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