Extratumoral biological determinants that decrease survival in older adults with glioblastoma

降低老年胶质母细胞瘤患者生存率的肿瘤外生物决定因素

• 批准号: 10741380
• 负责人: Derek Alan Wainwright
• 金额: $ 38.5万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-19 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741380
• 关键词: AP20187; Address; Adult; Adult Glioblastoma; Aftercare; Age; Age Years; Age of Onset; Aging; Alzheimer' s Disease; Animal Model; Autopsy; Benign; Biological; Brain; Brain Neoplasms; CDKN2A gene; Cells; Central Nervous System; Central Nervous System Neoplasms; Clinical; Clinical Trials; Cognitive; Dasatinib; Diagnosis; Elderly; Enrollment; Enzyme Inhibitor Drugs; Enzymes; Excision; Future; Gene Expression; Glioblastoma; Goals; Human; Immunity; Immunosuppression; Immunotherapy; Individual; Isocitrate Dehydrogenase; Knockout Mice; Kynurenine; Longevity; MGMT gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of central nervous system; Mediating; Metastatic Melanoma; Modeling; Monoclonal Antibodies; Mus; Neurology; Newly Diagnosed; Nivolumab; Outcome; Patients; Predictive Factor; Primary Brain Neoplasms; Prognosis; Prognostic Factor; Quercetin; Radiation; Radiation therapy; Reporting; Research; Resected; Standardization; Testing; Therapeutic immunosuppression; Tissues; Transgenic Model; Transgenic Organisms; Treatment Efficacy; Tryptophan; Tumor Bank; Universities; Wild Type Mouse; age group; age related; anticancer research; brain tissue; chemotherapy; enzyme activity; experience; human old age (65+); improved; in vivo; innovation; mouse model; negative affect; neuro-oncology; pharmacologic; phase III trial; programmed cell death protein 1; promoter; response; senescence; standard of care; survival outcome; temozolomide; therapy outcome; tumor; young adult

PROJECT SUMMARY Wild-type isocitrate dehydrogenase 1/2 glioblastoma (GBM) is the most common and aggressive form of malignant primary brain tumor in adults with a median age of onset at 68-70 years old. IDHwt GBM patients represent >70% of all GBM patient diagnoses, and among those individuals, older adults ≥65 years of age have a significantly decreased median overall survival (mOS) as compared to younger IDHwt GBM patients after treatment with standard of care radiation (RT) and temozolomide. We have also studied our ongoing clinical trial NCT04047706 and determined that newly-diagnosed older adult IDHwt MGMT promoter unmethylated GBM patients who are treated with RT, nivolumab (PD-1 mAb), and BMS-986205 [IDO enzyme inhibitor (IDOi)] have a decreased mOS as compared to similarly-treated younger GBM patients (p<0.0007). Strikingly, >33% of the youngest patients in this trial are still alive at 36 months post-treatment initiation. The poor prognosis of older adult GBM patients starkly contrasts with individuals who undergo treatment for other forms of aggressive cancer that arises outside of the brain. For example, former President Jimmy Carter was diagnosed with metastatic melanoma at 91 years of age and subsequently treated with immunotherapy. Strikingly, President Carter is still alive today at 98 years old. We hypothesize that major contributing factors to the worse survival outcomes of older adult GBM patients depend on: (i) how intratumoral gene expression levels do not change with differences in GBM patient age [Shah et al., 2021, Cell Reports. 37(10):110100], but rather, (ii) how extratumoral levels of immunosuppression increase in the older adult brain and potently suppress therapeutic efficacy in older adults with GBM [Ladomersky…Wainwright, 2020, Clinical Cancer Research. 26(19):5232-5245], and (iii) how extratumoral levels of senescence increase in the older adult brain [Kim…Wainwright, 2021, Neuro-Oncology Advances. 3(1):vdab125]. To understand the effects of advanced age-mediated changes in the extratumoral older adult brain, that in-turn, promotes the maladaptive response to GBM and/or GBM treatments, we will: (i) study extratumoral IDO-mediated immunosuppression of therapeutic efficacy in older adult mice with GBM; (ii) characterize extratumoral senescence levels and their effects on survival outcomes of older adult mice with GBM; (iii) quantify aging parameters in the extratumoral human brain from individuals across the lifespan that did or did not have GBM. This research is highly innovative and significant for its goal to understand aging- dependent mechanisms that contribute to worse survival outcomes in older adults with IDHwt GBM.

项目摘要 野生型异戊酸脱氢酶1/2胶质母细胞瘤（GBM）是最常见和侵略性的形式 成年人中位年龄为68-70岁的成年人的恶性原发性脑肿瘤。 IDHWT GBM患者 代表所有GBM患者诊断的70％，在这些人中，老年人≥65岁 与年轻的IDHWT GBM患者相比 用护理辐射（RT）和替莫唑胺的治疗。我们还研究了正在进行的临床试验 NCT04047706并确定新诊断的老年人IDHWT MGMT启动子未甲基化的GBM 接受RT，Nivolumab（PD-1 MAB）和BMS-986205治疗的患者[IDO酶抑制剂（IDOI）] 与经过类似治疗的年轻GBM患者相比，MOS降低（p <0.0007）。令人惊讶的是，> 33％ 该试验中最年轻的患者在治疗后36个月仍活着。老年预后不良 成年GBM患者与接受其他形式的侵略性癌症治疗的个体形成鲜明对比 那是在大脑外产生的。例如，前总统吉米·卡特（Jimmy Carter）被诊断出患有转移性 91岁的黑色素瘤，随后接受免疫疗法治疗。令人惊讶的是，卡特总统仍在 今天还活着98岁。我们假设主要的因素促成了较差的生存结果 老年人GBM患者依赖：（i）肿瘤内基因表达水平如何随着差异而变化 在GBM患者年龄中[Shah等，2021，细胞报告。 37（10）：110100]，但相反，（ii） 老年大脑的免疫抑制增加，并可能抑制老年人的治疗效率 与GBM [Ladomersky…Wainwright，2020年，临床癌症研究。 26（19）：5232-5245]和（iii） 老年大脑的感应水平增加[Kim…Wainwright，2021年，神经肿瘤学 进步。 3（1）：VDAB125]。了解高级年龄介导的肿瘤变化的影响 成年大脑，弯曲的，促进了对GBM和/或GBM治疗的不良适应反应，我们将：（i） 研究肿瘤外IDO介导的GBM老年小鼠治疗效率的免疫抑制； （ii） 表征肿瘤外感应水平及其对老年小鼠生存结果的影响 GBM; （iii）量化整个寿命中个体的肿瘤外人脑中的衰老参数 曾经或没有GBM。这项研究对于了解衰老的目标是高度创新和重要的 - 在IDHWT GBM的老年人中，依赖机制会导致较差的生存结果。