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Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma.

ABSTRACT: BACKGROUND:Glioblastoma (GBM) is the most common primary malignant adult brain tumor. Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Moreover, even initially responsive tumors develop a secondary resistance to TMZ and become untreatable. Since aberrant epidermal growth factor receptor (EGFR) signaling is widespread in GBM, EGFR inhibition has been tried in multiple clinical trials without success. We recently reported that inhibiting EGFR leads to increased secretion of tumor necrosis factor (TNF) and activation of a survival pathway in GBM. Here, we compare the efficacy of TMZ versus EGFR plus TNF inhibition in an orthotopic mouse model of GBM. METHODS:We use an orthotopic model to examine the efficacy of TMZ versus EGFR plus TNF inhibition in multiple subsets of GBMs, including MGMT methylated and unmethylated primary GBMs, recurrent GBMs, and GBMs rendered experimentally resistant to TMZ. RESULTS:The efficacy of the 2 treatments was similar in MGMT methylated GBMs. However, in MGMT unmethylated GBMs, a combination of EGFR plus TNF inhibition was more effective. We demonstrate that the 2 treatment approaches target distinct and non-overlapping pathways. Thus, importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ. CONCLUSION:EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a viable therapeutic approach in MGMT unmethylated and recurrent EGFR-expressing GBMs.

SUBMITTER: Guo G

PROVIDER: S-EPMC6917414 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma.

Guo Gao G Gong Ke K Puliyappadamba Vineshkumar Thidil VT Panchani Nishah N Pan Edward E Mukherjee Bipasha B Damanwalla Ziba Z Bharia Sabrina S Hatanpaa Kimmo J KJ Gerber David E DE Mickey Bruce E BE Patel Toral R TR Sarkaria Jann N JN Zhao Dawen D Burma Sandeep S Habib Amyn A AA

Neuro-oncology 20191201 12

<h4>Background</h4>Glioblastoma (GBM) is the most common primary malignant adult brain tumor. Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Moreover, even initially responsive tumors develop a secondary resistance to TMZ and become untreatable. Since aberrant epidermal growth factor receptor (EGFR) signaling is widespread in GBM, EGFR inhibition has been tried in multiple clinical trials wi ...[more]

PMID: 31363754

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Project description:The optimization of the management for elderly glioblastoma patients is crucial given the demographics of aging in many countries. We report the outcomes for a "real-life" patient cohort (i.e. unselected) comprising consecutive glioblastoma patients aged 70 years or more, treated with different radiotherapy +/- temozolomide regimens.From 2003 to 2016, 104 patients ??70 years of age, consecutively treated by radiotherapy for glioblastoma, were included in this study. All patients were diagnosed with IDH-wild type glioblastoma according to pathological criteria.Our patient cohort comprised 51 female patients (49%) and 53 male. The median cohort age was 75 years (70-88), and the median Karnofsky performance status (KPS) was 70 (30-100). Five (5%) patients underwent macroscopic complete resection, 9 (9%) had partial resection, and 90 (86%), a stereotactic biopsy. The MGMT promoter was methylated in 33/73 cases (45%). Fifty-two (50%), 38 (36%), and 14 (14%) patients were categorized with RPA scores of III, IV, and I-II. Thirty-three (32%) patients received normofractionated radiotherapy (60 Gy, 30 sessions) with temozolomide (Stupp), 37 (35%) received hypofractionated radiotherapy (median dose 40 Gy, 15 sessions) with temozolomide (HFRT?+?TMZ), and 34 (33%) HFRT alone. Patients receiving only HFRT were significantly older, with lower KPSs. The median overall survival (OS; all patients) was 5.2 months. OS rates at 12, 18, and 24 months, were 19%, 12%, and 5%, respectively, with no statistical differences between patients receiving Stupp or HFRT?+?TMZ (P?=?0.22). In contrast, patients receiving HFRT alone manifested a significantly shorter survival time (3.9 months vs. 5.9 months, P?=?0.018). In multivariate analyses, the prognostic factors for OS were: i) the type of surgery (HR: 0.47 [0.26-0.86], P?=?0.014), ii) RPA class (HR: 2.15 [1.17-3.95], P?=?0.014), and iii) temozolomide use irrespective of radiotherapy schedule (HR: 0.54 [0.33-0.88], P?<?0.02). MGMT promoter methylation was neither a prognostic nor a predictive factor.These outcomes agree with the literature in terms of optimal surgery and the use of HFRT as a standard treatment for elderly GBM patients. Our study emphasizes the potential benefit of using temozolomide with radiotherapy in a real-life cohort of elderly GBM patients, irrespective of their MGMT status.

Project description:PurposeDespite intensive treatment with surgery, radiation therapy, temozolomide (TMZ) chemotherapy, and tumor-treating fields, mortality of newly diagnosed glioblastoma (nGBM) remains very high. SurVaxM is a peptide vaccine conjugate that has been shown to activate the immune system against its target molecule survivin, which is highly expressed by glioblastoma cells. We conducted a phase IIa, open-label, multicenter trial evaluating the safety, immunologic effects, and survival of patients with nGBM receiving SurVaxM plus adjuvant TMZ following surgery and chemoradiation (ClinicalTrials.gov identifier: NCT02455557).MethodsSixty-four patients with resected nGBM were enrolled including 38 men and 26 women, in the age range of 20-82 years. Following craniotomy and fractionated radiation therapy with concurrent TMZ, patients received four doses of SurVaxM (500 μg once every 2 weeks) in Montanide ISA-51 plus sargramostim (granulocyte macrophage colony-stimulating factor) subcutaneously. Patients subsequently received adjuvant TMZ and maintenance SurVaxM concurrently until progression. Progression-free survival (PFS) and overall survival (OS) were reported. Immunologic responses to SurVaxM were assessed.ResultsSurVaxM plus TMZ was well tolerated with no serious adverse events attributable to SurVaxM. Of the 63 patients who were evaluable for outcome, 60 (95.2%) remained progression-free 6 months after diagnosis (prespecified primary end point). Median PFS was 11.4 months and median OS was 25.9 months measured from first dose of SurVaxM. SurVaxM produced survivin-specific CD8+ T cells and antibody/immunoglobulin G titers. Apparent clinical benefit of SurVaxM was observed in both methylated and unmethylated patients.ConclusionSurVaxM appeared to be safe and well tolerated. The combination represents a promising therapy for nGBM. For patients with nGBM treated in this manner, PFS may be an acceptable surrogate for OS. A large randomized clinical trial of SurVaxM for nGBM is in progress.

Dataset Information

Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma.

Publications

Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma.

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