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

描述(申请人提供)：与大多数实体癌症不同，睾丸生殖细胞肿瘤(TGCT)通常对传统化疗药物高度敏感。这项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以用于使其他对相同疗法耐药的癌症增敏。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，并在许多类型的细胞中被激活，以响应致癌事件。这为肿瘤的发展提供了障碍，但也为DDR基因突变创造了选择压力，导致晚期癌症携带功能障碍的DDR，因此无法对遗传毒性化疗药物做出反应。相比之下，在早期TGCT中没有观察到DDR激活，睾丸癌很少包含DDR基因突变。我们将使用一种新的小鼠TGCT模型来验证这一假设，即这些独特的DDR特征是TGCT化疗敏感性的基础，在该模型中，动物发生转移性畸胎癌，这是一种由畸胎瘤和胚胎癌组成的混合性生殖细胞瘤，后者由类似于胚胎干细胞的恶性多能干细胞组成。虽然目前的教条表明，许多癌症包含一个干细胞群体，可以在化疗中幸存下来，导致复发，但我们认为，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模型来阐明传统化疗药物对体内胚胎癌细胞的细胞和分子效应，并将识别这些癌症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发生DNA损伤方面是独特的，或者在响应癌基因诱导的DNA损伤时DDR激活的机制方面是独一无二的。总之，这些实验将揭示TGCT的DDR特性如何影响晚期癌症的致癌转化以及治疗敏感性程度。了解TGCT化疗敏感性的分子基础可能会为预测各种癌症的治疗反应提供新的生物标志物，并为提高传统化疗药物的疗效提供新的分子靶点。

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.