Metabolomic signature of brain cancer.

Despite advances in surgery and adjuvant therapy, brain tumors represent one of the leading causes of cancer-related mortality and morbidity in both adults and children. Gliomas constitute about 60% of all cerebral tumors, showing varying degrees of malignancy. They are difficult to treat due to dismal prognosis and limited therapeutics. Metabolomics is the untargeted and targeted analyses of endogenous and exogenous small molecules, which charact erizes the phenotype of an individual. This emerging "omics" science provides functional readouts of cellular activity that contribute greatly to the understanding of cancer biology including brain tumor biology. Metabolites are highly informative as a direct signature of biochemical activity; therefore, metabolite profiling has become a promising approach for clinical diagnostics and prognostics. The metabolic alterations are well-recognized as one of the key hallmarks in monitoring disease progression, therapy, and revealing new molecular targets for effective therapeutic intervention. Taking advantage of the latest high-throughput analytical technologies, that is, nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS), metabolomics is now a promising field for precision medicine and drug discovery. In the present report, we review the application of metabolomics and in vivo metabolic profiling in the context of adult gliomas and paediatric brain tumors. Analytical platforms such as high-resolution (HR) NMR, in vivo magnetic resonance spectroscopic imaging and high- and low-resolution MS are discussed. Moreover, the relevance of metabolic studies in the development of new therapeutic strategies for treatment of gliomas are reviewed.

Phase II Investigation of TVB-2640 (Denifanstat) with Bevacizumab in Patients with First Relapse High-Grade Astrocytoma.

PURPOSE: Glioblastoma represents the most common primary brain tumor. Although antiangiogenics are used in the recurrent setting, they do not prolong survival. Glioblastoma is known to upregulate fatty acid synthase (FASN) to facilitate lipid biosynthesis. TVB-2640, a FASN inhibitor, impairs this activity. PATIENTS AND METHODS: We conducted a prospective, single-center, open-label, unblinded, phase II study of TVB-2640 plus bevacizumab in patients with recurrent high-grade astrocytoma. Patients were randomly assigned to TVB-2640 (100 mg/m2 oral daily) plus bevacizumab (10 mg/kg i.v., D1 and D15) or bevacizumab monotherapy for cycle 1 only (28 days) for biomarker analysis. Thereafter, all patients received TVB-2640 plus bevacizumab until treatment-related toxicity or progressive disease (PD). The primary endpoint was progression-free survival (PFS). RESULTS: A total of 25 patients were enrolled. The most frequently reported adverse events (AE) were palmar-plantar erythrodysesthesia, hypertension, mucositis, dry eye, fatigue, and skin infection. Most were grade 1 or 2 in intensity. The overall response rate (ORR) for TVB-2640 plus bevacizumab was 56% (complete response, 17%; partial response, 39%). PFS6 for TVB-2640 plus bevacizumab was 31.4%. This represented a statistically significant improvement in PFS6 over historical bevacizumab monotherapy (BELOB 16%; P = 0.008) and met the primary study endpoint. The observed OS6 was 68%, with survival not reaching significance by log-rank test (P = 0.56). CONCLUSIONS: In this phase II study of relapsed high-grade astrocytoma, TVB-2640 was found to be a well-tolerated oral drug that could be safely combined with bevacizumab. The favorable safety profile and response signals support the initiation of a larger multicenter trial of TVB-2640 plus bevacizumab in astrocytoma.

Hypoxia-activated evofosfamide for treatment of recurrent bevacizumab-refractory glioblastoma: a phase I surgical study.

Background: Anti-angiogenic therapy is known to induce a greater degree of hypoxia, including in glioblastoma (GBM). Evofosfamide (Evo) is a hypoxia-activated prodrug which is reduced, leading to the release of the alkylating agent bromo-isophosphoramide mustard. We assessed the safety, tolerability, preliminary efficacy, and biomarkers of Evo plus bevacizumab (Bev) in Bev-refractory GBM. Methods: Twenty-eight patients with Bev-refractory GBM were enrolled in a dose escalation study receiving from 240 mg/m2 (cohort 1) to 670 mg/m2 (cohort 4) of Evo every 2 weeks in combination with Bev. Patients deemed surgical candidates underwent a single dose of Evo or placebo with pimonidazole immediately prior to surgery for biomarker evaluation, followed by dose escalation upon recovery. Assessments included adverse events, response, and survival. Results: Evo plus Bev was well tolerated up to and including the maximum dose of 670 mg/m2, which was determined to be the recommended phase II dose. Overall response rate was 17.4%, with disease control (complete response, partial response, and stable disease) observed in 14 (60.9%) of the 23 patients. The ratio of enhancement to non-enhancement was significant on log-rank analysis with time to progression (P = 0.023), with patients having a ratio of less than 0.37 showing a median progression-free survival of 98 days versus 56 days for those with more enhancement. Conclusions: Evo plus Bev was well tolerated in patients with Bev-refractory GBM, with preliminary evidence of activity that merits further investigation.

The C. elegans male exercises directional control during mating through cholinergic regulation of sex-shared command interneurons.

BACKGROUND: Mating behaviors in simple invertebrate model organisms represent tractable paradigms for understanding the neural bases of sex-specific behaviors, decision-making and sensorimotor integration. However, there are few examples where such neural circuits have been defined at high resolution or interrogated. METHODOLOGY/PRINCIPAL FINDINGS: Here we exploit the simplicity of the nematode Caenorhabditis elegans to define the neural circuits underlying the male's decision to initiate mating in response to contact with a mate. Mate contact is sensed by male-specific sensilla of the tail, the rays, which subsequently induce and guide a contact-based search of the hermaphrodite's surface for the vulva (the vulva search). Atypically, search locomotion has a backward directional bias so its implementation requires overcoming an intrinsic bias for forward movement, set by activity of the sex-shared locomotory system. Using optogenetics, cell-specific ablation- and mutant behavioral analyses, we show that the male makes this shift by manipulating the activity of command cells within this sex-shared locomotory system. The rays control the command interneurons through the male-specific, decision-making interneuron PVY and its auxiliary cell PVX. Unlike many sex-shared pathways, PVY/PVX regulate the command cells via cholinergic, rather than glutamatergic transmission, a feature that likely contributes to response specificity and coordinates directional movement with other cholinergic-dependent motor behaviors of the mating sequence. PVY/PVX preferentially activate the backward, and not forward, command cells because of a bias in synaptic inputs and the distribution of key cholinergic receptors (encoded by the genes acr-18, acr-16 and unc-29) in favor of the backward command cells. CONCLUSION/SIGNIFICANCE: Our interrogation of male neural circuits reveals that a sex-specific response to the opposite sex is conferred by a male-specific pathway that renders subordinate, sex-shared motor programs responsive to mate cues. Circuit modifications of these types may make prominent contributions to natural variations in behavior that ultimately bring about speciation.