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(申请人提供)：尽管癌症患者的年龄调整后的存活率在过去十年中有所改善，但随着美国人口老龄化，到2050年，新的癌症诊断总数和癌症发病率将大幅上升。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复杂化，目前这些毒性很难 由于缺乏可靠的临床使用模型和按时间顺序的年龄，预测不能准确预测毒性风险。衰老分子标志物的开发将有助于临床医生更准确地预测患者与治疗相关的毒性风险。夏普斯实验室的工作表明，细胞衰老因子p16INK4a可以作为人类分子年龄和生理储备的忠实生物标记物。重要的是，我们最近的临床试验数据表明，p16INK4a的表达与接受多西紫杉醇和环磷酰胺联合治疗(TC)的50岁早期乳腺癌患者的≥3/4级毒性反应的发生和入院治疗有关。因此，我们建议开发和验证使用p16INK4a生物标志物作为TC引起的毒性和相关住院的预测指标，以指导化疗方案的选择(药物和剂量)，并提醒临床医生考虑适当的预防策略。对中性粒细胞减少热等不良事件风险(或无风险)患者的准确预测，通过将生长因子治疗的目标对准那些骨髓抑制风险最高的患者，可以大幅节省医疗成本。此外，我们相信，我们的p16INK4a检测可以整合到现有的肿瘤学实践中，而不需要广泛的临床试验验证和医生培训，立即影响患者护理。这里建议的工作的完成，将使我们能够开发CLIA批准所需的分析性能数据，并巩固用于乳腺癌患者毒性风险评估的临床实用证据，这是商业化和市场采用所必需的。