Extratumoral biological determinants that decrease survival in older adults with glioblastoma

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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.