Metabolomic signatures of hypocaloric dietary interventions associate with breast cancer risk in the Nurses' Health Study II.

Background: An individual's metabolic state plays a critical role in breast cancer (BC) risk, influenced by factors such as obesity and insulin signaling. Hypocaloric diets induce metabolic changes that influence these metabolic factors, thereby potentially influencing BC risk. However, it remains unclear whether metabolic profiles like those induced by such beneficial diets are associated with BC risk.

Reduced Muscle Loss in Patients With NSCLC Taking Fibrates: Findings From a Retrospective Observational Study.

Background: The cancer-anorexia-cachexia syndrome (CACS) is a common and debilitating wasting disorder characterized by loss of skeletal muscle and worse morbidity and mortality. In pre-clinical studies, CACS is associated with loss of peroxisome proliferator-activated receptor alpha (PPAR-α) dependent ketone production in the liver. Fibrates are PPAR-α agonists that are commonly used to treat dyslipidemia.

Early-onset colorectal cancer as an emerging disease of metabolic dysregulation.

Colorectal cancer (CRC) is one of the most common malignancies and the second leading cause of cancer-related death worldwide. Early-onset CRC (EOCRC), diagnosed in adults under the age of 50 years, has emerged as a pressing public health concern owing to its alarming rise in incidence since the 1990s. This trend, observed in the USA and at least eight other high-income countries, starkly contrasts with the declining incidence rates of late-onset CRC (age 50 years and above), largely attributed to early disease detection and lifestyle changes.

Alpelisib for Long-term Management of Tumor-Induced Hypoglycemia.

Background/objective: Tumor-induced hypoglycemia (TIH) is a rare and often fatal complication of cancers that produce or induce secretion of hormones such as insulin, insulin-like growth factor 2, and proinsulin. We present a case series describing the effectiveness and tolerability of the phosphatidylinositol 3-kinase inhibitor alpelisib in 2 women with metastatic insulin-producing or proinsulin-producing tumors.

Case Presentation: Over 4 to 8 months of follow-up, it was observed that alpelisib resulted in reductions in hypoglycemic rates (<54 mg/dL) as assessed on continuous glucose monitoring.

Cachexia in Clinical Practice: Experience from an Endocrine-Led Care Model.

Background: Cachexia is a multifactorial syndrome of involuntary weight loss, skeletal muscle wasting, and metabolic dysregulation, commonly seen in advanced cancer and other chronic diseases. Despite its prevalence and prognostic significance, effective treatment strategies remain limited, and there is no standardized model of outpatient care in the US.

Objective: To describe the structure, patient characteristics, and outcomes of a multidisciplinary cancer cachexia clinic embedded within an academic endocrinology practice.

Sustained Glucose Turnover Flux Distinguishes Cancer Cachexia from Nutrient Limitation.

Cancer cachexia is an involuntary weight loss condition characterized by systemic metabolic disorder. A comprehensive flux characterization of this condition however is lacking. Here, we systematically isotope traced eight major circulating nutrients in mice bearing cachectic C26 tumors (cxC26) and food intake-matched mice bearing non-cachectic C26 tumors (ncxC26).

Multi-node inhibition targeting mTORC1, mTORC2 and PI3Kα potently inhibits the PI3K/AKT/mTOR pathway in endometrial and breast cancer models.

Background: While PI3K/AKT/mTOR signalling plays a critical role in cancer, targeting this pathway with single node inhibitors has limited efficacy due to several known factors such as pathway feedback reactivation, co-occurring pathway mutations, and systemic glucose dysregulation leading to hyperinsulinemia. While multi-node inhibition approaches have shown promising clinical efficacy, they require further mechanistic characterisation.

Methods: Using models of endometrial and breast cancer, we evaluated the efficacy of a multi-node PI3K/AKT/mTOR pathway inhibitor approach utilising the dual mTORC1/mTORC2 inhibitor sapanisertib, PI3Kα inhibitor serabelisib and an insulin-supressing diet.

Cancer-Associated Cachexia: Bridging Clinical Findings with Mechanistic Insights in Human Studies.

Unlabelled: Cancer-associated cachexia (CAC) is a chronic wasting disease typically associated with advanced cancer, resulting in progressive and debilitating loss of function and poor tolerance to anticancer therapy. Preclinical animal models have identified various potential mechanisms and mediators, which have had limited translational success in clinical trials. This review focuses on human studies and discusses the clinical phenotyping of CAC using imaging-derived body composition, quality-of-life and functional measures, existing evidence for mediators, current therapeutic options, and future directions to advance the field.

Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice.

Cachexia, a severe wasting syndrome characterized by tumour-induced metabolic dysregulation, is a leading cause of death in people with cancer, yet its underlying mechanisms remain poorly understood. Here we show that a longitudinal full-body single-nuclei-resolution transcriptome analysis in a Drosophila model of cancer cachexia captures interorgan dysregulations. Our study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of Pepck1 and Pdk, key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia.

Autophagy Suppresses CCL2 to Preserve Appetite and Prevent Lethal Cachexia.

Unlabelled: Macroautophagy (autophagy hereafter) captures intracellular components and delivers them to lysosomes for degradation and recycling . In adult mice, autophagy sustains metabolism to prevent wasting by cachexia and to survive fasting, and also suppresses inflammation, liver steatosis, neurodegeneration, and lethality . Defects in autophagy contribute to metabolic, inflammatory and degenerative diseases, however, the specific mechanisms involved were unclear .

Early identification of weight loss trajectories in advanced cancer and associations with survival.

Consensus criteria to diagnose unintentional weight loss, a condition often termed cachexia that affects most patients with advanced cancer, are based on 6-month changes by which time intervention is often ineffective. Leveraging the large and diverse population in Kaiser Permanente Northern California's community oncology practice, we studied 8338 patients with advanced lung, pancreatic, or colorectal cancers. We calculated weekly weight change measurements from 2 months pre- to 6 months post-diagnosis to identify 4 weight change trajectories (Gain, Stable, Moderate Loss, and Severe Loss) and associated these trajectories with survival.

Fueling metabolic disruption via FMD to boost chemotherapy in TNBC.

Triple-negative breast cancer (TNBC) is highly glycolytic and lacks effective biomarkers for therapy response. The BREAKFAST trial showed that a fasting-mimicking diet (FMD) improved pathological complete response (pCR) rates to 56.6% compared to historical chemotherapy averages (30%-40%), with minimal severe adverse events.

Call to Improve Coding of Cancer-Associated Cachexia.

Cachexia is a systemic wasting syndrome prevalent in patients with cancer that significantly affects quality of life, health care costs, and therapeutic outcomes. Despite its clinical importance, cachexia is rarely formally diagnosed. This deficiency presents a challenge for effective patient management and care, health care resource allocation, and the advancement of therapeutic approaches.

Plasma C-peptide mammographic features and risk of breast cancer.

Our study in the Nurses' Health Study (NHS) and NHS2, a nested case-control study with 1260 cases and 2221 controls, investigated the association between C-peptide levels, mammographic density (MD) parameters, V (a measure of gray scale variation), and breast cancer (BC) risk. We also examined how C-peptide and BC risk vary across quartiles of mammographic features. Linear and logistic regressions were used to study the associations between C-peptide and MD parameters, and breast cancer.

Restoring adiponectin via rosiglitazone ameliorates tissue wasting in mice with lung cancer.

Aim: To investigate systemic regulators of the cancer-associated cachexia syndrome (CACS) in a pre-clinical model for lung cancer with the goal to identify therapeutic targets for tissue wasting.

Methods: Using the Kras/Lkb1 (KL) mouse model, we found that CACS is associated with white adipose tissue (WAT) dysfunction that directly affects skeletal muscle homeostasis. WAT transcriptomes showed evidence of reduced adipogenesis, and, in agreement, we found low levels of circulating adiponectin.

AMPK as a mediator of tissue preservation: time for a shift in dogma?

Ground-breaking discoveries have established 5'-AMP-activated protein kinase (AMPK) as a central sensor of metabolic stress in cells and tissues. AMPK is activated through cellular starvation, exercise and drugs by either directly or indirectly affecting the intracellular AMP (or ADP) to ATP ratio. In turn, AMPK regulates multiple processes of cell metabolism, such as the maintenance of cellular ATP levels, via the regulation of fatty acid oxidation, glucose uptake, glycolysis, autophagy, mitochondrial biogenesis and degradation, and insulin sensitivity.

Diet and Cancer Metabolism.

Diet and exercise are modifiable lifestyle factors known to have a major influence on metabolism. Clinical practice addresses diseases of altered metabolism such as diabetes or hypertension by altering these factors. Despite enormous public interest, there are limited defined diet and exercise regimens for cancer patients.

Managing hyperglycemia and rash associated with alpelisib: expert consensus recommendations using the Delphi technique.

Hyperglycemia and rash are expected but challenging adverse events of phosphatidylinositol-3-kinase inhibition (such as with alpelisib). Two modified Delphi panels were conducted to provide consensus recommendations for managing hyperglycemia and rash in patients taking alpelisib. Experts rated the appropriateness of interventions on a 1-to-9 scale; median scores and dispersion were used to classify the levels of agreement.

Epinephrine inhibits PI3Kα via the Hippo kinases.

The phosphoinositide 3-kinase p110α is an essential mediator of insulin signaling and glucose homeostasis. We interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110α and found that the Hippo kinases phosphorylate p110α at T1061, which inhibits its activity. This inhibitory state corresponds to a conformational change of a membrane-binding domain on p110α, which impairs its ability to engage membranes.

Profiling of Skeletal Muscle and Adipose Tissue Depots in Men with Advanced Prostate Cancer Receiving Different Forms of Androgen Deprivation Therapy.

Background: Androgen deprivation therapy (ADT) is a common treatment modality for men with prostate cancer. Increases in adipose tissue mass and decreases in skeletal muscle mass are known on-target adverse effects of standard ADT. The effects of newer agents such as abiraterone acetate (ABI) and enzalutamide (ENZA) on body composition and how these compare with standard luteinizing hormone-releasing hormone agonists (aLHRHs) are unclear.

Spatiotemporal regulation of GIPR signaling impacts glucose homeostasis as revealed in studies of a common GIPR variant.

Objective: Glucose-dependent insulinotropic polypeptide (GIP) has a role in controlling postprandial metabolic tone. In humans, a GIP receptor (GIPR) variant (Q354, rs1800437) is associated with a lower body mass index (BMI) and increased risk for Type 2 Diabetes. To better understand the impacts of GIPR-Q354 on metabolism, it is necessary to study it in an isogeneic background to the predominant GIPR isoform, E354.

Biological role of fructose in the male reproductive system: Potential implications for prostate cancer.

Background: Over the last 20 years, fructose has gradually emerged as a potential metabolic substrate capable of promoting the growth and progression of various cancers, including prostate cancer (PCa). The biological and molecular mechanisms that underlie the effects of fructose on cancer are beginning to be elucidated.

Methods: This review summarizes the biological function of fructose as a potential carbon source for PCa cells and its role in the functionality of the male reproductive tract under normal conditions.