Neuronal differentiation drives the antitumor activity of mitogen-activated protein kinase kinase (MEK) inhibition in glioblastoma.

Background: Epidermal growth factor receptor (EGFR) amplification is found in nearly 40%-50% of glioblastoma cases. Several EGFR inhibitors have been tested in glioblastoma but have failed to demonstrate long-term therapeutic benefit, presumably because of acquired resistance. Targeting EGFR downstream signaling with mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) inhibitors would be a more effective approach to glioblastoma treatment. We tested the therapeutic potential of MEK1/2 inhibitors in glioblastoma using 3D cultures of glioma stem-like cells (GSCs) and mouse models of glioblastoma. Methods: Several MEK inhibitors were screened in an unbiased high-throughput platform using GSCs. Cell death was evaluated using flow cytometry and Western blotting (WB) analysis. RNA-seq, real-time quantitative polymerase chain reaction, immunofluorescence, and WB analysis were used to identify and validate neuronal differentiation. Results: Unbiased screening of multiple MEK inhibitors in GSCs showed antiproliferative and apoptotic cell death in sensitive cell lines. An RNA-seq analysis of cells treated with trametinib, a potent MEK inhibitor, revealed upregulation of neurogenesis and neuronal differentiation genes, such as achaete-scute homolog 1 (ASCL1), delta-like 3 (DLL3), and neurogenic differentiation 4 (NeuroD4). We validated the neuronal differentiation phenotypes in vitro and in vivo using selected differentiation markers (ß-III-tubulin, ASCL1, DLL3, and NeuroD4). Oral treatment with trametinib in an orthotopic GSC xenograft model significantly improved animal survival, with 25%-30% of mice being long-term survivors. Conclusions: Our findings demonstrated that MEK1/2 inhibition promotes neuronal differentiation in glioblastoma, a potential additional mechanism of action of MEK1/2 inhibitors. Thus, MEK inhibitors could be efficacious in glioblastoma patients with activated EGFR/MAPK signaling.

Characterization of recurrence patterns and outcomes of medulloblastoma in adults: The University of Texas MD Anderson Cancer Center experience.

Background: Medulloblastoma in adults is rare and treatment decisions are largely driven from pediatric literature. We sought to characterize recurrent medulloblastoma in adults. Methods: From a single-institution dataset of 200 adult patients diagnosed with medulloblastoma during 1978-2017, those with recurrence were analyzed for clinical features, treatment, and outcome. Results: Of the 200 patients, 82 (41%) with median age of 29 years (18-59) had recurrence after a median follow-up time of 8.4 years (95% CI = 7.1, 10.3). Of these, 30 (37%) were standard-risk, 31 (38%) were high-risk, and 21 (26%) had unknown-risk diseases at the time of initial diagnosis. Forty-eight (58%) presented with recurrence outside the posterior fossa, of whom 35 (43%) had distant recurrence only. Median Progression-free survival (PFS) and OS from initial surgery were 33.5 and 62.4 months, respectively. Neither PFS nor OS from initial diagnosis differed between the standard-risk and high-risk groups in those who experience recurrence (P = .505 and .463, respectively). Median OS from first recurrence was 20.3 months, also with no difference between the standard-risk and high-risk groups (P = .518). Recurrences were treated with combinations of re-resection (20 patients; 25%), systemic chemotherapy (61 patients; 76%), radiation (29 patients; 36%), stem cell transplant (6 patients; 8%), and intrathecal chemotherapy (4 patients; 5%). Patients who received radiation at recurrence had better OS (32.9 months) than those who did not (19.2 months) (P = .034). Conclusions: Recurrent medulloblastoma in adults has a poor prognosis irrespective of initial risk stratification. Recurrence commonly arises outside the posterior fossa years after initial diagnosis.

Preclinical Models of Low-Grade Gliomas.

Diffuse infiltrating low-grade glioma (LGG) is classified as WHO grade 2 astrocytoma with isocitrate dehydrogenase (IDH) mutation and oligodendroglioma with IDH1 mutation and 1p/19q codeletion. Despite their better prognosis compared with glioblastoma, LGGs invariably recur, leading to disability and premature death. There is an unmet need to discover new therapeutics for LGG, which necessitates preclinical models that closely resemble the human disease. Basic scientific efforts in the field of neuro-oncology are mostly focused on high-grade glioma, due to the ease of maintaining rapidly growing cell cultures and highly reproducible murine tumors. Development of preclinical models of LGG, on the other hand, has been difficult due to the slow-growing nature of these tumors as well as challenges involved in recapitulating the widespread genomic and epigenomic effects of IDH mutation. The most recent WHO classification of CNS tumors emphasizes the importance of the role of IDH mutation in the classification of gliomas, yet there are relatively few IDH-mutant preclinical models available. Here, we review the in vitro and in vivo preclinical models of LGG and discuss the mechanistic challenges involved in generating such models and potential strategies to overcome these hurdles.

Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between objective response rate and median overall survival.

Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single-arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1% [95% CI 4.23; 8.76%] for cytotoxic chemothera + pies (ORR = 7.59% for lomustine, 7.57% for temozolomide, 0.64% for irinotecan, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2= 0.4078, P < .0001), biologics (R2= 0.4003, P = .0003), and immunotherapy trials (R2= 0.8994, P < .0001), but not anti-angiogenic agents (R2= 0, P = .8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2= 0.3900, P < .0001; mOS [weeks] = 1.4xORR + 24.8). Assuming an ineffective cytotoxic (control) therapy has ORR = 7.6%, the average ORR for lomustine and temozolomide trials, a sample size of ≥40 patients with target ORR>25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P < .01) and adequate power (>80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR >25% (which translates to a median OS of approximately 15 months) and a sample size of ≥40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study.

Low-risk meningioma: Initial outcomes from NRG Oncology/RTOG 0539.

BACKGROUND: Three- and five-year progression-free survival (PFS) for low-risk meningioma managed with surgery and observation reportedly exceeds 90%. Herewith we summarize outcomes for low-risk meningioma patients enrolled on NRG/RTOG 0539. METHODS: This phase II trial allocated patients to one of three groups per World Health Organization grade, recurrence status, and resection extent. Low-risk patients had either gross total (GTR) or subtotal resection (STR) for a newly diagnosed grade 1 meningioma and were observed after surgery. The primary endpoint was 3-year PFS. Adverse events (AEs) were scored using Common Terminology Criteria for Adverse Events (CTCAE) version 3. RESULTS: Among 60 evaluable patients, the median follow-up was 9.1 years. The 3-, 5-, and 10-year rates were 91.4% (95% CI, 84.2 to 98.6), 89.4% (95% CI, 81.3 to 97.5), 85.0% (95% CI, 75.3 to 94.7) for PFS and 98.3% (95% CI, 94.9 to 100), 98.3%, (95% CI, 94.9 to 100), 93.8% (95% CI, 87.0 to 100) for overall survival (OS), respectively. With centrally confirmed GTR, 3/5/10y PFS and OS rates were 94.3/94.3/87.6% and 97.1/97.1/90.4%. With STR, 3/5/10y PFS rates were 83.1/72.7/72.7% and 10y OS 100%. Five patients reported one grade 3, four grade 2, and five grade 1 AEs. There were no grade 4 or 5 AEs. CONCLUSIONS: These results prospectively validate high PFS and OS for low-risk meningioma managed surgically but raise questions regarding optimal management following STR, a subcohort that could potentially benefit from adjuvant therapy.

Efficacy of laser interstitial thermal therapy (LITT) for newly diagnosed and recurrent IDH wild-type glioblastoma.

Background: Treatment options for unresectable new and recurrent glioblastoma remain limited. Laser ablation has demonstrated safety as a surgical approach to treating primary brain tumors. The LAANTERN prospective multicenter registry (NCT02392078) data were analyzed to determine clinical outcomes for patients with new and recurrent IDH wild-type glioblastoma. Methods: Demographics, intraprocedural data, adverse events, KPS, health economics, and survival data were prospectively collected and then analyzed on IDH wild-type newly diagnosed and recurrent glioblastoma patients who were treated with laser ablation at 14 US centers between January 2016 and May 2019. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable differences in survival, and median survival numbers. Results: A total of 29 new and 60 recurrent IDH wild-type WHO grade 4 glioblastoma patients were treated. Positive MGMT promoter methylation status was present in 5/29 of new and 23/60 of recurrent patients. Median physician-estimated extent of ablation was 91%-99%. Median overall survival (OS) was 9.73 months (95% confidence interval: 5.16, 15.91) for newly diagnosed patients and median post-procedure survival was 8.97 months (6.94, 12.36) for recurrent patients. Median OS for newly diagnosed patients receiving post-LITT chemo/radiation was 16.14 months (6.11, not reached). Factors associated with improved survival were MGMT promoter methylation, adjuvant chemotherapy within 12 weeks, and tumor volume <3 cc. Conclusions: Laser ablation is a viable option for patients with new and recurrent glioblastoma. Median OS for IDH wild-type newly diagnosed glioblastoma is comparable to outcomes observed in other tumor resection studies when those patients undergo radiation and chemotherapy following LITT.

Liquid biopsy in gliomas: A RANO review and proposals for clinical applications.

BACKGROUND: There is an extensive literature highlighting the utility of blood-based liquid biopsies in several extracranial tumors for diagnosis and monitoring. METHODS: The RANO (Response Assessment in Neuro-Oncology) group developed a multidisciplinary international Task Force to review the English literature on liquid biopsy in gliomas focusing on the most frequently used techniques, that is circulating tumor DNA, circulating tumor cells, and extracellular vesicles in blood and CSF. RESULTS: ctDNA has a higher sensitivity and capacity to represent the spatial and temporal heterogeneity in comparison to circulating tumor cells. Exosomes have the advantages to cross an intact blood-brain barrier and carry also RNA, miRNA, and proteins. Several clinical applications of liquid biopsies are suggested: to establish a diagnosis when tissue is not available, monitor the residual disease after surgery, distinguish progression from pseudoprogression, and predict the outcome. CONCLUSIONS: There is a need for standardization of biofluid collection, choice of an analyte, and detection strategies along with rigorous testing in future clinical trials to validate findings and enable entry into clinical practice.

Imaging Primer on Chimeric Antigen Receptor T-Cell Therapy for Radiologists.

Chimeric antigen receptor (CAR) T-cell therapy is a recently approved breakthrough treatment that has become a new paradigm in treatment of recurrent or refractory B-cell lymphomas and pediatric or adult acute lymphoid leukemia. CAR T cells are a type of cellular immunotherapy that artificially enhances T cells to boost eradication of malignancy through activation of the native immune system. The CAR construct is a synthetically created functional cell receptor grafted onto previously harvested patient T cells, which bind to preselected tumor-associated antigens and thereby activate host immune signaling cascades to attack tumor cells. Advantages include a single treatment episode of 2-3 weeks and durable disease elimination, with remission rates of over 80%. Responses to therapy are more rapid than with conventional chemotherapy or immunotherapy, with intervening short-interval edema. CAR T-cell administration is associated with therapy-related toxic effects in a large percentage of patients, notably cytokine release syndrome, immune effect cell-associated neurotoxicity syndrome, and infections related to immunosuppression. Knowledge of the expected evolution of therapy response and potential adverse events in CAR T-cell therapy and correlation with the timeline of treatment are important to optimize patient care. Some toxic effects are radiologically evident, and familiarity with their imaging spectrum is key to avoiding misinterpretation. Other clinical toxic effects may be occult at imaging and are diagnosed on the basis of clinical assessment. Future directions for CAR T-cell therapy include new indications and expanded tumor targets, along with novel ways to capture T-cell activation with imaging. An invited commentary by Ramaiya and Smith is available online. Online supplemental material is available for this article. ©RSNA, 2022.

Isocitrate Dehydrogenase Wild-type Glial Tumors, Including Glioblastoma.

Isocitrate dehydrogenase (IDH) 1 and 2 mutations represent essential components for the diagnosis of diffuse astrocytic tumors and oligodendroglioma. IDH wild-type glial tumors include a wide spectrum of tumors with differences in prognosis and recommended therapeutic approaches. Tumors characterized as molecular glioblastoma in the World Health Organization 2021 classification should be treated according to the glioblastoma therapeutic principles and included in glioblastoma trials. Improving on existing treatments options including targeted and immunotherapy approaches is imperative for most patients with IDH wild-type glial tumors, and enrollment in clinical trials is encouraged.

Intrinsic Interferon Signaling Regulates the Cell Death and Mesenchymal Phenotype of Glioblastoma Stem Cells.

Interferon (IFN) signaling contributes to stemness, cell proliferation, cell death, and cytokine signaling in cancer and immune cells; however, the role of IFN signaling in glioblastoma (GBM) and GBM stem-like cells (GSCs) is unclear. Here, we investigated the role of cancer-cell-intrinsic IFN signaling in tumorigenesis in GBM. We report here that GSCs and GBM tumors exhibited differential cell-intrinsic type I and type II IFN signaling, and high IFN/STAT1 signaling was associated with mesenchymal phenotype and poor survival outcomes. In addition, chronic inhibition of IFN/STAT1 signaling decreased cell proliferation and mesenchymal signatures in GSCs with intrinsically high IFN/STAT1 signaling. IFN-ß exposure induced apoptosis in GSCs with intrinsically high IFN/STAT1 signaling, and this effect was abolished by the pharmacological inhibitor ruxolitinib and STAT1 knockdown. We provide evidence for targeting IFN signaling in a specific sub-group of GBM patients. IFN-ß may be a promising candidate for adjuvant GBM therapy.

Aggressiveness of care at end of life in patients with high-grade glioma.

BACKGROUND: Patients with high-grade glioma (HGG) face unique challenges toward the end of life (EoL), given their aggressive trajectory and neurologic deterioration. Aggressiveness of medical care at EoL has been identified as an important quality metric for oncology patients. At this time, limited data exist around the nature of EoL care of patients with HGG. METHODS: Patients with HGG and palliative care (PC) referral seen between 2010 and 2015 were identified (N = 80). Of these, N = 52 met inclusion criteria. Random selections of patients with (1) HGG not referred to PC (n = 80), and (2) non-CNS cancers with PC referral (n = 80) were identified for comparison. A composite score of aggressiveness of medical care at EoL was calculated for each patient from predetermined variables. A time of eligibility for PC was defined for each patient when predetermined criteria based on symptom burden, functional status, and prognosis were met. RESULTS: Among the patients analyzed with HGG referred to PC, 59.6% (N = 31) were referred as inpatients, and 53.8% (N = 28) were referred within the last 12 weeks of life. Patients with HGG had similar aggressiveness of care at EoL regardless of PC referral, and HGG patients had less aggressive care at EoL than patients with non-CNS cancers (p = 0.007). Care was more aggressive at EoL in HGG patients who received late versus early PC referrals (p = 0.012). Motor weakness at time of eligibility (OR = 2.55, p = 0.002) and more disease progressions (OR = 1.25, p = 0.043) were associated with less aggressive care at EoL. CONCLUSIONS: Early clinical- and disease-related features predict the aggressiveness of medical care at EoL in patients with HGG. Formal PC consultation is used infrequently and suboptimally in patients with HGG. Our data suggest that the role of PC in improving EoL outcomes in HGG warrants further evaluation.

Validation of diffusion MRI as a biomarker for efficacy using randomized phase III trial of bevacizumab with or without VB-111 in recurrent glioblastoma.

BACKGROUND: Evidence from single and multicenter phase II trials have suggested diffusion MRI is a predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF therapy. The current study confirms these findings in a large, randomized phase III clinical trial. METHODS: Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus BV in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pretreatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 µm2/ms) or low (<1.24 µm2/ms) ADCL, the mean value of the lower peak of the ADC histogram, within the contrast enhancing tumor. RESULTS: Baseline tumor volume (P = .3460) and ADCL (P = .2143) did not differ between treatment arms. Univariate analysis showed patients with high ADCL had a significant survival advantage in all patients (P = .0006), as well as BV (P = .0159) and BV+VB-111 individually (P = .0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume, and ADCL identified continuous measures of tumor volume (P < .0001; HR = 1.0212) and ADCL phenotypes (P = .0012; HR = 0.5574) as independent predictors of OS. CONCLUSION: Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111.

IDH mutation status and the development of venous thromboembolism in astrocytoma patients.

BACKGROUND: Venous thromboembolism (VTE) is a very common adverse event for astrocytoma patients, but validation of proposed risk biomarkers has been elusive. We examine whether the status of the isocitrate dehydrogenase (IDH) gene is a risk factor for the development of venous thromboembolism (VTE) in astrocytoma patients. METHODS: We conducted a retrospective chart review of 282 astrocytoma patients enrolled in the PROACTIVE (Prospective Assessment of Correlative Biomarker) study at MD Anderson Cancer Center (MDACC) from 9/1/2000 until 12/31/2013. RESULTS: We identified 282 astrocytoma patients consisting of 49 IDH mutant astrocytomas and 233 IDH wildtype astrocytomas. Glioblastoma was the initial histopathologic diagnosis in 30 (61.2%) of the IDH mutated astrocytomas compared to 227(97.4%) of the IDH wild type astrocytomas. VTE was identified in 52 (18.4%) of patients. VTE was diagnosed in 7 (14.3%) of the IDH mutated astrocytomas compared to 45(19.3%) of the IDH wild type astrocytoma s (p = 0.4094). Median time to VTE from diagnosis was 2.71 months. Median time to VTE from diagnosis was 2.6 months for IDH mutated astrocytomas compared to 3.06 months for the IDH wild type astrocytomas (p = 0.8663). CONCLUSIONS: IDH gene status did not appear as a significant risk factor for the development of venous thromboembolism (VTE) in our cohort of astrocytoma patients. Further research into potential biomarkers for VTE may be warranted.

Report of National Brain Tumor Society roundtable workshop on innovating brain tumor clinical trials: building on lessons learned from COVID-19 experience.

On July 24, 2020, a workshop sponsored by the National Brain Tumor Society was held on innovating brain tumor clinical trials based on lessons learned from the COVID-19 experience. Various stakeholders from the brain tumor community participated including the US Food and Drug Administration (FDA), academic and community clinicians, researchers, industry, clinical research organizations, patients and patient advocates, and representatives from the Society for Neuro-Oncology and the National Cancer Institute. This report summarizes the workshop and proposes ways to incorporate lessons learned from COVID-19 to brain tumor clinical trials including the increased use of telemedicine and decentralized trial models as opportunities for practical innovation with potential long-term impact on clinical trial design and implementation.

The promise of DNA damage response inhibitors for the treatment of glioblastoma.

Glioblastoma (GBM), the most aggressive primary brain tumor, has a dismal prognosis. Despite our growing knowledge of genomic and epigenomic alterations in GBM, standard therapies and outcomes have not changed significantly in the past two decades. There is therefore an urgent unmet need to develop novel therapies for GBM. The inter- and intratumoral heterogeneity of GBM, inadequate drug concentrations in the tumor owing to the blood-brain barrier, redundant signaling pathways contributing to resistance to conventional therapies, and an immunosuppressive tumor microenvironment, have all hindered the development of novel therapies for GBM. Given the high frequency of DNA damage pathway alterations in GBM, researchers have focused their efforts on pharmacologically targeting key enzymes, including poly(ADP-ribose) polymerase (PARP), DNA-dependent protein kinase, ataxia telangiectasia-mutated, and ataxia telangiectasia and Rad3-related. The mainstays of GBM treatment, ionizing radiation and alkylating chemotherapy, generate DNA damage that is repaired through the upregulation and activation of DNA damage response (DDR) enzymes. Therefore, the use of PARP and other DDR inhibitors to render GBM cells more vulnerable to conventional treatments is an area of intense investigation. In this review, we highlight the growing body of data behind DDR inhibitors in GBM, with a focus on putative predictive biomarkers of response. We also discuss the challenges involved in the successful development of DDR inhibitors for GBM, including the intracranial location and predicted overlapping toxicities of DDR agents with current standards of care, and propose promising strategies to overcome these hurdles.

A prospective phase II randomized trial of proton radiotherapy vs intensity-modulated radiotherapy for patients with newly diagnosed glioblastoma.

BACKGROUND: To determine if proton radiotherapy (PT), compared to intensity-modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma (GBM). METHODS: Eligible patients were randomized unblinded to PT vs IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes (PROs). RESULTS: A total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45-1.75; P = .74). PT was associated with a lower rate of fatigue (24% vs 58%, P = .05), but otherwise, there were no significant differences in PROs at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44-1.23; P = .24) or OS (HR, 0.86; 95% CI, 0.49-1.50; P = .60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P = .02). CONCLUSIONS: In this signal-seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient-reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for GBM and cognitive preservation in patients with lower-grade gliomas with a longer survival time.

A validated integrated clinical and molecular glioblastoma long-term survival-predictive nomogram.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor in adulthood. Despite multimodality treatments, including maximal safe resection followed by irradiation and chemotherapy, the median overall survival times range from 14 to 16 months. However, a small subset of GBM patients live beyond 5 years and are thus considered long-term survivors. METHODS: A retrospective analysis of the clinical, radiographic, and molecular features of patients with newly diagnosed primary GBM who underwent treatment at The University of Texas MD Anderson Cancer Center was conducted. Eighty patients had sufficient quantity and quality of tissue available for next-generation sequencing and immunohistochemical analysis. Factors associated with survival time were identified using proportional odds ordinal regression. We constructed a survival-predictive nomogram using a forward stepwise model that we subsequently validated using The Cancer Genome Atlas. RESULTS: Univariate analysis revealed 3 pivotal genetic alterations associated with GBM survival: both high tumor mutational burden (P = .0055) and PTEN mutations (P = .0235) negatively impacted survival, whereas IDH1 mutations positively impacted survival (P < .0001). Clinical factors significantly associated with GBM survival included age (P < .0001), preoperative Karnofsky Performance Scale score (P = .0001), sex (P = .0164), and clinical trial participation (P < .0001). Higher preoperative T1-enhancing volume (P = .0497) was associated with shorter survival. The ratio of TI-enhancing to nonenhancing disease (T1/T2 ratio) also significantly impacted survival (P = .0022). CONCLUSIONS: Our newly devised long-term survival-predictive nomogram based on clinical and genomic data can be used to advise patients regarding their potential outcomes and account for confounding factors in nonrandomized clinical trials.

PARP-mediated PARylation of MGMT is critical to promote repair of temozolomide-induced O6-methylguanine DNA damage in glioblastoma.

BACKGROUND: Temozolomide (TMZ) resistance in glioblastoma multiforme (GBM) is mediated by the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT). MGMT promoter methylation (occurs in about 40% of patients) is associated with loss of MGMT expression (MGMT-) that compromises DNA repair, leading to a favorable response to TMZ therapy. The 60% of patients with unmethylated MGMT (MGMT+) GBM experience resistance to TMZ; in these patients, understanding the mechanism of MGMT-mediated repair and modulating MGMT activity may lead to enhanced TMZ activity. Here, we report a novel mode of regulation of MGMT protein activity by poly(ADP-ribose) polymerase (PARP). METHODS: MGMT-PARP interaction was detected by co-immunoprecipitation. PARylation of MGMT and PARP was detected by co-immunoprecipitation with anti-PAR antibody. O6-methylguanine (O6-MetG) adducts were quantified by immunofluorescence assay. In vivo studies were conducted in mice to determine the effectiveness of PARP inhibition in sensitizing GBM to TMZ. RESULTS: We demonstrated that PARP physically binds with MGMT and PARylates MGMT in response to TMZ treatment. In addition, PARylation of MGMT by PARP is required for MGMT binding to chromatin to enhance the removal of O6-MetG adducts from DNA after TMZ treatment. PARP inhibitors reduced PARP-MGMT binding and MGMT PARylation, silencing MGMT activity to repair O6-MetG. PARP inhibition restored TMZ sensitivity in vivo in MGMT-expressing GBM. CONCLUSION: This study demonstrated that PARylation of MGMT by PARP is critical for repairing TMZ-induced O6-MetG, and inhibition of PARylation by PARP inhibitor reduces MGMT function rendering sensitization to TMZ, providing a rationale for combining PARP inhibitors to sensitize TMZ in MGMT-unmethylated GBM.

Immunotherapy for Neuro-oncology.

Immunotherapy has changed the landscape of treatment of many solid and hematological malignancies and is at the forefront of cancer breakthroughs. Several circumstances unique to the central nervous system (CNS) such as limited space for an inflammatory response, difficulties with repeated sampling, corticosteroid use for management of cerebral edema, and immunosuppressive mechanisms within the tumor and brain parenchyma have posed challenges in clinical development of immunotherapy for intracranial tumors. Nonetheless, the success of immunotherapy in brain metastases (BMs) from solid cancers such as melanoma and non-small cell lung cancer (NSCLC) proves that the CNS is not an immune-privileged organ and is capable of initiating and regulating immune responses that lead to tumor control. However, the development of immunotherapeutics for the most malignant primary brain tumor, glioblastoma (GBM), has been challenging due to systemic and profound tumor-mediated immunosuppression unique to GBM, intratumoral and intertumoral heterogeneity, and lack of stably expressed clonal antigens. Here, we review recent advances in the field of immunotherapy for neuro-oncology with a focus on BM, GBM, and rare CNS cancers.