Clonal hematopoiesis and therapy-emergent myeloid neoplasms in patients with ovarian cancer

卵巢癌患者的克隆性造血和治疗引起的骨髓肿瘤

基本信息

批准号：
10661251
负责人：
ELIZABETH MARY SWISHER
金额：
$ 64.9万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661251
关键词：
Acute Myelocytic Leukemia Address Age Alleles BRCA1 gene BRCA2 gene Biology Blood Blood Cells Blood specimen Cancer Patient Cancer Survivor Cells Chromosome abnormality Clinical Clonal Evolution Clonal Expansion Collection Complex Country Cytotoxic Chemotherapy Data Development Diagnosis Disease Dose Dysmyelopoietic Syndromes Early Diagnosis Early Intervention Enrollment Exposure to Gene Frequency Genes Genetic Genetic Determinism Germ-Line Mutation Goals Hematologic Neoplasms Hematological Disease Hematopoiesis Hematopoietic Neoplasms Incidence Individual Intervention Karyotype Kinetics Learning Leukocytes Life Maintenance Maintenance Therapy Malignant - descriptor Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Marrow Measures Modeling Molecular Abnormality Monitor Mutate Mutation Mutation Analysis Myelogenous Myeloid Cells Myeloproliferative disease Neoplasms Non-Malignant Oncogenic Oral Pathogenicity Patient-Focused Outcomes Patients Persons Platinum Poly(ADP-ribose) Polymerase Inhibitor Precancerous Conditions Predisposition Prevalence Prevention Prognosis Prospective Studies Radiation therapy Recording of previous events Reporting Risk Risk Factors Second Primary Cancers Secondary Prevention Selection for Treatments Signal Transduction Solid Neoplasm Survivors Susceptibility Gene TP53 gene Time Tobacco use Toxic effect Treatment-related toxicity Woman age related cancer genetics cancer therapy cancer type chemotherapy clinical diagnosis cost cytotoxic driver mutation drug maintenance genetic variant genome integrity improved improved outcome induced pluripotent stem cell inhibitor therapy insight leukemia malignant breast neoplasm neoplastic normal aging novel patient subsets prevent primary outcome prospective response risk minimization risk mitigation stem cell model surveillance strategy therapy development therapy outcome transcriptome treatment optimization

项目摘要

ABSTRACT Most women diagnosed with ovarian cancer are treated with many rounds of chemotherapy and often years of a an oral PARP inhibitor drug for “maintenance” therapy. These therapies have extended life for women with metastatic ovarian cancer, but at the cost of increased toxicity. One long term toxicity is the development of leukemia or other blood disorders, often called therapy related myeloid neoplasia (TMN). These secondary malignancies are a known risk of chemotherapy, and ovarian cancer survivors have one of the highest rates of TMN of any group of cancer survivors. The diagnosis of TMN is usually fatal, with survival measured in months. TMN is nearly always detectable in a pre-malignant state as a clonal expansion of blood cells years before a clinical diagnosis. Non-malignant clonal expansion of white blood cells is often termed clonal hematopoiesis of indeterminate potential (CHIP). The interval between CHIP and development of blood cancers is many years, providing an opportunity to better understand the natural progression of TMN and perhaps a window for intervention and prevention. Clonal hematopoiesis (CH) can also arise during normal aging, but only a small fraction progress to a blood cancer. A better understanding of the natural progression of CH in ovarian cancer survivors is needed to tailor safe and effective ovarian cancer therapies. Our team is co-led by experts in ovarian cancer genetics and hematological malignancies and will enroll 2000 survivors across the country with ovarian cancer, including 200 with CH. We will follow these individuals with CH with serial blood draws obtained every 6 months for at least 3 years to define risk factors for progression of CH to TMN. For a subset of patients with acquisition of TMN during the study, we will evaluate clonal dynamics and genetic and chromosomal alterations over time at the single cell level, which will provide novel data on the changes that occur in the malignant transformation of myeloid cells in response to cytotoxic therapy. In this way, we will learn who is at risk of TMN and develop strategies for the monitoring and prevention of this deadly long-term treatment toxicity. These studies will improve outcomes for patients with ovarian cancer and also will be applicable to survivors or many cancer types, who are also at risk for TMN.

抽象的大多数被诊断患有卵巢癌的女性都会接受多轮化疗和治疗这些疗法通常需要多年的口服 PARP 抑制剂药物来进行“维持”治疗。延长了患有转移性卵巢癌的女性的生命，但代价是毒性增加。一种长期毒性是白血病或其他血液疾病的发展，通常称为治疗相关的骨髓瘤（TMN）是已知的继发性恶性肿瘤风险。化疗和卵巢癌幸存者是所有群体中 TMN 发生率最高的人群之一 TMN 的诊断通常是致命的，生存期以月为单位。 TMN 几乎总是可以在癌前状态下检测到，表现为血细胞的克隆扩增临床诊断前数年通常会出现白细胞非恶性克隆性扩增。称为不确定潜力克隆造血 (CHIP) CHIP 和之间的间隔。血癌的发展已经有很多年了，这提供了一个更好地了解血癌的机会 TMN 的自然进展可能是克隆干预和预防的窗口。造血作用（CH）也可能在正常衰老过程中出现，但只有一小部分进展为造血作用更好地了解卵巢癌中 CH 的自然进展。我们的团队由幸存者共同领导，以制定安全有效的卵巢癌疗法。卵巢癌遗传学和血液恶性肿瘤专家，将招收 2000 名全国各地患有卵巢癌的幸存者，其中包括 200 名患有 CH 的患者，我们将关注这些患者。慢性肝炎患者每 6 个月进行一次连续抽血，持续至少 3 年定义 CH 进展为 TMN 的风险因素。 TMN 在研究期间，我们将评估克隆动力学以及遗传和染色体单细胞水平随时间的变化，这将提供有关变化的新数据发生在响应细胞毒治疗的骨髓细胞的恶性转化中。通过这种方式，我们将了解哪些人面临 TMN 风险，并制定监测和预防策略预防这种致命的长期治疗毒性这些研究将改善治疗结果。卵巢癌患者，也适用于幸存者或多种癌症类型，也面临 TMN 的风险。