Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas.

Background: Primary and posttreatment resistance to BRAF mutation-targeting inhibitors leads to disease relapse in a majority of melanoma patients. In many instances, this resistance is promoted by upregulation of mitochondrial oxidative phosphorylation (OxPhos) in melanoma cells. We recently showed that a novel electron transport chain (ETC) complex I inhibitor, IACS-010759 (IACS), abolished OxPhos and significantly inhibited tumor growth of high-OxPhos, BRAF inhibitor (BRAFi)-resistant human melanomas.

Clinical, molecular, metabolic, and immune features associated with oxidative phosphorylation in melanoma brain metastases.

Background: Recently, we showed that melanoma brain metastases (MBMs) are characterized by increased utilization of the oxidative phosphorylation (OXPHOS) metabolic pathway compared to melanoma extracranial metastases (ECMs). MBM growth was inhibited by a potent direct OXPHOS inhibitor, but observed toxicities support the need to identify alternative therapeutic strategies. Thus, we explored the features associated with OXPHOS to improve our understanding of the pathogenesis and potential therapeutic vulnerabilities of MBMs.

The Glutaminase Inhibitor CB-839 (Telaglenastat) Enhances the Antimelanoma Activity of T-Cell-Mediated Immunotherapies.

Immune-checkpoint inhibitors and adoptive tumor-infiltrating lymphocyte (TIL) therapies have profoundly improved the survival of patients with melanoma. However, a majority of patients do not respond to these agents, and many responders experience disease relapse. Although numerous innovative treatments are being explored to offset the limitations of these agents, novel therapeutic combinations with immunotherapies have the potential to improve patient responses.

A Novel Mitochondrial Inhibitor Blocks MAPK Pathway and Overcomes MAPK Inhibitor Resistance in Melanoma.

Purpose: The purpose of this study is to determine if inhibition of mitochondrial oxidative phosphorylation (OxPhos) is an effective strategy against MAPK pathway inhibitor (MAPKi)-resistant BRAF-mutant melanomas. The antimelanoma activity of IACS-010759 (OPi), a novel OxPhos complex I inhibitor, was evaluated and . Mechanistic studies and predictors of response were evaluated using molecularly and metabolically stratified melanoma cell lines.

Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases.

There is a critical need to improve our understanding of the pathogenesis of melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival.

Social studies: incorporating all children using community and cultural universals as the centerpiece.

This article features an elementary teacher who has worked with the authors for the past 10 years in research on building a classroom community and using cultural universals as the centerpiece for elementary social studies for all children. Cultural universals are basic human needs and social experiences found in all societies, past and present, and include food, shelter, clothing, transportation, communication, family living, money, childhood, government, and so on. Actions related to cultural universals are experienced by all children regardless of their cultures, socioeconomic backgrounds, achievement levels, or special needs, so teachers can connect to these experiences as bases for developing historical, geographic, political, economic, sociological, psychological, or anthropological understandings.