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: 9031454
• 负责人: Amanda Elam
• 金额: $ 57.22万
• 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/9031454
• 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; Clinical; Clinical Trials; Cost Savings; Coupling; Cyclophosphamide; Data; Development; Doxorubicin; Education; Elderly; Environment; Fatigue; Fright; Gold; Growth; Health Care Costs; Hospitalization; Hospitals; Human; Incidence; Life; Longevity; Malignant Neoplasms; Marketing; 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; Staging; 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 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（由适用提供）：尽管过去十年中癌症患者的年龄调整后的存活率有所改善，但随着美国人口衰老的衰老，在2050年到2050年，新的癌症诊断和癌症发病率的总数将急剧增加。在65岁以上的患者中，这些新病例中的绝大多数将在65岁以上的患者中。 由于缺乏可靠，临床使用模型和年龄年龄的预测，预测并不是毒性风险的准确预测指标。衰老的分子标志物的发展将有助于临床医生预测患者的治疗风险与更确定性相关的毒性。 Sharples实验室的工作表明，细胞感官p16ink4a可以用作人类分子年龄和生理储备的忠实生物标志物。重要的是，我们最新临床试验的数据表明，P16INK4A表达与发生生命威胁3/4级毒性的发生和患者≥50岁的医院入院相关，而早期乳腺癌接受了多西他赛和环磷酰胺治疗（TC）。因此，我们建议开发和验证使用P16INK4A生物标志物作为TC诱导的毒性和相关住院治疗的预测指标，以指导化学疗法方案（药物和剂量）的选择，并提醒临床医生考虑适当的预防策略。通过将生长因子治疗靶向最高的骨髓抑制风险患者，可以准确预测不良事件（或缺乏风险）的患者（或缺乏风险），从而可以节省大量医疗费用。此外，我们认为我们的P16INK4A可以纳入现有的肿瘤学实践中，而无需进行广泛的临床试验验证和体育教育，从而立即影响患者护理。完成此处提出的工作的完成，将使我们能够制定CLIA批准所必需的分析性能数据，并巩固临床实用性的毒性风险评估的证据，以评估乳腺癌患者的毒性风险评估，以进行商业化和采用市场采用。