Trends in Malignant Glioma Monoclonal Antibody Therapy
Ontology highlight
ABSTRACT:
SUBMITTER: Chekhonin I
PROVIDER: S-EPMC4997917 | biostudies-literature | 2015 Jun
REPOSITORIES: biostudies-literature
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Project description:Glioma is the most frequent and aggressive type of brain neoplasm, being anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), its most malignant forms. The survival rate in patients with these neoplasms is 15 months after diagnosis, despite a diversity of treatments, including surgery, radiation, chemotherapy, and immunotherapy. The resistance of GBM to various therapies is due to a highly mutated genome; these genetic changes induce a de-regulation of several signaling pathways and result in higher cell proliferation rates, angiogenesis, invasion, and a marked resistance to apoptosis; this latter trait is a hallmark of highly invasive tumor cells, such as glioma cells. Due to a defective apoptosis in gliomas, induced autophagic death can be an alternative to remove tumor cells. Paradoxically, however, autophagy in cancer can promote either a cell death or survival. Modulating the autophagic pathway as a death mechanism for cancer cells has prompted the use of both inhibitors and autophagy inducers. The autophagic process, either as a cancer suppressing or inducing mechanism in high-grade gliomas is discussed in this review, along with therapeutic approaches to inhibit or induce autophagy in pre-clinical and clinical studies, aiming to increase the efficiency of conventional treatments to remove glioma neoplastic cells.
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Project description:Monoclonal antibodies (mAb) have been used as targeted treatments against cancer for more than a decade, with mixed results. Research is needed to understand mAb mechanisms of action with the goal of improving the efficacy of currently used mAbs and guiding the design of novel mAbs. While some mAb-induced tumor cell killing is a result of direct effects on tumor cell signaling, mAb opsonization of tumor cells also triggers activation of immune responses due to complement activation and engagement of antibody receptors on immune effector cells. In fact, complement has been shown to play an important role in modulating the anti-tumor activity of many mAb through complement-dependent cytotoxicity, antibody-dependent cytotoxicity, and through indirect effects by modulating the tumor microenvironment. Complement activity can have both agonistic and antagonistic effects on these processes. How the balance of such effects impacts on the clinical efficacy of mAb therapy remains unclear. In this review, we discuss the mAbs currently approved for cancer treatment and examine how complement can impact their efficacy with a focus on how this information might be used to improve the clinical efficacy of mAb treatment.
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Project description:Pulmonary fibrosis (PF) is a chronic interstitial lung disease that causes irreversible and progressive lung scarring and respiratory failure. Activation of fibroblasts (FBs) play a central role in progression of PF. Here we report that platelet endothelial aggregation receptor 1 (Pear1) in FBs is a new molecular target for PF therapy. Pear1 deficiency spontaneously caused respiratory function decline and alveolar collagens accumulation in old mice. The degree of PF and mortality induced by bleomycin were significantly enhanced in Pear1 deficient mice. FB Mesenchyme-specific Pear1 deficiency aggravated bleomycin-induced PF, confirming that Pear1 modulates PF progression probably byvia regulation of FBs function. Single cell RNA-seq analysis of pulmonary FB and functional enrichment analysis revealed drastic expansion of Aactivated- FB clusters and enrichment of activated FB marker genes in extracellular matrix (ECM) development and pulmonary fibrosis in Pear1-/- fibrotic lungs. CD140+ bulk tissue RNA-seq analysis further confirmed that multiple mesenchyme development pathways especially epithelial mesenchymal transition (EMT) are enriched with up-regulated genes involving FB mediated ECM organization and development in in Pear1-/- fibrotic lungs. We further found that Pear1 associated with Protein Phosphatase 1 to suppress fibrotic factors such as TGFß, FGF or PDGF-induced intracellular signalling and FB activation. Intratracheal aerosolization of monoclonal antibody activating Pear1 greatly ameliorates PF in both wild-type mice and Pear1-humanized mice, suggesting that targeting Pear1 may serve as a new therapeutic strategy for PFand significantly improves their survival rate.
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