A Precision Medicine Approach to Metabolic Therapy for Breast Cancer in Mice

Increasing evidence highlights the possibility for approaches targeting metabolism as potential adjuvants to cancer therapy. Sodium-glucose transport protein 2 (SGLT2) inhibitors are the newest class of antihyperglycemic therapies and have recently been highlighted as a novel therapeutic approach to breast cancer. To our knowledge, however, SGLT2 inhibitors have not been applied in the neoadjuvant setting as a precision medicine approach to combining metabolic therapy with standard of care therapy for this devastating disease. In this study, we combine the SGLT2 inhibitor dapagliflozin with paclitaxel chemotherapy in both lean and obese mice. We show that dapagliflozin enhances the efficacy of paclitaxel, reducing tumor glucose uptake and prolonging survival in an insulin-dependent manner in some but not all breast tumors. Our data find a genetic signature for breast tumors most likely to respond to dapagliflozin in combination with paclitaxel. Tumors driven by mutations upstream of canonical insulin signaling pathways are likely to respond to such treatment, whereas tumors driven by mutations downstream of canonical insulin signaling are not. These data demonstrate that dapagliflozin enhances the response to chemotherapy in mice with breast cancer and suggest that breast cancer patients with driver mutations upstream of canonical insulin signaling may be most likely to benefit from this neoadjuvant approach. A clinical trial is currently in preparation, with an application recently submitted for Yale Human Investigations Committee approval, to test this hypothesis in breast cancer patients.

Investigation of the Effectiveness of Cortexin in the Treatment of Cardiac Arrhythmias in Children

In this article, a new look at cardiac rhythm and conduction disorders in children is outlined. These deviations, along with congenital malformations, have taken one of the first places in the structure of cardiovascular pathologies. This is one of the most serious problems that stands at the intersection of cardiology and pediatrics. The frequency of occurrence of severe forms of arrhythmias reaches 1:5000 of the child population, and life-threatening arrhythmias – 1:7000. Treatment of cardiac arrhythmias and conduction disorders is one of the most difficult sections of clinical pediatrics. There are medicinal and non-medicinal methods. According to experimental new data, nootropics, in particular the drug Cortexin, along with cardiotrophic drugs, form the basis of neuro-metabolic therapy and correction of children's arrhythmias.

Nanofactory for metabolic and chemodynamic therapy: pro-tumor lactate trapping and anti-tumor ROS transition

Lactate plays a critical role in tumorigenesis, invasion and metastasis. Exhausting lactate in tumors holds great promise for the reversal of the immunosuppressive tumor microenvironment (TME). Herein, we report on a “lactate treatment plant” (i.e., nanofactory) that can dynamically trap pro-tumor lactate and in situ transformation into anti-tumor cytotoxic reactive oxygen species (ROS) for a synergistic chemodynamic and metabolic therapy. To this end, lactate oxidase (LOX) was nano-packaged by cationic polyethyleneimine (PEI), assisted by a necessary amount of copper ions (PLNPCu). As a reservoir of LOX, the tailored system can actively trap lactate through the cationic PEI component to promote lactate degradation by two-fold efficiency. More importantly, the byproducts of lactate degradation, hydrogen peroxide (H2O2), can be transformed into anti-tumor ROS catalyzing by copper ions, mediating an immunogenic cell death (ICD). With the remission of immunosuppressive TME, ICD process effectively initiated the positive immune response in 4T1 tumor model (88% tumor inhibition). This work provides a novel strategy that rationally integrates metabolic therapy and chemodynamic therapy (CDT) for combating tumors. Graphical Abstract

Nanofactory for Metabolic and Chemodynamic Therapy: Pro-Tumor Lactate Trapping and Anti-Tumor ROS Transition

Lactate plays a critical role in tumorigenesis, invasion and metastasis. Exhausting lactate in tumors holds great promise for the reversal of the immunosuppressive tumor microenvironment (TME). Herein, we report on a “lactate treatment plant” (i.e., nanofactory) that can dynamically trap pro-tumor lactate and in situ transformation into anti-tumor cytotoxic reactive oxygen species (ROS) for a synergistic chemodynamic and metabolic therapy. To this end, lactate oxidase (LOX) was nano-packaged by cationic polyethyleneimine (PEI), assisted by a necessary amount of copper ions (PLNPCu). As a reservoir of LOX, the tailored system can actively trap lactate through the cationic PEI component to promote lactate degradation by two-fold efficiency. More importantly, the byproducts of lactate degradation, hydrogen peroxide (H2O2), can be transformed into anti-tumor ROS catalyzing by copper ions, mediating an immunogenic cell death (ICD). With the remission of immunosuppressive TME, ICD process effectively initiated the positive immune response in 4T1 tumor model (88% tumor inhibition). This work provides a novel strategy that rationally integrates metabolic therapy and chemodynamic therapy (CDT) for combating tumors.

The gut-liver axis in nonalcoholic fatty liver disease: association of intestinal permeability with disease severity and treatment outcomes

Objective To investigate the association between intestinal permeability and severity of nonalcoholic fatty liver disease (NAFLD), and the value of intestinal permeability in predicting the efficacy of metabolic therapy for NAFLD. Methods Disease severity was compared between patients with normal and elevated intestinal permeability; correlations between D-lactate and different NAFLD parameters were analyzed; and the effects of metabolic therapy on NAFLD patients with normal and elevated intestinal permeability were evaluated. Results A total of 190 patients with NAFLD were enrolled. NAFLD patients with elevated intestinal permeability had significantly higher levels of liver test parameters, liver ultrasonographic fat attenuation parameter, triglyceride, homeostasis model assessment of insulin resistance value and diamine oxidase (all P˂0.05) than NAFLD patients with normal intestinal permeability. Further, serum D-lactate levels were positively correlated with alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase, total bilirubin, indirect bilirubin, fat attenuation parameter, triglyceride, and diamine oxidase (all P˂0.05). Moreover, NAFLD patients with elevated intestinal permeability showed less improvement in TG levels (P=0.014) after metabolic therapy. Conclusion Intestinal permeability correlates with the disease severity in patients with NAFLD. Moreover, intestinal permeability may have value for predicting the efficacy of metabolic therapy for NAFLD patients.

Ketogenic Metabolic Therapy, Without Chemo or Radiation, for the Long-Term Management of IDH1-Mutant Glioblastoma: An 80-Month Follow-Up Case Report

Background: Successful treatment of glioblastoma (GBM) remains futile despite decades of intense research. GBM is similar to most other malignant cancers in requiring glucose and glutamine for growth, regardless of histological or genetic heterogeneity. Ketogenic metabolic therapy (KMT) is a non-toxic nutritional intervention for cancer management. We report the case of a 32-year-old man who presented in 2014 with seizures and a right frontal lobe tumor on MRI. The tumor cells were immunoreactive with antibodies to the IDH1 (R132H) mutation, P53 (patchy), MIB-1 index (4–6%), and absent ATRX protein expression. DNA analysis showed no evidence of methylation of the MGMT gene promoter. The presence of prominent microvascular proliferation and areas of necrosis were consistent with an IDH-mutant glioblastoma (WHO Grade 4).Methods: The patient refused standard of care (SOC) and steroid medication after initial diagnosis, but was knowledgeable and self-motivated enough to consume a low-carbohydrate ketogenic diet consisting mostly of saturated fats, minimal vegetables, and a variety of meats. The patient used the glucose ketone index calculator to maintain his Glucose Ketone Index (GKI) near 2.0 without body weight loss.Results: The tumor continued to grow slowly without expected vasogenic edema until 2017, when the patient opted for surgical debulking. The enhancing area, centered in the inferior frontal gyrus, was surgically excised. The pathology specimen confirmed IDH1-mutant GBM. Following surgery, the patient continued with a self-administered ketogenic diet to maintain low GKI values, indicative of therapeutic ketosis. At the time of this report (May 2021), the patient remains alive with a good quality of life, except for occasional seizures. MRI continues to show slow interval progression of the tumor.Conclusion: This is the first report of confirmed IDH1-mutant GBM treated with KMT and surgical debulking without chemo- or radiotherapy. The long-term survival of this patient, now at 80 months, could be due in part to a therapeutic metabolic synergy between KMT and the IDH1 mutation that simultaneously target the glycolysis and glutaminolysis pathways that are essential for GBM growth. Further studies are needed to determine if this non-toxic therapeutic strategy could be effective in providing long-term management for other GBM patients with or without IDH mutations.