Genetics and Genomics of Leiomyosarcoma (LMS): Improved understanding of cancer biology and new approaches to diagnosis and treatment

平滑肌肉瘤 (LMS) 的遗传学和基因组学：增进对癌症生物学和诊断和治疗新方法的了解

• 批准号: 10493627
• 负责人: SCOTT Michael SCHUETZE
• 金额: $ 228.28万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493627
• 关键词: Achievement; Affect; Age; Autonomic nervous system; Behavior; Biological; Biological Markers; Biology; Black American; Blood Vessels; Bone Tissue; Cancer Biology; Carcinoma; Cervix carcinoma; Cessation of life; Chromosomal Instability; Clinic; Clinical; Clinical Research; Communities; Complex; DNA Repair; DNA Repair Gene; DNA-dependent protein kinase; Databases; Dedifferentiated Liposarcomas; Detection; Development; Diagnosis; Disease; Distant Metastasis; Dose; Doxorubicin; Economics; Elderly; Epidemiology; Esophageal carcinoma; Evolution; Frequencies; Gastrointestinal Stromal Tumors; Gastrointestinal tract structure; Gene Mutation; Genes; Genetic; Genomics; Germ-Line Mutation; Glioma; Goals; Heart; Hodgkin Disease; Image; Imatinib; Incidence; Infrastructure; Investigation; Knowledge; Laboratory Finding; Li-Fraumeni Syndrome; Limb structure; Liver; Malignant Fibrous Histiocytoma; Malignant Neoplasms; Metastatic Neoplasm to the Lung; Microscopic; Multiple Myeloma; Muscle; Mutate; Mutation; Myxoid Malignant Fibrous Histiocytoma; Names; Necrosis; Organ; Pathogenesis; Pathogenicity; Pathologic; Patient-Focused Outcomes; Patients; Phase I/II Trial; Plasma; Population; Prevalence; Prognosis; Public Health; Quality of life; Recording of previous events; Reporting; Research; Retroperitoneal Space; Risk; Role; SEER Program; Secondary to; Signal Pathway; Site; Smooth Muscle; Smooth Muscle Myocytes; Soft tissue sarcoma; Solid Neoplasm; Somatic Mutation; Susceptibility Gene; TP53 gene; Technology; Testicular Carcinoma; Therapeutic; Translating; Translational Research; Tumor Burden; Uterine Leiomyosarcoma; Uterus; Variant; Woman; aggressive therapy; anticancer research; base; bone; cancer genetics; cancer predisposition; career; clinical biomarkers; clinically relevant; data resource; drug development; effective therapy; epidemiology study; gene repair; genetic epidemiology; improved; improved outcome; insight; leiomyosarcoma; leukemia/lymphoma; liquid biopsy; malignant breast neoplasm; multidisciplinary; novel strategies; novel therapeutics; patient biomarkers; peripheral blood; personalized medicine; precursor cell; prognostic; programs; rare cancer; research study; resistance mechanism; response; sarcoma; success; targeted treatment; therapeutic target; translational impact; tumor; tumor heterogeneity; tumorigenesis

Overall: Project Summary / Abstract This SPORE entitled, Genetics and Genomics of Leiomyosarcoma (LMS): Improved understanding of cancer biology and new approaches to diagnosis and treatment, represents a collaborative initiative with strong expertise in sarcoma investigation, epidemiology, and cancer genetics. Our primary goals include advancing knowledge regarding the impact of somatic and germline mutation of TP53 and other DNA repair genes on the pathogenesis of leiomyosarcoma as well as translational and clinical research studies to facilitate significant and tangible improvements in the survival and quality of life of sarcoma patients. Although sarcomas are a diverse group of malignant tumors, we focus on leiomyosarcoma, a common soft tissue sarcoma, that is more frequent in women (uterine LMS), Black Americans and older adults. LMS because of its chromosomal instability, has a clinical behavior similar to other soft tissue sarcomas including undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, myxofibrosarcoma and MPNST. LMS is most often aggressive, and treatments are generally lacking. Sarcomas like leukemias and lymphomas, are mesodermal malignancies and carry biological significance disproportionate to their clinical prevalence. The diverse histotypes of sarcoma, and its relative rarity, demand that translational and clinical sarcoma research be conducted in the context of multi-disciplinary, multi-institutional initiatives. The projects are: (1) Genomic Vulnerabilities in Leiomyosarcoma; (2) Understanding the role of TP53 in LMS development; and (3) Applying liquid biopsy technologies to detect clinical response and mechanisms of resistance in the treatment of LMS. The projects are integrated with high functioning cores and programs for career enhancement and developmental projects. This multi-institutional SPORE will investigate contemporary and fundamental issues in sarcoma research, with its major focus on translational research including the development of new therapies and relevant clinical biomarkers. Project 1 identified an important new target in DNA repair which is so potent it permits combination with low dose doxorubicin and introduces this new therapy in advanced drug development studies and a Phase 1/2 trial. Project 3 pursues detection of LMS ultra-rare tumor fragments found in peripheral blood. Quantification of this ctDNA permits accurate assessment of tumor burden and accelerates exploration of tumor evolution. Project 2 is a genetic epidemiology study focusing on risk for sporadic LMS as well as secondary to Li-Fraumeni syndrome. The emphasis will be on TP53 gene, which is somatically mutated in almost (92%) all LMS patients and other genes affecting DNA repair. Patients with Li-Fraumeni have germline mutation of this gene.

总体：项目摘要 /摘要 这种标题为平滑肌肉瘤（LMS）的孢子，遗传学和基因组学：对癌症的理解有所提高 生物学和诊断和治疗的新方法代表了一项协作计划 肉瘤研究，流行病学和癌症遗传学方面的专业知识。我们的主要目标包括前进 关于TP53和其他DNA修复基因的体细胞和种系突变对体细胞和种系突变对该的影响的知识 平滑肌肉瘤的发病机理以及转化和临床研究，以促进重要和 肉瘤患者的生存和生活质量的切实改善。虽然肉瘤是多元化的 一组恶性肿瘤，我们专注于平民肉瘤（一种常见的软组织肉瘤），更频繁 在女性（子宫LMS），黑人美国人和老年人中。 LMS由于其染色体不稳定性，具有 临床行为类似于其他软组织肉瘤，包括未分化的多态性肉瘤， 去分化的脂肪肉瘤，粘纤维果肉瘤和mpnst。 LMS通常是侵略性的，治疗是 通常缺乏。白血病和淋巴瘤等肉瘤是中胚层恶性肿瘤，携带生物学 与其临床流行率不成比例。 肉瘤的各种组织型及其相对稀有性要求翻译和临床肉瘤研究 在多学科的多机构倡议中进行。项目是：（1）基因组 平滑肌肉瘤中的脆弱性； （2）了解TP53在LMS开发中的作用； （3） 应用液体活检技术来检测临床反应和抗药性机制 LMS的处理。这些项目与高功能的核心和计划集成在一起，以提高职业 和发展项目。 这种多机构的孢子将调查肉瘤研究中的当代和基本问题， 它主要关注转化研究，包括开发新疗法和相关临床 生物标志物。项目1确定了DNA维修中一个重要的新目标，这是如此有效，以至于允许组合 使用低剂量的阿霉素，并在晚期药物开发研究中引入了这种新疗法 1/2试验。项目3追求周围血液中发现的LMS超稀有肿瘤碎片的检测。定量 该ctDNA允许准确评估肿瘤负担，并加速肿瘤进化的探索。 项目2是一项遗传流行病学研究，侧重于零星LMS的风险以及继发于Li-Fraumeni的风险 综合征。重点将放在TP53基因上，该基因在几乎（92％）所有LMS患者中被体形突变 以及其他影响DNA修复的基因。 Li-Fraumeni患者具有该基因的种系突变。