Biomarkers of Molecular Age to Predict the Toxicity of Cancer Chemotherapy

分子年龄的生物标志物可预测癌症化疗的毒性

• 批准号: 9205493
• 负责人: HYMAN MUSS
• 金额: $ 54.26万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-12 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205493
• 关键词: Adjuvant Chemotherapy; Admission activity; Adoption; Adverse effects; Adverse event; Affect; Age; Age-Years; Aging; Anemia; Biological Assay; Biological Markers; Bone Marrow; Breast Cancer Patient; CDKN2A gene; Cancer Patient; Cell Aging; Cessation of life; Chemotherapy-Oncologic Procedure; Chronology; Clinical; Clinical Trials; Cost Savings; Coupling; Cyclophosphamide; Data; Development; Doxorubicin; Education; Elderly; Environment; Fatigue; Fright; Gold; Growth Factor; Health Care Costs; Hospitalization; Hospitals; Human; Incidence; Life; Longevity; Malignant Neoplasms; Measures; Modeling; Molecular; Morbidity - disease rate; Mortality Decline; Mucositis; Myelosuppression; Neuropathy; Neutropenia; Neutropenic Fever; Oncologist; Organism; Patient Care; Patient risk; Patients; Performance; Pharmaceutical Preparations; Physicians; Physiological; Population; Predictive Value; Prevention strategy; Quality of life; Regimen; Relapse; Research; Risk; Risk Assessment; Risk stratification; T-Lymphocyte; Thrombocytopenia; Toxic effect; Toxicity due to chemotherapy; Training; Treatment Effectiveness; Treatment Factor; Treatment-related toxicity; United States; Validation; Work; acute toxicity; age related; aging population; base; cancer care; cancer diagnosis; cancer survival; cancer therapy; cancer type; chemotherapy; cohort; commercialization; cost effective; docetaxel; dosage; frailty; high risk; improved; in vivo; malignant breast neoplasm; molecular marker; older patient; older women; predictive modeling; public health relevance; regenerative; senescence

 DESCRIPTION (provided by applicant): Although the age-adjusted survival of cancer patients has improved over the last decade, with US population aging, there will be a sharp rise in total numbers of new cancer diagnoses and cancer morbidity through 2050. The vast majority of these new cases will be in patients over the age of 65. Treatment of cancer in the elderly is complicated by the increased risk of treatment-related toxicities, which are currently difficult to predict due to the lack of reliable, clinical use models and chronological age is not an accurate predictor of toxicity risks. Development of a molecular marker of aging would help clinicians to predict a patients' risk of treatment- related toxicity with higher certainty. Work in the Sharples lab has revealed that the cellular senescent factor, p16INK4a, can be used as a faithful biomarker of molecular age and physiologic reserve in humans. Importantly, data from our recent clinical trial demonstrate that p16INK4a expression correlates with the occurrence of life- threatening grade 3/4 toxicities and hospital admission in patients' ≥50 years of age with early stage breast cancer receiving combination docetaxel and cyclophosphamide therapy (TC). Therefore, we propose to develop and validate the use of p16INK4a biomarker as a predictor of TC-induced toxicities and related hospitalizations to guide choice of chemotherapy regimen (drugs and dosage) and to alert clinicians to consider appropriate prevention strategies. Accurate prediction of patients at risk (or lack of risk) of adverse events such as neutropenic fever could result in substantial healthcare cost savings by targeting growth factor treatment to those at highest risk of myelosuppression. Additionally, we believe that our p16INK4a assay could be incorporated into existing oncological practice without the need for extensive clinical trial validation and physician education, immediately impacting patient care. Completion of the work proposed here, will allow us to develop analytical performance data necessary for CLIA approval and solidify evidence of clinical utility for toxicity risk assessment in breast cancer patients necessary for commercialization and market adoption.

 描述（由申请人提供）：尽管癌症患者的年龄调整生存率在过去十年中有所改善，但随着美国人口老龄化，到2050年，新癌症诊断和癌症发病率的总数将急剧上升。这些新病例中的绝大多数将发生在65岁以上的患者中。老年人癌症的治疗因治疗相关毒性的风险增加而变得复杂，目前难以确定治疗相关毒性的风险。 由于缺乏可靠的临床使用模型和实际年龄，预测毒性风险并不准确。开发一种衰老的分子标志物将有助于临床医生更准确地预测患者发生治疗相关毒性的风险。Sharples实验室的工作揭示了细胞衰老因子p16INK4a可以作为人类分子年龄和生理储备的可靠生物标志物。重要的是，来自我们最近的临床试验的数据表明，在接受多西他赛和环磷酰胺联合治疗（TC）的年龄≥ 50岁的早期乳腺癌患者中，p16INK4a表达与危及生命的3/4级毒性的发生和住院相关。因此，我们建议开发和验证p16INK4a生物标志物作为TC诱导的毒性和相关住院的预测因子，以指导化疗方案（药物和剂量）的选择，并提醒临床医生考虑适当的预防策略。准确预测患者的风险（或缺乏风险）的不良事件，如血小板减少性发热可能会导致大量的医疗保健成本节省的目标生长因子治疗的骨髓抑制的风险最高的人。此外，我们相信我们的p16INK4a检测可以纳入现有的肿瘤学实践，而无需广泛的临床试验验证和医生教育，立即影响患者护理。完成本文提出的工作，将使我们能够开发CLIA批准所需的分析性能数据，并巩固商业化和市场采用所需的乳腺癌患者毒性风险评估的临床实用性证据。