Exogenous Metabolic Modulators Improve Response to Carboplatin in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) lacks targeted therapies, leaving cytotoxic chemotherapy as the current standard treatment. However, chemotherapy resistance remains a major clinical challenge. Increased insulin-like growth factor 1 signaling can potently blunt chemotherapy response, and lysosomal processes including the nutrient scavenging pathway autophagy can enable cancer cells to evade chemotherapy-mediated cell death. Thus, we tested whether inhibition of insulin receptor/insulin-like growth factor 1 receptor with the drug BMS-754807 and/or lysosomal disruption with hydroxychloroquine (HCQ) could sensitize TNBC cells to the chemotherapy drug carboplatin. Using in vitro studies in multiple TNBC cell lines, in concert with in vivo studies employing a murine syngeneic orthotopic transplant model of TNBC, we show that BMS-754807 and HCQ each sensitized TNBC cells and tumors to carboplatin and reveal that exogenous metabolic modulators may work synergistically with carboplatin as indicated by Bliss analysis. Additionally, we demonstrate the lack of overt in vivo toxicity with our combination regimens and, therefore, propose that metabolic targeting of TNBC may be a safe and effective strategy to increase sensitivity to chemotherapy. Thus, we conclude that the use of exogenous metabolic modulators, such as BMS-754807 or HCQ, in combination with chemotherapy warrants additional study as a strategy to improve therapeutic responses in women with TNBC.

Tirzepatide attenuates mammary tumor progression in diet-induced obese mice.

We report for the first time an anticancer benefit of tirzepatide-a dual glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptor agonist-in a model of obesity and breast cancer in female mice. Long-term tirzepatide treatment induced weight loss, mitigated obesity-driven changes in circulating metabolic hormone levels, and suppressed orthotopic E0771 mammary tumor growth. Relative to tirzepatide, chronic calorie restriction, an established anticancer intervention in preclinical models, promoted even greater weight loss, systemic hormonal regulation, and tumor suppression. We conclude that tirzepatide represents a promising pharmacologic approach for mitigating the procancer effects of obesity. Moreover, strategies promoting greater weight loss than achieved with tirzepatide alone may augment the anticancer benefits of tirzepatide.

Myxedema coma: Recognition and treatment.

ABSTRACT: Myxedema coma (MC) develops from a long-standing, unrecognized, or untreated hypothyroidism. This article discusses the pathophysiology, clinical manifestations, treatment, and nursing considerations for patients with MC.

Unraveling and targeting RAS-driven metabolic signaling for therapeutic gain.

RAS mutations are among the most frequent oncogenic drivers observed in human cancers. With a lack of available treatment options, RAS-mutant cancers account for many of the deadliest cancers in the United States. Recent studies established that altered metabolic requirements are a hallmark of cancer, and many of these alterations are driven by aberrant RAS signaling. Specifically, RAS-driven cancers are characterized by upregulated glycolysis, the differential channeling of glycolytic intermediates, upregulated nutrient scavenging pathways such as autophagy and macropinocytosis, and altered glutamine utilization and mitochondrial function. This unique metabolic landscape promotes tumorigenesis, proliferation, survival in nutrient deficient environments and confers resistance to conventional cytotoxic and targeted therapies. Emerging work demonstrates how these dependencies can be therapeutically exploited in vitro and in vivo with many metabolic inhibitors currently in clinical trials. This review aims to outline the unique metabolic requirements induced by aberrant RAS signaling and how these altered dependencies present opportunities for therapeutic intervention.

Making the Enterobacterial Common Antigen Glycan and Measuring Its Substrate Sequestration.

The enterobacterial common antigen (ECA), a three-sugar repeat unit polysaccharide produced by Enterobacteriaceae family members, impacts bacterial outer membrane permeability, and its biosynthesis affects the glycan landscape of the organism. ECA synthesis impacts the production of other polysaccharides by reducing the availability of shared substrates, the most notable of which is the 55-carbon polyisoprenoid bactoprenyl phosphate (BP), which serves as a carrier for the production of numerous bacterial glycans including ECA, peptidoglycan, O-antigen, and more. Here, using a combination of in vitro enzymatic synthesis and liquid chromatography-mass spectrometry (LC-MS) analysis of bacterial lysates, we provide biochemical evidence for the effect on endogenous polyisoprenoid pools from cell culture that arises from glycan pathway disruption. In this work, we have cloned and expressed each gene involved in ECA repeat unit biosynthesis and reconstituted the pathway in vitro, providing LC-MS characterized standards for the investigation of cellular glycan-linked intermediates and BP. We then generated ECA deficient mutants in genes associated with production of the polysaccharide, which we suspected would accumulate materials identical to our standards. We found that indeed accumulated products from these cells were indistinguishable from our enzymatically prepared standards, and moreover we observed a concomitant decrease in cellular BP levels with each mutant. This work provides the first direct biochemical evidence for the sequestration of BP upon the genetic disruption of glycan biosynthesis pathways in bacteria. This work also provides methods for the direct assessment of both the ECA glycan, and a new understanding of the dynamic interdependence of the bacterial polysaccharide repertoire.

General Utilization of Fluorescent Polyisoprenoids with Sugar Selective Phosphoglycosyltransferases.

The protective surfaces of bacteria are comprised of polysaccharides and are involved in host invasion and colonization, host immune system evasion, and antibacterial resistance. A major barrier to our fundamental understanding of these complex surface polysaccharides lies in the tremendous diversity in glycan composition among bacterial species. The polyisoprenoid bactoprenyl phosphate (or undecaprenyl phosphate) is an essential lipid carrier necessary for early stages of glycopolymer assembly. Because of the ubiquity of bactoprenyl phosphate in these critical processes, molecular probes appended to this lipid carrier simplify identification of enzymatic roles during polysaccharide bioassembly. A limited number of these probes exist in the literature or have been assessed with such pathways, and the limits of their use are not currently known. Herein, we devise an efficient method for producing fluorescently modified bactoprenyl probes. We further expand our previous efforts utilizing 2-nitrileaniline and additionally prepare nitrobenzoxadizol-tagged bactoprenyl phosphate for the first time. We then assess the enzyme promiscuity of these two probes utilizing four well-characterized initiating phosphoglycosyltransferases: CPS2E (Streptococcus pneumoniae), WbaP (Salmonella enterica), WecA (Escherichia coli), and WecP (Aeromonas hydrophilia). Both probes serve as substrates for these enzymes and could be readily used to investigate a wide range of bacterial glycoassembly pathways. Interestingly, we have also identified unique solubility requirements for the nitrobenzoxadizol moiety for efficient enzymatic utilization that was not observed for the 2-nitrileaniline.