Targeting PGC1α to wrestle cancer: a compelling therapeutic opportunity

mTOR regulates several processes that control tumor development, including cancer cell growth, angiogenesis and the immune response to tumor. Accordingly, mTOR inhibitors have been thoroughly explored in cancer therapy but have failed to provide long-lasting anticancer benefits. Several resistance mechanisms that counteract the antitumor effect of mTOR inhibitors have been identified and have highlighted the need to use mTOR inhibitors in combination therapies. In this context, emerging evidence has demonstrated that mTOR inhibitors, despite their immunosuppressive properties, provide anticancer benefits to immunotherapies. In fact, mTOR inhibitors also display immunostimulatory effects, in particular by promoting memory CD8+ T cell generation. Hence, mTOR inhibitors represent a therapeutic opportunity to promote antitumor CD8 responses and to boost the efficacy of different modalities of cancer immunotherapy. In this context, strategies to reduce the immunosuppressive activity of mTOR inhibitors and therefore to shift the immune response toward antitumor immunity will be useful. In this review, we present the different classes of mTOR inhibitors and discuss their effect on immune cells by focusing mainly on CD8+ T cells. We further provide an overview of the different preclinical studies that investigated the anticancer effects of mTOR inhibitors combined to immunotherapies.

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Proton therapy: A therapeutic opportunity for aggressive pediatric meningioma

Pediatric Blood & Cancer ◽

10.1002/pbc.28919 ◽

2021 ◽

Author(s):

Barbara Rombi ◽

Alessandro Ruggi ◽

Iacopo Sardi ◽

Mino Zucchelli ◽

Mirko Scagnet ◽

...

Keyword(s):

Proton Therapy ◽

Therapeutic Opportunity ◽

Pediatric Meningioma

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CBIO-05. LIPID METABOLIC REPROGRAMMING SENSITIZES A MOLECULARLY-DEFINED SUBSET OF GLIOBLASTOMAS TO FERROPTOSIS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.065 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii16-ii16

Author(s):

Danielle Morrow ◽

David Nathanson ◽

Timothy Cloughesy ◽

Robert Prins ◽

Nicholas Bayley ◽

...

Keyword(s):

Lipid Metabolism ◽

Lipid Droplets ◽

Metabolic Reprogramming ◽

Membrane Phospholipids ◽

Molecular Alterations ◽

Lipidomic Analysis ◽

Novel Association ◽

Therapeutic Opportunity ◽

Dependent Cell ◽

Main Components

Abstract Cancers, including the universally lethal glioblastoma (GBM), have reprogrammed lipid metabolism to fuel tumor growth. However, the molecular alterations responsible for aberrant lipid metabolism, and the potential for identifying new therapeutic opportunities are not fully understood. To systematically investigate the GBM lipidome, we performed integrated transcriptomic, genomic and shotgun lipidomic analysis of an extensive library of molecularly diverse patient-derived GBM samples. Using this comprehensive approach, we discovered two GBM sub-groups defined by their combined molecular and lipidomic profile. Triacylglycerides (TAGs) enriched in polyunsaturated fatty acids (PUFAs) were among the most significantly altered lipids between the two groups of GBM tumors. TAGs are the main components of lipid droplets, which sequester PUFA-TAGs away from membrane phospholipids where their peroxidation can lead to ferroptosis – a regulated from of PUFA-peroxidation dependent cell death. Accordingly, the GBM subgroup with a depletion of PUFA TAGs showed heightened sensitivity to ferroptosis. Our findings suggest a novel association between specific molecular signatures of GBM, lipid metabolism and ferroptosis. This relationship may present a new therapeutic opportunity to target reprogrammed lipid metabolism in a molecularly-defined subset of GBMs.

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Reply: Reply to Oluf Anderson's Reply: Predicting a window of therapeutic opportunity in multiple sclerosis

Brain ◽

10.1093/brain/awq339 ◽

2011 ◽

Vol 134 (5) ◽

pp. e176-e176

Author(s):

O. Andersen

Keyword(s):

Multiple Sclerosis ◽

Therapeutic Opportunity

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Oncogenetic landscape and clinical impact of IDH1 and IDH2 mutations in T-ALL

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01068-4 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Mathieu Simonin ◽

Aline Schmidt ◽

Christophe Bontoux ◽

Marie-Émilie Dourthe ◽

Etienne Lengliné ◽

...

Keyword(s):

Lymphoblastic Leukemia ◽

Genetic Alterations ◽

Clinical Impact ◽

Loss Of Function ◽

Targeted Next Generation Sequencing ◽

Epigenetic Regulator ◽

Therapeutic Opportunity ◽

Cell Acute Lymphoblastic Leukemia ◽

Prognostic Implications ◽

Idh1 And Idh2 Mutations

AbstractIDH1 and IDH2 mutations (IDH1/2Mut) are recognized as recurrent genetic alterations in acute myeloid leukemia (AML) and associated with both clinical impact and therapeutic opportunity due to the recent development of specific IDH1/2Mut inhibitors. In T-cell acute lymphoblastic leukemia (T-ALL), their incidence and prognostic implications remain poorly reported. Our targeted next-generation sequencing approach allowed comprehensive assessment of genotype across the entire IDH1 and IDH2 locus in 1085 consecutive unselected and newly diagnosed patients with T-ALL and identified 4% of, virtually exclusive (47 of 49 patients), IDH1/2Mut. Mutational patterns of IDH1/2Mut in T-ALL present some specific features compared to AML. Whereas IDH2R140Q mutation was frequent in T-ALL (25 of 51 mutations), the IDH2R172 AML hotspot was absent. IDH2 mutations were associated with older age, an immature phenotype, more frequent RAS gain-of-function mutations and epigenetic regulator loss-of-function alterations (DNMT3A and TET2). IDH2 mutations, contrary to IDH1 mutations, appeared to be an independent prognostic factor in multivariate analysis with the NOTCH1/FBXW7/RAS/PTEN classifier. IDH2Mut were significantly associated with a high cumulative incidence of relapse and very dismal outcome, suggesting that IDH2-mutated T-ALL cases should be identified at diagnosis in order to benefit from therapeutic intensification and/or specific IDH2 inhibitors.

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Abstract 3672: Loss of Perivascular Adipocyte Paracrine Function Leads to Increased Vascular Tone and Glucose Intolerance in Hypertension

Circulation ◽

10.1161/circ.118.suppl_18.s_463-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Kaivan Khavandi ◽

Adam Greenstein ◽

Sarah Withers ◽

Kazuhiko Sonoyama ◽

Sarah Lewis ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Vascular Tone ◽

Tnf Alpha ◽

Perivascular Adipose Tissue ◽

The Metabolic Syndrome ◽

Adipocyte Cell ◽

Therapeutic Opportunity

In order to investigate the contribution of perivascular adipose tissue (PVAT) to arterial function, a total of 55 small arteries harvested from 35 skin biopsies of patients with Metabolic Syndrome and matched controls were mounted as ring preparations in a wire myograph. Contractility to cumulative doses of Norepinephrine in the presence or absence of PVAT showed an anticontractile effect in arteries from healthy volunteers (p=0.009), which was lost in patients with Metabolic Syndrome. Bioassay studies confirmed that PVAT releases a hydrophilic anticontractile factor in health, which is absent in obesity. Using a soluble fragment of the human Type 1 receptor, we identified that the anticontractile factor was adiponectin, which is the sole mediator of vasodilation, acting by increasing endothelial bioavailability of nitric oxide. Significant endothelial dysfunction was observed in patients with Metabolic Syndrome (p<0.001). Quantitative image analysis of adipose tissue revealed significantly increased adipocyte cell size in patients with Metabolic Syndrome, compared with healthy controls (p<0.006). There was immunohistochemical evidence of inflammation with upregulation of TNF-alpha receptor 1 in these patients (p<0.001). Application of exogenous TNF-alpha abolished the anticontractile effect of PVAT by reducing adiponectin bioavailability. Oxidative stress also induced by cytokines TNF-alpha and IL-6 but not IL-1, reduced adiponectin production from PVAT and increased basal tone. When the obese microenvironment was replicated in vitro by inflicting hypoxia on PVAT, adiponectin activity was lost but then rescued by incubation with cytokine antagonists. Further application of the adiponectin receptor fragment abolished PVAT relaxation. We conclude that in healthy arteries, PVAT releases adiponectin which reduces vascular tone. In obesity, this is lost by a cascade of adipocyte hypertrophy, hypoxia, inflammation and oxidative stress. The resulting vasoconstriction contributes to hypertension, hypertriglyceridaemia and insulin resistance. Direct targeting of adiponectin release from PVAT therefore provides a novel therapeutic opportunity in the Metabolic Syndrome.

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Methodological Considerations in the Assessment of Effectiveness of Homeopathic Care: A Critical Review of the EPI3 Study

Homeopathy ◽

10.1055/s-0041-1732335 ◽

2021 ◽

Author(s):

Yola Moride

Keyword(s):

Critical Review ◽

Patient Characteristics ◽

Upper Respiratory Tract ◽

Specific Patient ◽

Outcome Measurements ◽

Apparent Loss ◽

Therapeutic Opportunity ◽

Methodological Considerations ◽

Tract Infections ◽

And Control

Abstract Background EPI3 is an observational study of a representative sample of general practitioners (GPs) and patients in France, demonstrating that patient characteristics differ according to the prescribing preferences of their GPs for homeopathy. For selected conditions (musculoskeletal disorders, sleep disorders, anxiety/depression, upper respiratory tract infections), progression of symptoms and adverse events over follow-up in the homeopathy preference group did not significantly differ from other practice preferences, but there was a two-fold to four-fold lower usage of conventional medicines. The EPI3 study's validity was challenged due to absence of head-to-head comparison of medicines to conclude on a causal association between homeopathy and outcomes. Methods A critical review of the nine EPI3 publications was conducted, focusing on generalizability, selection bias, outcome measurements and confounding. Results The conceptual framework of EPI3 rests on a systemic construct, i.e., the homeopathic treatment concept assessed using the type of GP prescribing preference, taking into account the clinical, human and social aspects. The enrollment process enhanced the generalizability of findings. Validated instruments for outcome measurements were used for three conditions, and control of confounding was rigorous. Conclusion EPI3 was conducted according to best practices. Homeopathy prescribing preference met specific patient needs with less use of conventional medicines and without an apparent loss in therapeutic opportunity.

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Molecular Mechanism of Inhibition of Polysialyltransferase Domain (PSTD) by Heparin

Current Topics in Medicinal Chemistry ◽

10.2174/1568026621666210713165251 ◽

2021 ◽

Vol 21 ◽

Author(s):

Si-Min Liao ◽

Xue-Hui Liu ◽

Li-Xing Peng ◽

Bo Lu ◽

Ri-Bo Huang ◽

...

Keyword(s):

Polysialic Acid ◽

Neuronal Cell ◽

Selective Inhibition ◽

Migration And Invasion ◽

Heparin Binding ◽

Nmr Studies ◽

Clinical Prognosis ◽

Neuronal Cell Adhesion Molecule ◽

Mechanism Of Inhibition ◽

Therapeutic Opportunity

: Polysialic acid (polySia) is a unique carbohydrate polymer produced on the neuronal cell adhesion molecule (NCAM) in many cancer cells. It strongly correlates with the migration and invasion of tumor cells and aggressive, metastatic disease, and poor clinical prognosis in the clinic. Its synthesis is catalyzed by two polysialyltransferases (polySTs), ST8SiaIV (PST) and ST8SiaII (STX). Therefore, selective inhibition of polySTs presents a therapeutic opportunity to inhibit tumor invasion and metastasis due to NCAM polysialylation. It has been proposed that NCAM polysialylation could be inhibited by two types of heparin inhibitors, low molecular heparin (LMWH) and heparin tetrasaccharide (DP4). This review summarizes the interactions between Polysialyltransferase Domain (PSTD) in ST8SiaIV and CMP-Sia, and between the PSTD and polySia; and how LMWH and DP4 inhibit these interactions. Our NMR studies indicate that LMWH is a more effective inhibitor than DP4 for inhibition of NCAM polysialylation. The NMR identification of heparin-binding sites in the PSTD may provide insight into the design of specific inhibitors of polysialylation.

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