Cancer Genes and Pathways

项目摘要/摘要 癌症基因和途径研究(CGP)计划的重点是定义必要的分子和 肿瘤发病机制的生物学机制和成功的治疗。这一基本目标的主要目标是 科学计划是发现、表征和验证新的肿瘤变化(基因、分子和 细胞途径)，以推动转化型癌症研究，从而改善癌症患者的预后。这 是通过以1)结构和功能研究为中心的三个重叠的研究目标来完成的 促进肿瘤发生的遗传和核变化，2)内在的细胞过程和途径 推动恶性转化和肿瘤进展；3)肿瘤外在因素，如免疫细胞 和环境致癌物质，有助于癌症的发展和抑制。关键科学 在前一资助期间取得的成就包括确定了RAD52蛋白在受损DNA修复中的作用 和基因组稳定性，识别转移基因信号和驱动神经内分泌的可用药途径 肿瘤(Net)的发病机制，以及破译外力作用的基本机制 影响肿瘤细胞代谢。CGP成员包括42名正式成员和9名准成员 四所学院的17个系。最近一年与癌症相关的年度直接同行评审资助 预算年度为670万美元，其中120万美元来自NCI。CGP成员高度协作，拥有 在过去四年中，撰写或共同撰写了384篇与癌症相关的同行评议出版物，其中22%(n= 85)方案内出版物、30%(n=117)方案间出版物和54%(n=206)机构间出版物。57 手稿出现在影响较大的期刊上(影响因子&>10)。富有成效的方案内/方案间和 多机构组织正在领导的调查反映了CGP研究的广度，包括 DNA修复和基因组不稳定的机制以及血液中的遗传和分子事件研究进展 细胞转化，动物肿瘤模型发展，肉瘤的可用药途径，新靶点和 Nets的治疗，G蛋白信号在乳腺癌干细胞和转移中的作用，免疫细胞激活和 肿瘤微环境、爱荷华州环境毒素致癌作用及耐药性 黑色素瘤。在CCSG的背景下，CGP是由其指导和驱动的基础科学基础 通过与其他霍尔登综合癌症中心(HCCC)的合作，翻译肿瘤学 程序。这一点的例证是CGP成员对肿瘤采购的指导，CGP提供的积分 基因组、免疫学和生物信息学支持涉及所有四个HCCC同事的临床研究 方案、方案间出版物的杰出数量以及CGP的主要领导作用 U01和两个NCI孢子奖助金的会员。

PROJECT SUMMARY/ABSTRACT Research in the Cancer Genes and Pathways (CGP) program focuses on defining essential molecular and biological mechanisms underlying tumor pathogenesis and successful therapy. The primary goal of this basic science program is to discover, characterize, and validate new tumor alterations (genetic, molecular and cellular pathways) to fuel translational cancer research that will lead to improved cancer patient outcomes. This is accomplished through three overlapping research aims centered on the study of 1) structural and functional genetic and nuclear alterations that promote tumorigenesis, 2) intrinsic cellular processes and pathways that drive malignant transformation and tumor progression, and 3) tumor extrinsic factors, such as immune cells and environmental carcinogens, that contribute to cancer development and suppression. Key scientific achievements over the prior funding period include defining the role of RAD52 protein in damaged DNA repair and genome stability, identifying metastatic gene signatures and druggable pathways driving neuroendocrine tumor (NET) pathogenesis, and deciphering fundamental mechanisms by which external mechanical forces influence tumor cell metabolism. CGP membership includes 42 full and nine associate members spanning seventeen departments across four colleges. Annual direct cancer-relevant peer-reviewed funding in the last budget year was $6.7 million with $1.2 million from the NCI. CGP members are highly collaborative, having authored or co-authored 384 cancer-related peer-reviewed publications in the past four years, with 22% (n= 85) intraprogrammatic, 30% (n= 117) interprogrammatic, and 54% (n= 206) inter-institutional publications. 57 manuscripts appeared in high impact journals (Impact Factor >10). Productive intra/interprogrammatic and multi-institutional groups are leading investigations that reflect the breadth of CGP research, including advances in mechanisms of DNA repair and genome instability, genetic and molecular events underlying blood cell transformation, animal tumor model development, druggable pathways in sarcoma, novel targets and therapies for NETs, G-protein signaling in breast cancer stemness and metastasis, immune cell activation and the tumor microenvironment, carcinogenic effects of Iowa environmental toxins, and drug resistance in melanoma. In the context of the CCSG, CGP is the basic science foundation that is guided by and drives translational oncology through its partnership with other Holden Comprehensive Cancer Center (HCCC) programs. This is exemplified by CGP member direction of tumor procurement, CGP provision of integral genomic, immunological, and bioinformatics support for clinical studies involving colleagues in all four HCCC programs, the outstanding number of interprogrammatic publications, and key leadership roles of CGP members on a U01 and two NCI SPORE grants.