TGCT中的多能干细胞是否在致癌事件后DNA损伤的发生方面或在响应于致癌基因诱导的DNA损伤的DDR激活机制方面是独特的。总之，这些实验将揭示TGCT的DDR特性如何影响致癌转化以及晚期癌症的治疗敏感性程度。了解TGCT化疗敏感性的分子基础将可能提供新的生物标志物，用于预测各种癌症的治疗反应，并产生新的分子靶点，用于增强常规化疗药物的疗效。