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

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

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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出患有卵巢癌的妇女接受了多轮化疗和通常，多年的口服PARP抑制剂药物进行“维持”疗法。这些疗法具有卵巢癌转移性妇女的寿命延长，但毒性增加。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髓样肿瘤（TMN）。这些次要恶性肿瘤是已知的风险化学疗法和卵巢癌存活率是任何组中TMN的最高率之一癌症存活。 TMN的诊断通常是致命的，生存期在几个月内测量。作为血细胞的克隆膨胀，TMN几乎总是可以在预防态下检测到临床诊断前几年。白细胞的非恶性克隆膨胀通常是称为不确定电势（CHIP）的克隆造血。芯片和血液癌的发展是多年的，提供了一个机会来更好地了解 TMN的自然发展，也许是干预和预防的窗口。克隆在正常衰老期间也可能出现造血（CH），但只有很小的部分进展到血液癌。更好地了解卵巢癌中CH的自然发展需要幸存者来量身定制安全有效的卵巢癌疗法。我们的团队由卵巢癌遗传学和血液系统恶性肿瘤的专家，并将招募2000年全国各地患有卵巢癌的幸存者，其中包括200个。我们将遵循这些每6个月每6个月获得连续血抽取的人至少3年获得定义CH向TMN的进展的危险因素。对于收购的一部分患者 TMN在研究期间，我们将评估克隆动力学以及遗传和染色体随着时间的推移在单细胞级别的变化，这将提供有关变化的新数据在这个方式，我们将了解谁有TMN的风险，并制定监视策略和预防这种致命的长期治疗毒性。这些研究将改善结果卵巢癌患者，也适用于冲浪者或许多癌症类型也有TMN的风险。