PURPOSE: Glioblastoma (GBM) is classified as one of the most aggressive and lethal brain tumor. Great strides have been made in understanding the genomic and molecular underpinnings of GBM, which translated into development of new therapeutic approaches to combat such deadly disease. However, there are only few therapeutic agents that can effectively inhibit GBM invasion in a clinical framework. In an effort to address such challenges, we have generated anti-SEMA3A monoclonal antibody as a potential therapeutic antibody against GBM progression. MATERIALS AND METHODS: We employed public glioma datasets, Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas, to analyze SEMA3A mRNA expression in human GBM specimens. We also evaluated for protein expression level of SEMA3A via tissue microarray (TMA) analysis. Cell migration and proliferation kinetics were assessed in various GBM patient-derived cells (PDCs) and U87-MG cell-line for SEMA3A antibody efficacy. GBM patient-derived xenograft (PDX) models were generated to evaluate tumor inhibitory effect of anti-SEMA3A antibody in vivo. RESULTS: By combining bioinformatics and TMA analysis, we discovered that SEMA3A is highly expressed in human GBM specimens compared to non-neoplastic tissues. We developed three different anti-SEMA3A antibodies, in fully human IgG form, through screening phage-displayed synthetic antibody library using a classical panning method. Neutralization of SEMA3A significantly reduced migration and proliferation capabilities of PDCs and U87-MG cell line in vitro. In PDX models, treatment with anti-SEMA3A antibody exhibited notable tumor inhibitory effect through down-regulation of cellular proliferative kinetics and tumor-associated macrophages recruitment. CONCLUSION: In present study, we demonstrated tumor inhibitory effect of SEMA3A antibody in GBM progression and present its potential relevance as a therapeutic agent in a clinical framework.
Antibodies ; Brain ; Brain Neoplasms ; Cell Line ; Cell Movement ; Computational Biology ; Dataset ; Down-Regulation ; Genome ; Glioblastoma* ; Glioma ; Heterografts ; Humans ; Immunoglobulin G ; In Vitro Techniques ; Kinetics ; Macrophages ; Mass Screening ; Methods ; RNA, Messenger ; Semaphorin-3A

Purpose: Targeted next-generation sequencing (NGS) panels for solid tumors have been useful in clinical framework for accurate tumor diagnosis and identifying essential molecular aberrations. However, most cancer panels have been designed to address a wide spectrum of pan-cancer models, lacking integral prognostic markers that are highly specific to gliomas. Materials and Methods: To address such challenges, we have developed a glioma-specific NGS panel, termed “GliomaSCAN,” that is capable of capturing single nucleotide variations and insertion/deletion, copy number variation, and selected promoter mutations and structural variations that cover a subset of intron regions in 232 essential glioma-associated genes. We confirmed clinical concordance rate using pairwise comparison of the identified variants from whole exome sequencing (WES), immunohistochemical analysis, and fluorescence in situ hybridization. Results: Our panel demonstrated high sensitivity in detecting potential genomic variants that were present in the standard materials. To ensure the accuracy of our targeted sequencing panel, we compared our targeted panel to WES. The comparison results demonstrated a high correlation. Furthermore, we evaluated clinical utility of our panel in 46 glioma patients to assess the detection capacity of potential actionable mutations. Thirty-two patients harbored at least one recurrent somatic mutation in clinically actionable gene. Conclusion We have established a glioma-specific cancer panel. GliomaSCAN highly excelled in capturing somatic variations in terms of both sensitivity and specificity and provided potential clinical implication in facilitating genome-based clinical trials. Our results could provide conceptual advance towards improving the response of genomically guided molecularly targeted therapy in glioma patients.

BACKGROUND: Many of the leading causes of mortality and morbidity in the Philippines are controllable with nature-based products, either as agents of intervention, or prevention, as nutritional supplements or for the control of side-effects of medications. The different R&D programs on nature-based products in the Philippines are usually conducted in isolation, or through silos. These often lead to products that are shortsighted, duplicate products, or products with minimal innovation, not readily applicable to population and environmental sustainability.

OBJECTIVE: The study aimed to draft an internationally benchmarked and integrated blueprint for a population health and environmental health-led nature-based product development and conservation for the Philippines.

METHODS: The methodology consisted of a review of literature; regional educational visits; and a series of consultative meetings with stakeholders.

RESULTS: The study resulted in a stakeholder-validated blueprint that assigns the Philippine Institute of Traditional and Alternative Health Care (PITAHC) to lead the way for Filipinos to produce more nature-based products that are of international quality and attuned with local health needs. The blueprint has identified "9 Optimizations" in the realization of this aspiration, including an expanded role for PITAHC, a national database, an ethical researchers list, and to produce at least five commercial products and 20 intellectual property rights within 5 years with an estimated total investment of approximately PhP 816 M.