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：项目总结/摘要 这孢子题为，遗传学和基因组学的平滑肌肉瘤（LMS）：提高认识的癌症 生物学和新的诊断和治疗方法，代表了一个合作倡议， 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 关于TP 53和其他DNA修复基因的体细胞和生殖系突变对 平滑肌肉瘤的发病机制以及转化和临床研究，以促进重要的， 肉瘤患者的生存率和生活质量得到切实改善。虽然肉瘤是一种多样的 在恶性肿瘤中，我们关注平滑肌肉瘤，一种常见的软组织肉瘤， 女性（子宫LMS）、美国黑人和老年人。LMS由于其染色体的不稳定性， 临床表现与其他软组织肉瘤包括未分化多形性肉瘤相似， 去分化脂肪肉瘤、粘液纤维肉瘤和MPNST。LMS通常是侵略性的，治疗方法是 普遍缺乏。肉瘤像白血病和淋巴瘤一样，是中胚层恶性肿瘤， 与其临床患病率不成比例。 肉瘤组织类型的多样性及其相对的罕见性要求肉瘤的转化和临床研究 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TP 53在LMS发展中的作用;（3） 应用液体活检技术检测临床反应和耐药机制 治疗LMS。这些项目与高功能核心和职业提升计划相集成 和发展项目。 这个多机构的孢子将调查当代和基本问题，在肉瘤研究， 它的主要重点是转化研究，包括新疗法的开发和相关的临床 生物标志物。项目1确定了DNA修复中一个重要的新靶点，该靶点非常有效，可以结合 与低剂量阿霉素，并介绍了这种新的治疗在先进的药物开发研究和阶段 1/2审判。项目3旨在检测外周血中发现的LMS超罕见肿瘤碎片。定量 这种ctDNA的快速扩增允许准确评估肿瘤负荷并加速肿瘤演变的探索。 项目2是一项遗传流行病学研究，重点关注散发性LMS以及继发于Li-Fraumeni的风险 综合征重点将放在TP 53基因上，几乎所有LMS患者（92%）都发生了体细胞突变 和其他影响DNA修复的基因。Li-Fraumeni患者存在该基因的种系突变。