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.

总体而言：项目摘要/摘要 该 SPORE 的标题是平滑肌肉瘤 (LMS) 的遗传学和基因组学：增进对癌症的了解 生物学和新的诊断和治疗方法代表了一项具有强大实力的合作倡议 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转化和临床研究，以促进重要和 肉瘤患者的生存率和生活质量得到切实改善。尽管肉瘤是多种多样的 在恶性肿瘤组中，我们重点关注平滑肌肉瘤，这是一种常见的软组织肉瘤，更常见 女性（子宫 LMS）、美国黑人和老年人。 LMS由于其染色体不稳定，具有 临床行为与其他软组织肉瘤相似，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 通常具有攻击性，治疗方法是 普遍缺乏。肉瘤如白血病和淋巴瘤，是中胚层恶性肿瘤并携带生物 其重要性与其临床患病率不成比例。 肉瘤的不同组织型及其相对罕见，要求进行转化和临床肉瘤研究 应在多学科、多机构举措的背景下进行。这些项目是：（1）基因组 平滑肌肉瘤的脆弱性； (2)了解TP53在LMS发展中的作用；和（3） 应用液体活检技术检测临床反应和耐药机制 LMS 的治疗。这些项目与高功能核心和职业提升计划相结合 和发展项目。 这个多机构 SPORE 将调查肉瘤研究中的当代和基本问题， 它的主要重点是转化研究，包括新疗法和相关临床的开发 生物标志物。项目 1 确定了 DNA 修复中的一个重要新靶点，该靶点非常有效，可以进行组合 与低剂量阿霉素一起使用，并将这种新疗法引入高级药物开发研究和阶段 1/2 试用。项目 3 致力于检测外周血中发现的 LMS 极其罕见的肿瘤碎片。量化 对这种 ctDNA 的分析可以准确评估肿瘤负荷并加速对肿瘤进化的探索。 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 综合症。重点是 TP53 基因，几乎 (92%) 所有 LMS 患者都发生体细胞突变 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。