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BIOM-26. MOLECULAR PREDICTORS OF RESPONSE TO SELINEXOR IN RECURRENT GLIOBLASTOMA (GBM)

ABSTRACT: Abstract The nuclear export protein exportin 1 (XPO1) is overexpressed in many cancers, including GBM. Selinexor is an inhibitor of XPO1 that crosses the blood-brain-barrier and targets cancer cells by sequestering tumor suppressor proteins and oncoprotein mRNAs in the nucleus, inducing cancer cell apoptosis. We previously reported encouraging results from a phase II trial of selinexor for molecularly unselected patients with recurrent GBM (ASCO 2019). Pre-treatment tumors from 57 patients were exome and RNA sequenced to explore molecular correlates of response, in a hypothesis generating, post-hoc, exploratory analysis. We compared overall survival (OS) and progression-free survival (PFS) between mutated and wild-type patients. Two mutated genes were associated with longer survival in selinexor treated patients: DOCK8 (n=7; PFS, P=0.013, hazard ratio [HR]=3.75 [1.32–10.62]; overall survival, P=0.009, HR=15.39 [2.00–118.34]) and PDX1 (n=5, PFS, P=0.014, HR=4.468 [1.361–14.670]). Other commonly mutated genes in glioma, including IDH1 (n=9) were observed but not associated with survival. RNAseq data were used to infer differential protein activities, which were input into a machine learning model that compared patients with selinexor sensitive disease (best response of partial or complete response, n=7) and resistant disease (best response of progressive disease, n=23). We found the inferred activities of three proteins emerged as the most associated with response and could be combined in a model to accurately predict benefit from selinexor treatment (area under the ROC curve from leave one out cross validation = 0.89 permutation test P< 0.04). The three proteins were ZC3H12A (also called MCPIP-1), a negative regulator of inflammation; RAB43, a member of the RAS family that binds GTP and regulates vesicle trafficking, and SOCS3, a suppressor of cytokine signaling that can antagonize JAK/STAT signaling. Together these data identified mutations and proteins activities for identifying patients most likely to benefit from selinexor treatment. Further studies are required for validation. ClinicalTrials.gov:NCT01986348.

SUBMITTER: Walker C

PROVIDER: S-EPMC7650493 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Median survival for patients with recurrent GBM is <6 months. Front-line systemic therapy is temozolomide but resistance due to O6-methylguanine-DNA-methyltransferase (MGMT) activity is implicated in poor outcomes. Dianhydrogalactitol (VAL-083) is a structurally unique bi-functional DNA alkylating agent that accumulates in brain tumor tissue. In in vitro studies, VAL-083 demonstrated activity in pediatric and adult GBM cell lines, as well as GBM cancer stem cells. Notably, VAL-083 overcomes resistance to MGMT in vitro. Previous clinical studies suggest that VAL-083 has anti-tumor activity against a range of tumors, including GBM. In light of extensive safety data from clinical trials and promising efficacy in CNS tumors, we initiated a new clinical study to establish the maximum tolerated dose (MTD) and identify a dose and dosing regimen for future efficacy trials in GBM. Early in the development of VAL-083, a cumulative IV dose of 125 mg/m2 delivered in a 35 day cycle in combination with radiation was shown superior to radiation alone in brain cancer (Eagan, et al. 1979). In the present study, the cumulative dose in a 33 day cycle ranges from 9 mg/m2 (cohort 1) to 240 mg/m2 (cohort 7). Six dose cohorts have completed the trial with no drug-related serious adverse events: MTD was not yet reached. Enrollment for cohort 7 (33 day cumulative dose: 240 mg/m2) has been initiated and higher doses may be explored; the results will determine the design of the safety and efficacy registration trial. METHODS: Open-label, single-arm Phase I/II dose-escalation study in patients with histologically-confirmed initial diagnosis of malignant GBM. The study utilizes a 3 + 3 dose-escalation design. Patients receive VAL-083 IV on days 1, 2, and 3 of a 21 day cycle. GBM patients previously been treated with surgery and/or radiation, if appropriate, must have failed both bevacizumab and temozolomide, unless contraindicated. ClinicalTrials.gov Identifier NCT01478178.

Project description:Glioblastoma (GBM) is a highly aggressive primary brain tumor with dismal outcome for affected patients. Because of the significant neo-angiogenesis exhibited by GBMs, anti-angiogenic therapies have been intensively evaluated during the past years. Recent clinical studies were however disappointing, although a subpopulation of patients may benefit from such treatment. We have previously shown that anti-angiogenic targeting in GBM increases hypoxia and leads to a metabolic adaptation toward glycolysis, suggesting that combination treatments also targeting the glycolytic phenotype may be effective in GBM patients. The aim of this study was to identify marker proteins that are altered by treatment and may serve as a short term readout of anti-angiogenic therapy. Ultimately such proteins could be tested as markers of efficacy able to identify patient subpopulations responsive to the treatment. We applied a proteomics approach based on selected reaction monitoring (SRM) to precisely quantify targeted protein candidates, selected from pathways related to metabolism, apoptosis and angiogenesis. The workflow was developed in the context of patient-derived intracranial GBM xenografts developed in rodents and ensured the specific identification of human tumor versus rodent stroma-derived proteins. Quality control experiments were applied to assess sample heterogeneity and reproducibility of SRM assays at different levels. The data demonstrate that tumor specific proteins can be precisely quantified within complex biological samples, reliably identifying small concentration differences induced by the treatment. In line with previous work, we identified decreased levels of TCA cycle enzymes, including isocitrate dehydrogenase, whereas malectin, calnexin, and lactate dehydrogenase A were augmented after treatment. We propose the most responsive proteins of our subset as potential novel biomarkers to assess treatment response after anti-angiogenic therapy that warrant future analysis in clinical GBM samples.

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BIOM-26. MOLECULAR PREDICTORS OF RESPONSE TO SELINEXOR IN RECURRENT GLIOBLASTOMA (GBM)

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