Extratumoral biological determinants that decrease survival in older adults with glioblastoma

项目摘要 野生型异柠檬酸脱氢酶1/2胶质母细胞瘤（GBM）是胶质母细胞瘤的最常见和侵袭性形式。 成人恶性原发性脑肿瘤，发病年龄中位数为68-70岁。IDHwt GBM患者 占所有GBM患者诊断的>70%，并且在这些个体中，年龄≥65岁的老年人 与年轻的IDHwt GBM患者相比， 用标准护理放射（RT）和替莫唑胺治疗。我们还研究了我们正在进行的临床试验 NCT 04047706，并确定新诊断的老年人IDHwt MGMT启动子未甲基化GBM 接受RT、纳武单抗（PD-1 mAb）和BMS-986205 [IDO酶抑制剂（IDOi）]治疗的患者， 与接受类似治疗的年轻GBM患者相比，mOS降低（p<0.0007）。令人惊讶的是，33%以上的 本试验中最年轻的患者在治疗开始后36个月仍然存活。老年人预后不良 成年GBM患者与接受其他形式侵袭性癌症治疗的个体形成鲜明对比 产生于大脑之外。例如，前总统吉米·卡特被诊断出患有转移性癌症， 在91岁时患有黑色素瘤，随后用免疫疗法治疗。令人惊讶的是，卡特总统仍然是 活到了98岁我们假设，主要的促成因素，较差的生存结果， 老年GBM患者取决于：（i）肿瘤内基因表达水平如何不随差异而变化 在GBM患者年龄中[Shah等人，2021，细胞报告。37（10）：110100]，而是，（ii）肿瘤外水平如何 老年人大脑中的免疫抑制增加并有效抑制老年人的治疗效果 与GBM [Ladomersky.温赖特，2020，临床癌症研究。26（19）：5232-5245]，以及（iii）如何 老年人大脑中肿瘤外衰老水平增加[Kim.温赖特，2021，神经肿瘤学 预付款。3（1）：VDAB 125]。为了了解晚期年龄介导的肿瘤外变化的影响， 老年人的大脑，这反过来又促进了对GBM和/或GBM治疗的适应不良反应，我们将：（i） 研究肿瘤外IDO介导的免疫抑制在患有GBM的老年小鼠中的治疗功效;（ii） 表征肿瘤外衰老水平及其对老年小鼠存活结果的影响， GBM;（iii）量化来自个体的肿瘤外人脑在整个生命周期中的老化参数， 是否患有GBM这项研究具有高度的创新性，对于了解衰老的目标具有重要意义- 依赖性机制导致IDHwt GBM老年人的生存结局更差。

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.