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: 10705677
• 负责人: JONATHAN Alfred FLETCHER
• 金额: $ 227.42万
• 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/10705677
• 关键词: Acceleration; 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; Combined Modality Therapy; 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; Institution; 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; anticancer research; bone; cancer genetics; cancer predisposition; career; clinical biomarkers; clinically relevant; data resource; drug development; effective therapy; 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 这篇题为《平滑肌肉瘤的遗传学和基因组学》的文章：提高了对癌症的认识 生物学和新的诊断和治疗方法，代表着与强大的 在肉瘤调查、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推进 关于TP53和其他DNA修复基因的体细胞和种系突变对 平滑肌肉瘤的发病机制以及翻译和临床研究，以促进重要的和 肉瘤患者生存和生活质量的切实改善。虽然肉瘤是一种多样化的 在恶性肿瘤组中，我们重点关注的是平滑肌肉瘤，这是一种常见的软组织肉瘤，它是比较常见的 在女性(子宫LMS)、美国黑人和老年人中。LMS由于其染色体不稳定，具有 临床表现类似于其他软组织肉瘤，包括未分化的多形性肉瘤， 去分化脂肪肉瘤、粘液纤维肉瘤和MPNST。LMS通常是侵略性的，治疗是 普遍缺乏。肉瘤像白血病和淋巴瘤一样，是中胚层恶性肿瘤，具有生物学特性。 与其临床流行率不成比例的重要性。 肉瘤组织类型的多样性及其相对少见，要求对其进行翻译和临床研究。 将在多学科、多机构倡议的背景下进行。这些项目是：(1)基因组 平滑肌肉瘤的脆弱性；(2)了解TP53在LMS发生中的作用；以及(3) 应用液体活检技术检测耐甲氧西林的临床反应及耐药机制 LMS的治疗。这些项目与高功能的核心和职业提升计划相结合 和发展项目。 这个多机构的孢子将调查肉瘤研究中的当代和基本问题， 它主要专注于转化性研究，包括新疗法的开发和相关临床 生物标志物。项目1在DNA修复中发现了一个重要的新靶点，它的效力如此强大，以至于可以结合 小剂量阿霉素，并在高级药物开发研究和一个阶段推出这种新疗法 1/2试验。项目3致力于检测在外周血中发现的LMS超罕见肿瘤碎片。量化 这种ctDNA可以准确地评估肿瘤的负担，并加速探索肿瘤的进化。 项目2是一项遗传流行病学研究，重点是散发性LMS的风险以及Li-Fraumeni的继发性 综合症。重点将放在TP53基因上，该基因在几乎(92%)LMS患者中发生体细胞突变 以及其他影响DNA修复的基因。Li-Fraumeni患者存在该基因的种系突变。