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Background Glioblastoma (GBM) is an aggressive malignant brain tumor where median survival is approximately 15 months after best available multimodal treatment. Recurrence is inevitable, largely due to O6 methylguanine DNA methyltransferase (MGMT) that renders the tumors resistant to temozolomide (TMZ). We hypothesized that pretreatment with bortezomib (BTZ) 48 hours prior to TMZ to deplete MGMT levels would be safe and tolerated by patients with recurrent GBM harboring unmethylated MGMT promoter. The secondary objective was to investigate whether 26S proteasome blockade may enhance differentiation of cytotoxic immune subsets to impact treatment responses measured by radiological criteria and clinical outcomes. Methods Ten patients received intravenous BTZ 1.3 mg/m2 on days 1, 4, and 7 during each 4th weekly TMZ‐chemotherapy starting on day 3 and escalated from 150 mg/m2 per oral 5 days/wk via 175 to 200 mg/m2 in cycles 1, 2, and 3, respectively. Adverse events and quality of life were evaluated by CTCAE and EQ‐5D‐5L questionnaire, and immunological biomarkers evaluated by flow cytometry and Luminex enzyme‐linked immunosorbent assay. Results Sequential BTZ + TMZ therapy was safe and well tolerated. Pain and performance of daily activities had greatest impact on patients' self‐reported quality of life and were inversely correlated with Karnofsky performance status. Patients segregated a priori into three groups, where group 1 displayed stable clinical symptoms and/or slower magnetic resonance imaging radiological progression, expanded CD4+ effector T‐cells that attenuated cytotoxic T‐lymphocyte associated protein‐4 and PD‐1 expression and secreted interferon γ and tumor necrosis factor α in situ and ex vivo upon stimulation with PMA/ionomycin. In contrast, rapidly progressing group 2 patients exhibited tolerised T‐cell phenotypes characterized by fourfold to sixfold higher interleukin 4 (IL‐4) and IL‐10 Th‐2 cytokines after BTZ + TMZ treatment, where group 3 patients exhibited intermediate clinical/radiological responses. Conclusion Sequential BTZ + TMZ treatment is safe and promotes Th1‐driven immunological responses in selected patients with improved clinical outcomes (Clinicaltrial.gov (NCT03643549))., Schematic of trial schedule. A, Timeline showing BORTEM‐17 treatment regimen. Bortezomib administered intravenous at days 1, 4, and 7 (48 hours pretreatment to deplete MGMT protein) before target TMZ 200 mg/m2 dose for 5 days (from and including days 3‐7), repeated in six cycles. In n = 3 patients per each dose 150 vs 175 vs 200 mg/m2 TMZ in dose pathfinding, safety evaluation. Clinical chemistry for renal, hepatic, and bone marrow monitoring for toxicity based on CTCAE v. 4.03. MRI tumor monitoring radiological response assessment based on RANO criteria. Rationale for sequential treatment schedule based on preclinical data. B, sequential administration in BORTEM‐17 clinical trial vs (C) previous studies where BTZ on days 1, 4, 8, and 11 was given concomitantly with TMZ from day 1 to 5, when MGMT levels were high. Dashed boxes mark days when TMZ doses might be more effective, (B) all five doses vs (C) three doses every month. BTZ, bortezomib; CBC Diff, complete blood count with differential test; CMP, comprehensive metabolic panel; KPS, Karnofsky performance score; LFT, liver function test; MGMT, O6‐methyl guanine DNA methyltransferase; MRI, magnetic resonance imaging; NANO, neurologic assessment in neuro‐oncology; QoL, quality of life; TMZ, temozolomide.

IntroductionThe use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2–3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life.Methods and analysisPRO-GLIO (PROton versus photon therapy inIDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18–65 years withIDH-mutated diffuse gliomas grade 2–3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints.Ethics and disseminationTo implement proton therapy as part of standard of care for patients withIDH-mutated diffuse gliomas grade 2–3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums.Trial registration numberClinicalTrials.gov Registry (NCT05190172).

Therapy of recurrent glioblastoma (GBM) is challenging due to lack of standard treatment. We investigated physicians’ treatment choice at recurrence and prognostic and predictive factors for survival in GBM patients from Norway’s two largest regional hospitals. Clinicopathological data from n = 467 patients treated at Haukeland and Oslo university hospitals from January 2015 to December 2017 was collected. Data included tumour location, promoter methylation of O6 methylguanine-DNA methyltransferase (MGMT) and mutation of isocitrate dehydrogenase (IDH), patient age, sex, extent of resection at primary diagnosis and treatment at successive tumour recurrences. Cox-proportional hazards regression adjusting for multiple risk factors was used. Median overall survival (OS) was 12.1 months and 21.4% and 6.8% of patients were alive at 2 and 5 years, respectively. Median progression-free survival was 8.1 months. Treatment at recurrence varied but was not associated with difference in overall survival (OS) (p = 0.201). Age, MGMT hypermethylation, tumour location and extent of resection were independent prognostic factors. Patients who received 60 Gray radiotherapy with concomitant and adjuvant temozolomide at primary diagnosis had 16.1 months median OS and 9.3% were alive at 5 years. Patients eligible for gamma knife/stereotactic radiosurgery alone or combined with chemotherapy at first recurrence had superior survival compared to chemotherapy alone (p

Background: Glioblastoma (GBM) is an aggressive brain tumor where median survival is approx. 12 months in unselected patients, largely due to activity of O6-methylguanine DNA methyltransferase (MGMT) that renders GBM resistant to temozolomide (TMZ) chemotherapy. There is no standard treatment for recurrent GBM patients who progress under TMZ treatment. We previously demonstrated that bortezomib (BTZ) depletes MGMT protein and sensitizes MGMT unmethylated GBM cells to TMZ in vitro and in PDX models when administered in precise dose and sequential schedule. TMZ dose escalation in phase IB part of the trial was tolerated, safe and associated with immunological responses in selected patients. We hypothesized that recurrent GBM patients with unmethylated MGMT promoter may obtain clinical benefit from sequential combination of BTZ and TMZ treatment. Methods: The sample size was calculated to 63 patients for this phase IB/II study, 10 were included in the phase IB and the rest are ongoing in phase II. A cohort of 467 patients treated at Oslo and Haukeland University Hospitals were used as controls. We report interim results of n=32 MGMT unmethylated recurrent GBM patients progressing at least 12 weeks after completion of postoperative radiotherapy, with adequate organ function, Karnofsky performance status (KPS) ≥70 and radiologically measurable lesions treated on BORTEM-17 protocol. The patients received intravenous BTZ 1.3mg/m2 on days 1,4,7, during each 4-week chemotherapy cycle starting on day 3 with per oral TMZ at 200mg/m2 5 days/week. Mantel-Cox regression analyses was used to calculate survival. Results: Until January 2022, 32 patients with median age 54 yrs (range 25-66 yrs), 23 male and 9 female were treated at 3 different referral university hospitals in Norway. 81% (26/32) were IDH wt. Median KPS was 90 (70-100) and median NANO score was 1 (0-7). 9/32 patients are still alive. Preliminary data indicates 20% of patients showed clinical and radiological responses, where 4/6 (67%) obtained partial response and 2/6 (33%) had stable disease. BORTEM-17 patients’ median survival was significantly better than all controls (23.7 months vs 12.1 months) HR0.61, 95% CI [0.44-0.85], P=0.003. The Median survival for BORTEM-17 patients was 23.7 months vs 11.4 months for control MGMT unmethylated patients HR0.46, 95% CI [0.33-0.63], P Conclusion: Combination of BTZ and TMZ administered sequentially is safe. Interim analysis indicates objective radiological response and increased median survival of MGMT unmethylated patients. ClinicalTrials.gov identifier: NCT03643549 Citation Format: Dorota Goplen, Mohummad Aminur Rahman, Jorunn Brekke, Victoria Arnesen, Anne Simonsen, Andreas Waha, Kirstin Marienhagen, Leif Oltedal, Judit Haasz, Hrvoje Miletic, Tora Skeidsvoll Solheim, Petter Brandal, Stein Atle Lie, Martha Chekenya. BORTEM-17 - phase IB/II single arm, non-randomized controlled multicenter study investigating whether sequential bortezomib and temozolomide is safe and effective in recurrent GBM with unmethylated MGMT promoter [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT114.

TPS2081 Background: Patients with glioblastoma with functional O6 methylguanine DNA methyltransferase ( MGMT) DNA repair enzyme gain limited benefit from temozolomide (TMZ). Bortezomib depletes the MGMT enzyme, restoring the tumor ́s susceptibility to TMZ, if the chemotherapy is administered in the precise schedule. Additionally, bortezomib inhibits the tumor growth by blocking autophagy flux. Thus, pre-treatment with bortezomib prior to temozolomide leads to DNA repair enzyme depletion and blockade of autophagy-induced survival signals. Methods: The academic, industry independent, multicenter, open label, single arm, non-randomized phase II trial is designed to investigate the survival benefits for patients treated with bortezomib 48hrs prior to TMZ. Efficacy of this therapy will be compared to historical cohorts receiving standard management. The study will include 53 patients with recurrent or progressive, MGMT unmethylated glioblastoma. The additional 10 patients were treated in the phase IB. All patients will receive a combination of bortezomib 1.3mg/m2 administered IV on days 1, 4, 7, during each 4-week chemotherapy cycle with PO TMZ at 200mg/m2 5 days/week q4w starting on day 3. Dose reduction of TMZ is allowed if reduced bone marrow tolerance is present. Major eligibility criteria include histologically confirmed glioblastoma with unmethylated MGMT promoter, MRI evidence of recurrence within 14 days prior to enrolment, age ≥ 18 years with life expectancy > 8 weeks, KPS ≥ 70, radiologically (MRI) confirmed tumor relapse/progression ≥ 12 weeks since completed radiotherapy, tumor not available for radiosurgery, adequate bone marrow, renal and liver function, no contraindications for bortezomib and/or TMZ. Endpoints: Estimation of the median progression free survival (PFS) and overall survival (OS) of patients with recurrent or progressed glioblastoma as well as progression free rate at 6 months. Secondary objectives: Therapy response assessed by contrast enhanced MRI (RANO criteria) and neurological examination (NANO criteria) as well as identification of novel biomarkers that correlate with treatment response. Twenty-four of the planned 53 patients are enrolled. Five of them receive treatment. The prespecified activity goal for the first stage of the study was met. Discussion: Patients with glioblastoma harboring active MGMT enzyme have median survival of 12.7 months, compared to 21.7 months for patients with the MGMT gene promoter silenced by methylation. This dismal prognosis for the approx. 55% of GBM patients underscores the unmet need for novel combination therapies that sensitize the tumors to chemotherapy. Results from this trial will serve as preliminary evidence of the role of bortezomib administered in a precise manner to abolish the temozolomide resistance of GBM with unmethylated MGMT promotor. The study is currently active and recruiting. Clinical trial information: NCT03643549.

Introduction The direct oral anti-coagulants (DOAC) edoxaban and rivaroxaban are suggested treatment alternatives for cancer-associated venous thromboembolism (VTE) together with low molecular-weight heparins. New studies indicate that the DOAC apixaban also is an option for cancer-associated VTE. The current study assessed recurrent VTE, arterial thrombosis, bleedings and adverse events in a cohort of apixaban treated cancer patients with VTE. Materials and methods Single-arm, interventional study of apixaban as treatment of cancer-associated VTE. Inclusion criteria were cancer with objectively verified VTE. Patients received apixaban 10 mg bid for seven days, then 5 mg bid for six months. Primary efficacy and safety outcomes were recurrent VTE and bleeding respectively. This trial is registered with ClinicalTrials.gov identifier NCT02581176 . Results We recruited 298 cancer patients with VTE. During six months treatment, recurrent VTE or death related to VTE occurred in 12 patients (4.0%, 95% confidence interval (CI) 2.1–6.9%). Major bleeding occurred in 16 patients (5.4%, 95% CI 2.8–7.9), most frequently gastrointestinal bleeding. There were no overrepresentation of major bleedings among patients with gastrointestinal cancer (7/126, 5.5%, 95% CI 2.3–11%). Twenty-six patients experienced one or more clinically relevant non-major bleedings (8.9%, 95% CI 5.5–12%). Twelve patients had arterial thrombosis (4.0%, 95% CI 2.1–6.9%), of which the majority were strokes in patients with pancreatic cancer. Death occurred in 35 patients (12%, 95% CI 8.3–16%). Conclusion The frequency of recurrent VTE and major bleedings are in line with other studies on apixaban in cancer-associated VTE. Arterial thrombosis was a frequent serious adverse event.

Background Oropharyngeal squamous cell carcinoma (OPSCC) positive for human papillomavirus (HPV) increases wolrd wide. Aims/objectives The objective for this study has been to evaluate tumor phenotypes and tumor host responses with respect to five-year disease-specific survival (DSS) in HPV(+) and HPV(-) patients. Material and methods Two hundred patients with OPSCC have been treated between 1992 and 2010. Histopathology slides from these patients have been morphologically evaluated in formalin-fixed, paraffin-embedded (FFPE) stained with hematoxylin-eosin (HE). From HE-stained sections tumor phenotype (keratinization, fraction of mature cancer cells and pattern of invasion) and tumor host responses (inflammation and stromal desmoplasia) were evaluated with respect to five years DSS. Results High tumor inflammatory response and low stromal desmoplasia had an independent effect predicting better five-year DSS among all patients and when analyzed separately in the HPV(-) and HPV(+) cohort of patients using a Cox regression survival analysis that also included standard clinical prognostic variables among OPSCC patients. Conclusion Tumor host responses, inflammation and stromal desmoplasia may become part of routine work-up in OPSCC patients due to prognostic value. Significance We present a method, accessible in most clinical locations and would give important additional information about prognosis in OPSCC patients.

Background: Apixaban is a treatment option for venous thromboembolism (VTE) in cancer patients. There are no data on the effect of low dose apixaban after 6 months treatment. We wanted to assess the efficacy and safety of apixaban 2.5 mg twice daily as prophylaxis for recurrent VTE after 6 months initial treatment with full-dose apixaban. Patients and methods: We included 298 patients with cancer and any type of VTE. All patients were treated with full dose apixaban for the first 6 months. After 6 months, all patients with active cancer continued with apixaban 2.5 mg twice daily and were followed for the next 30 months. The primary endpoint of efficacy was recurrent VTE, the primary safety endpoint was major bleedings. Clinically relevant non-major bleedings was a secondary endpoint. The endpoints are reported as incidence rates or fractions with 95% confidence intervals, and as Kaplan-Meier plots. Results: During the first 6 months of full-dose anticoagulation 12 of 298 patients had recurrent VTE (4.0%, 95% confidence interval 2.1-6.9), 16 experienced major bleeding (5.4%, 95% CI 2.8-7.9%), and 26 patients experienced one or more episodes of CRNMB (8.9%, 95% CI 5.5-12) as previously reported. 1 Of the 298 patients included, 196 continued with apixaban 2.5 mg twice daily after 6 months. During treatment from 6 to 36 months with low-dose apixaban 15 of 196 (7.6%, 95% CI: 4.4-12) patients had recurrent VTE, 7 (3.6%, CI: 1.5-7.2) patients experienced major bleeding and 16 (8.2%, 95% CI: 4.7-13) patients experienced CRNMB. The highest incidence rate of both recurrent VTE and major bleedings were seen during the first month of full-dose apixaban (Table 1). After the dose reduction of apixaban, the incidence rate of recurrent VTE increased slightly during 6 to 12 months while the incidence rate of major bleeding decreased during the same time-period. After 12 months the incidence rate of both recurrent VTE and major bleeding was low and remained low during the entire 30 months follow-up (Table 1 and Figure 1). The Kaplan-Meier plot of the composite endpoint of recurrent VTE or major bleeding did not change after dose-reduction. After about 9 months treatment (i.e. 3 months on low dose apixaban) the Kaplan-Meier curve of the composite endpoint flattened out. Conclusion: Dose reduction of apixaban to 2.5 mg twice daily after 6 months of full dose anticoagulation resulted in a small increase in recurrent VTE, but a marked decrease in major bleedings during the 6-12 months period. After approximately 9 months the frequency of recurrent VTE and major bleedings remained low compared with the first 6 months of full-dose treatment. Reducing the dose of apixaban to 2.5 mg twice daily after 6 months of full-dose treatment appears safe and effective. References 1. Hannevik TL, Brekke J, Enden T, et al: Thrombosis and bleedings in a cohort of cancer patients treated with apixaban for venous thromboembolism. Thromb Res, 2020 Figure 1 Figure 1. Disclosures Hannevik: Pfizer/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Garresori: Pfizer: Honoraria; Amgen: Honoraria; Bayer: Honoraria. Froen: Bristol-Myers Squibb: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees. Porojnicu: Bristol-Myers Squibb: Honoraria. Ghanima: Bayer, BMS/Pfizer: Research Funding; Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Griffols, Sanofi: Honoraria; Amgen, Novartis, Pfizer, Principia Biopharma Inc- a Sanofi Company, Sanofi, SOBI, Griffols, UCB, Argenx: Consultancy. Dahm: Pfizer: Honoraria; Novartis: Honoraria; Pfizer/Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

BACKGROUND Glioblastoma (GBM) is the most malignant primary brain tumor in adults where median survival in unselected patients is approximately 10 months. There is no standard treatment for patients who progress on temozolomide and patients are best treated within investigational clinical protocols. Patients harbouring tumours with functional O6 methylguanine DNA methyltransferase (MGMT) DNA repair enzyme have particularly poor prognosis with median overall survival of 12.7 months, compared to 21.7 months for patients with hypermethylated MGMT promoter. The pre-clinical studies have shown that Bortezomib depletes the MGMT enzyme, restoring the tumour ́s susceptibility to Temozolomide, if the chemotherapy is administered in the precise schedule when the MGMT enzyme is depleted. Additionally, Bortezomib shows an antitumour effect by blocking autophagy flux. Based on the promising pre-clinical results, a non-randomized, open label phase IB/II clinical trial was designed. The primary endpoints include assessment of safety of Bortezomib administered with Temozolomide for phase IB and median progression free survival, overall survival as well as progression free rate at 6 months. MATERIAL AND METHODS Recurrent glioblastoma patients with unmethylated MGMT promotor, progressing at least 12 weeks after completion of postoperative radiotherapy, with adequate organ function, performance status Karnofsky 70 or better and radiologically measurable lesions are screened for study inclusion. The experimental treatment consists of Bortezomib 1.3mg/m2 administered IV on days 1, 4, 7, during each 4-week chemotherapy cycle with per oral Temozolomide at 200mg/m2 5 days/week every 4 weeks starting on day 3. Study group will be compared to historical controls on conventional management. The sample size was calculated to 63 patients, ten of them were included in the phase IB. RESULTS The phase IB of the trial was completed in 2019 and the combination of Temozolomide and Bortezomib was shown to be safe and well tolerated. Until April 2021 a total number of 23 patients were included into the trial. The patients are treated at 4 different referral university hospitals in Norway. A clinical treatment benefit with both radiological tumor volume response and stable disease were observed. The patient inclusion in the trial is delayed due COVID-19. The majority of observed side effects are mild or moderate. The grade 3 or 4 adverse effects included thrombocytopenia, ataxia, muscle weakness, delirium and hyperglycemia. Patients that progressed under the treatment received another line of therapy according to the institutional practice. CONCLUSION A combination of Bortezomib and Temozolomide administered in a defined time sequence to achieve sensitization of glioblastoma to alkylating agent is safe and feasible and may represent a novel treatment option for patients with this devastating disease.

BACKGROUND Glioblastoma (GBM) is an aggressive primary brain tumor with median overall survival (OS) of less than one year in unselected adult patients. There is no standard therapy at recurrence. We aimed to evaluate OS in a consecutive series of GBM patients from Norway’s two largest regional health authorities, compare the effect of physicians’ choice of antineoplastic treatment upon recurrence and identify prognostic and predictive factors. MATERIAL AND METHODS Clinicopathological data from n=467 patients with histologically confirmed GBM diagnosed and treated at Haukeland and Oslo university hospitals from January 2015 to December 2017 was retrospectively collected. Data included tumor location, methylation status of the methylguanine-DNA methyltransferase (MGMT) promoter and mutation of the isocitrate dehydrogenase (IDH) genes, patient age and sex, extent of tumor resection at primary diagnosis, and treatment at first, second and third tumor recurrences. Cox-proportional hazards regression with pairwise analyses adjusted for multiple testing with Scheffé’s post-hoc test were used to adjust effect of multiple risk factors on mortality. RESULTS Median OS was 12.1 months and 21.4 % and 6.8 % of patients were alive at 2 and 5 years, respectively. Treatment at recurrence varied between institutions but did not impact OS (p=0.201). Median time to progression was 8.2 months. Age, MGMT promoter methylation, tumor location and extent of tumor resection were all independent prognostic factors for OS. Patients receiving radiotherapy to 60 Gray with concomitant and adjuvant temozolomide at primary diagnosis had best outcome with median OS of 16.1 months and 9.3% were alive at 5 years. At first recurrence patients eligible for gammaknife/stereotactic radiosurgery (GK/SRS) or surgery, alone or combined with chemotherapy, had superior survival compared to chemotherapy alone (p CONCLUSION Recurrence treatment differed between the two institutions but there was no difference in OS. Our findings underline the lack of standard therapy upon GBM recurrence and the urgent need for novel therapeutic strategies.

Background: Glioblastoma with unmethylated O6-methyl guanine DNA methyltransferase (MGMT) promoter is highly resistant to temozolomide (TMZ) chemotherapy. Strategies that ameliorate drug resistance are sorely needed. Recent trials of the proteasome inhibitor bortezomib (BTZ) (Velcade) in combination with various drugs failed due to inappropriate schedule timing and dosing. We hypothesized that pretreatment with BTZ prior to TMZ administration may sensitize glioblastoma cell to TMZ chemotherapy. Methods: We investigated treatment efficacy through DNA damage, apoptosis and autophagy flux by flow cytometry, western blotting, long-lived protein degradation assays, electron and fluorescence microscopy in cell lines (U87, T98G, HF66) and patient biopsy-derived cells (P3, 2012-18, BG5 and BG7). Treatment efficacy and tolerability was investigated in vivo in mice implanted orthotopically with patient-derived GBM xenografts and subsequently treated with human equivalent dose (HED) of BTZ 1.3 mg/m2 on days 1, 4, 8 and 11 for two cycles during TMZ 82 mg/m2 or 164 mg/m2 by oral gavage 5 days/week for 5 weeks. MRI, mouse survival times, tandem LC-MS/MS and clinical chemistry were used to monitor tumor growth and evaluate tissue and blood samples for biomarkers of treatment efficacy and toxicity. Results: Patient-derived glioblastoma cells were universally more sensitive to BTZ than carfilzomib or MG-132 (P Conclusion: Pretreatment with BTZ chemo-sensitized resistant glioblastoma through aborted autophagic flux and MGMT depletion to augment DNA damage, apoptosis and prolonged survival. Our findings warrant a controlled investigation of the treatment schedule in selected patients. Citation Format: Mohummad A. Rahman, Andrea G. Navarro, Jorunn Brekke, Christian Bindesbøll, Agnete Engelsen, Shahin Sarowar, Marzieh Bahador, Bjørn T. Gjertsen, Dorota Goplen, Per Ø. Enger, Frode Selheim, Anne Simonsen, Martha Chekenya. Bortezomib sensitizes glioblastoma with unmethylated MGMT promoter to temozolomide-chemotherapy through MGMT depletion and abrogated autophagy flux [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2928.