Explore the vast range of titles available.

Recent studies have revealed that metformin influences gut microbiota and the immune system although neither is a classic target of the drug. This research has revealed complexity not previously appreciated, and opened new research directions. The extent to which immunomodulatory effects and actions on the microbiota are related to each other and account for effects on host energy metabolism remains to be determined. These sites of action may be relevant not only to the efficacy of metformin for its established use in type 2 diabetes, but also to proposed novel indications in oncology and other diseases.

Key Points The incidences of obesity, type 2 diabetes mellitus (T2DM), and many cancers are rapidly increasing worldwide; clinicians are increasingly required to treat patients with both T2DM and cancer, or both obesity and cancer Obesity is a risk factor for some cancers, and obesity at and weight gain after diagnosis are associated with adverse cancer outcomes; the interactions of diabetes and/or its treatments with cancer risk and outcomes are complex and controversial Laboratory findings provide a rationale for clinical trials of the antidiabetic drug metformin for cancer treatment; although the first two studies (in pancreatic cancer) revealed no survival benefit, many additional studies are ongoing Concerns about an increased cancer risk associated with other antidiabetic agents have been raised; in general, follow-up studies have failed to confirm such risks, but data on long-term exposure remain sparse and pharmacovigilance is necessary Certain drugs used in the treatment of cancer lead to metabolic toxicities, chiefly hyperglycaemia, which might be dose-limiting for some patients, especially those with pre-existing diabetes Clarification of the mechanisms underlying the relationships between obesity and neoplasia might provide clues relevant to novel cancer treatments and prevention strategies The prevalence rates of obesity, type 2 diabetes mellitus, and cancer are increasing globally. Herein, the relationships between these diseases and their treatments are reviewed, and the practical principles relevant to the increasingly common challenge of managing patients who have been diagnosed with both diabetes and cancer are outlined. The prevalence of obesity, of type 2 diabetes mellitus (T2DM), and of cancer are all increasing globally. The relationships between these diseases are complex, and thus difficult to elucidate; nevertheless, evidence supports the hypothesis that obesity increases the risks of both T2DM and certain cancers. Further complexity arises from controversial evidence that specific drugs used in the treatment of T2DM increase or decrease cancer risk or influence cancer prognosis. Herein, we review the current evidence from studies that have addressed these relationships, and summarize the methodological challenges that are frequently encountered in such research. We also outline the physiology that links obesity, T2DM, and neoplasia. Finally, we outline the practical principles relevant to the increasingly common challenge of managing patients who have been diagnosed with both diabetes and cancer.

In preclinical work and retrospective population studies, the anti-diabetic drug metformin has been associated with antineoplastic activity and decreased burden of many cancers, including pancreatic cancer. There is therefore interest in the hypothesis that this drug might be repurposed for indications in oncology. We aimed to assess the efficacy of the addition of metformin to a standard systemic therapy in patients with advanced pancreatic cancer, and provide the first report of a clinical trial with a survival endpoint of metformin for an oncological indication. We did this double-blind, randomised, placebo-controlled phase 2 trial at four centres in the Netherlands. Patients aged 18 years or older with advanced pancreatic cancer were randomly assigned (1:1), via a permutated computer-generated block allocation scheme (block size of six) to receive intravenous gemcitabine (1000 mg/m2) on days 1, 8, and 15 every 4 weeks and oral erlotinib (100mg) once daily in combination with either oral metformin or placebo twice daily. Metformin dose was escalated from 500 mg (in the first week) to 1000 mg twice daily in the second week. Randomisation was stratified by hospital, diabetes status, and tumour stage. The primary endpoint was overall survival at 6 months in the intention-to-treat population. This trial is complete and is registered with ClinicalTrials.gov, number NCT01210911. Between May 31, 2010, and Jan 3, 2014, we randomly assigned 121 patients to receive gemcitabine and erlotinib with either placebo (n=61) or metformin (n=60). Overall survival at 6 months was 63·9% (95% CI 51·9–75·9) in the placebo group and 56·7% (44·1–69·2) in the metformin group (p=0·41). There was no difference in overall survival between groups (median 7·6 months [95% CI 6·1–9·1] vs 6·8 months [95% CI 5·1–8·5] in the metformin group; hazard ratio [HR] 1·056 [95% CI 0·72–1·55]; log-rank p=0·78). The most frequent grade 3–4 toxic effects were neutropenia (15 [25%] patients in placebo group vs 15 [25%] in metformin group), skin rash (six [10%] vs four [7%]), diarrhoea (three [5%] vs six [10%]), and fatigue (two [3%] vs six [10%]). Addition of a conventional anti-diabetic dose of metformin does not improve outcome in patients with advanced pancreatic cancer treated with gemcitabine and erlotinib. Future research should include studies of more potent biguanides, and should focus on patients with hyperinsulinaemia and patients with tumours showing markers of sensitivity to energetic stress, such as loss of function of AMP kinase, a key regulator of cellular energy homoeostasis. Academic Medical Centre, Amsterdam, and The Terry Fox Foundation, Vancouver, Canada.

Key Points Preclinical evidence for a role of insulin and insulin-like growth factor (IGF) signalling in promoting neoplastic growth is impressive. Several different targeting strategies for the insulin and IGFI receptor family exist, and dozens of drug candidates have shown activity in model systems. Phase III clinical trials have so far been undertaken only with IGFI receptor-specific antibodies. Although the final results have not yet been published, disappointing reports have been presented for some of these trials. Future trials may differ by incorporating predictive biomarkers, by using rational combination therapy approaches and by using other pharmacological approaches to targeting, such as anti-ligand antibodies or tyrosine kinase inhibitors. The insulin and IGFI receptor family may be involved in resistance mechanisms to therapies that target other signalling nodes in cancer cells, suggesting that there may be situations in which co-targeting will confer benefit. The insulin and IGFI receptor family is now known to have a role in the important relationships between macronutrient intake and cancer, diabetes and cancer, and obesity and cancer. Biguanides, such as metformin, which is widely used in diabetes treatment, have been reported in hypothesis-generating retrospective population studies of subjects with diabetes to be associated with reduced cancer burden. These agents lower insulin levels if they are increased, and have a variety of effects on cellular signalling and cellular metabolism. However, there are gaps in knowledge related to their pharmacokinetics and mechanisms of action that require elucidation. This Review reflects on the recent disappointing initial results from Phase III trials of insulin-like growth factor I receptor (IGF1R)-specific antibodies for cancer treatment, and discusses the next steps in targeting insulin and IGFI signalling in cancer therapy. Although several early phase clinical trials raised enthusiasm for the use of insulin-like growth factor I receptor (IGF1R)-specific antibodies for cancer treatment, initial Phase III results in unselected patients have been disappointing. Further clinical studies may benefit from the use of predictive biomarkers to identify probable responders, the use of rational combination therapies and the consideration of alternative targeting strategies, such as ligand-specific antibodies and receptor-specific tyrosine kinase inhibitors. Targeting insulin and IGF signalling also needs to be considered in the broader context of the pathophysiology that relates obesity and diabetes to neoplasia, and the effects of anti-diabetic drugs, including metformin, on cancer risk and prognosis. The insulin and IGFI receptor family is also relevant to the development of PI3K–AKT pathway inhibitors.

Key Points Insulin and insulin-like growth factor (IGF) signalling systems are ancient and involve regulation of physiology in ways beyond their well-known medically recognized roles concerning regulation of carbohydrate metabolism and growth. There is substantial experimental and clinical evidence that cancer cells express insulin and IGF1 receptors, and that these receptors are important activators of the Akt and mitogen-activated protein kinase signalling networks in neoplastic tissue. Population studies provide substantial direct and circumstantial evidence that cancer risk and cancer prognosis are influenced by IGF1 and insulin levels. Preclinical evaluation of drug candidates that target IGF1 and/or insulin signalling has revealed antineoplastic activity. At least 10 different drug candidates are being evaluated in clinical trials; early results have justified expansion of clinical trial programmes. Energy metabolism is an important topic in cancer research. IGF1 and insulin might have roles, along with other regulators, in mediating effects of perturbations of whole organism energy balance (for example, dietary excess, caloric restriction and exercise) on cellular energy physiology. Insulin and insulin-like growth factors (IGFs) are well-known as key regulators of energy metabolism and growth and have important roles in neoplasia. This Review documents the various methods are being used to investigate novel cancer prevention and treatment strategies related to insulin and IGF signalling. Insulin and insulin-like growth factors (IGFs) are well known as key regulators of energy metabolism and growth. There is now considerable evidence that these hormones and the signal transduction networks they regulate have important roles in neoplasia. Epidermiological, clinical and laboratory research methods are being used to investigate novel cancer prevention and treatment strategies related to insulin and IGF signalling. Pharmacological strategies under study include the use of novel receptor-specific antibodies, receptor kinase inhibitors and AMP-activated protein kinase activators such as metformin. There is evidence that insulin and IGF signalling may also be relevant to dietary and lifestyle factors that influence cancer risk and cancer prognosis. Recent results are encouraging and have justified the expansion of many translational research programmes.

Metformin is widely prescribed for the treatment of type II diabetes. Recently, it has been proposed that this compound or related biguanides may have antineoplastic activity. Biguanides may exploit specific metabolic vulnerabilities of transformed cells by acting on them directly, or may act by indirect mechanisms that involve alterations of the host environment. Preclinical data suggest that drug exposure levels are a key determinant of proposed direct actions. With respect to indirect mechanisms, it will be important to determine whether recently demonstrated metformin-induced changes in levels of candidate systemic mediators such as insulin or inflammatory cytokines are of sufficient magnitude to achieve therapeutic benefit. Results of the first generation of clinical trials now in progress are eagerly anticipated. Ongoing investigations may justify a second generation of trials that explore pharmacokinetic optimization, rational drug combinations, synthetic lethality strategies, novel biguanides, and the use of predictive biomarkers.

Recent advances indicate that biological aging is a potentially modifiable driver of late-life function and chronic disease and have led to the development of geroscience-guided therapeutic trials such as TAME (Targeting Aging with MEtformin). TAME is a proposed randomized clinical trial using metformin to affect molecular aging pathways to slow the incidence of age-related multi-morbidity and functional decline. In trials focusing on clinical end-points (e.g., disease diagnosis or death), biomarkers help show that the intervention is affecting the underlying aging biology before sufficient clinical events have accumulated to test the study hypothesis. Since there is no standard set of biomarkers of aging for clinical trials, an expert panel was convened and comprehensive literature reviews conducted to identify 258 initial candidate biomarkers of aging and age-related disease. Next selection criteria were derived and applied to refine this set emphasizing: (1) measurement reliability and feasibility; (2) relevance to aging; (3) robust and consistent ability to predict all-cause mortality, clinical and functional outcomes; and (4) responsiveness to intervention. Application of these selection criteria to the current literature resulted in a short list of blood-based biomarkers proposed for TAME: IL-6, TNFα-receptor I or II, CRP, GDF15, insulin, IGF1, cystatin C, NT-proBNP, and hemoglobin A1c. The present report provides a conceptual framework for the selection of blood-based biomarkers for use in geroscience-guided clinical trials. This work also revealed the scarcity of well-vetted biomarkers for human studies that reflect underlying biologic aging hallmarks, and the need to leverage proposed trials for future biomarker discovery and validation.

The mammalian/mechanistic target of rapamycin (mTOR) is a key component of cellular metabolism that integrates nutrient sensing with cellular processes that fuel cell growth and proliferation. Although the involvement of the mTOR pathway in regulating life span and aging has been studied extensively in the last decade, the underpinning mechanisms remain elusive. In this review, we highlight the emerging insights that link mTOR to various processes related to aging, such as nutrient sensing, maintenance of proteostasis, autophagy, mitochondrial dysfunction, cellular senescence, and decline in stem cell function.

Rapamycin and its analogues inhibit mTOR, which leads to decreased protein synthesis and decreased cancer cell proliferation in many experimental systems. Adenosine 5′- monophosphate-activated protein kinase (AMPK) activators such as metformin have similar actions, in keeping with the TSC2/1 pathway linking activation of AMPK to inhibition of mTOR. As mTOR inhibition by rapamycin is associated with attenuation of negative feedback to IRS-1, rapamycin is known to increase activation of AKT, which may reduce its anti-neoplastic activity. We observed that metformin exposure decreases AKT activation, an action opposite to that of rapamycin. We show that metformin (but not rapamycin) exposure leads to increased phosphorylation of IRS-1 at Ser⁷⁸⁹, a site previously reported to inhibit downstream signaling and to be an AMPK substrate phosphorylated under conditions of cellular energy depletion. siRNA methods confirmed that reduction of AMPK levels attenuates both the IRS-1 Ser⁷⁸⁹ phosphorylation and the inhibition of AKT activation associated with metformin exposure. Although both rapamycin and metformin inhibit mTOR (the former directly and the latter through AMPK signaling), our results demonstrate previously unrecognized differences between these agents. The data are consistent with the observation that maximal induction of apoptosis and inhibition of proliferation are greater for metformin than rapamycin.