Michael Pollak

• MD
• Professor (Full) at McGill University

Background Prolactin, a hormone produced by the pituitary gland, regulates breast development and may contribute to breast cancer etiology. However, most epidemiologic studies of prolactin and breast cancer have been restricted to single, often small, study samples with limited exploration of effect modification. Methods The Biomarkers in Breast C...

Background Poor diet quality lacking plant-based foods, elevated body mass index (BMI), insulin resistance, microbiome dysbiosis, as well as inflammation have all been implicated in progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM. Whether a dietary intervention can delay progres...

Introduction Poor diet quality, elevated body mass index (BMI), insulin resistance, microbiome dysbiosis, inflammation as well as immune dysfunction have all been implicated in progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to multiple myeloma (MM). Plant-based diets have been associ...

Cancer cells reprogram their metabolism to meet the energy demands of neoplasia. We observed that the level of expression of mitochondrial enzyme electron transfer flavoprotein dehydrogenase (ETFDH) is unexpectedly decreased in most human malignancies relative to that in tissue-of-origin. Reduced ETFDH expression increases proliferation and neoplas...

Background Circulating total insulin-like growth factor-I (IGF-I) is an established risk factor for prostate cancer. However, only a small proportion of circulating IGF-I is free or readily dissociable from IGF-binding proteins (its bioavailable form), and few studies have investigated the association of circulating free IGF-I with prostate cancer...

Tirzepatide, a drug used in management of type II diabetes, is an activator of both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptors. Tirzepatide treatment leads to weight loss in murine models of obesity, and clinical trials have shown the drug can achieve ∼ 20% weight loss in obese patients. Obesity...

Introduction Obesity, low adiponectin, high leptin, high insulin, and diets lacking plant-based foods are risk factors for plasma cell disorders (PCDs). Patients (pts) with monoclonal gammopathy (MGUS) and smoldering myeloma (SMM) and an elevated body mass index (BMI) are twice as likely to progress to myeloma (MM). There is evidence of microbiome...

Primary prevention of breast cancer in women at elevated risk includes several strategies such as endocrine prevention and risk-reducing mastectomy (RRM). The objective of this study was to evaluate awareness of different preventive strategies across high-risk subgroups. Women referred for high risk evaluation between 2020 and 2023 completed an ini...

Tirzepatide, a drug used in management of type II diabetes, is an activator of both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptors. Tirzepatide treatment leads to weight loss in murine models of obesity, and clinical trials have shown the drug can lead to weight loss up to ∼ 20% in overweight patien...

Metabolic scaling, the inverse correlation of metabolic rates to body mass, has been appreciated for more than 80 years. Studies of metabolic scaling have largely been restricted to mathematical modeling of caloric intake and oxygen consumption, and mostly rely on computational modeling. The possibility that other metabolic processes scale with bod...

Obesity, defined as a body mass index (BMI) ≥ 30, is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated BMI is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear because of inconsistent findings from epidemiological studies and a lack of mechanistic stud...

The molecular mode of action of biguanides, including the drug metformin, which is widely used in the treatment of diabetes, is incompletely characterized. Here, we define the inhibitory drug-target interaction(s) of a model biguanide with mammalian respiratory complex I by combining cryo-electron microscopy and enzyme kinetics. We interpret these...

Pancreatic cancer (pancreatic ductal adenocarcinoma: PDAC) is one of the most aggressive neoplastic diseases. Metformin use has been associated with reduced pancreatic cancer incidence and better survival in diabetics. Metformin has been shown to inhibit PDAC cells growth and survival, both in vitro and in vivo. However, clinical trials using metfo...

Pancreatic cancer (pancreatic ductal adenocarcinoma: PDAC) is one of the most aggressive neoplastic diseases. Metformin use was associated with reduced pancreatic cancer incidence or better survival in diabetics. Metformin has been shown to inhibit PDAC cells survival and growth in vitro and in vivo. However, clinical trials using metformin failed...

The molecular mode of action of metformin, a biguanide used widely in the treatment of diabetes, is incompletely characterized. Here we define the inhibitory drug-target interaction(s) of a model biguanide with mammalian respiratory complex I by combining cryo-electron microscopy and enzyme kinetics. We explain the unique selectivity of biguanide b...

Obesity is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated bodyweight is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear due to inconsistent findings from epidemiological studies and lack of mechanistic studies in this population. Here, we show tha...

Self-reported type 2 diabetes mellitus (T2DM) is a risk factor for many cancers, suggesting its pathology relates to carcinogenesis. We conducted a case-cohort study to examine associations of hemoglobin A1c (HbA1c) and c-peptide with cancers associated with self-reported T2DM. This study was drawn from a prospective cohort of 32,383 women and men...

Background Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the asso...

MNK is a serine/threonine kinase signaling node in the MAPK pathway, which is phosphorylated and activated by ERK. MNK phosphorylates eIF4E to promote translation of a subset of mRNAs that encode oncogenically relevant proteins including c-Myc, Cyclin D1 and PD-L1. We conducted a phase 1B study [NCT04261218] of tomivosertib (T), an orally administe...

Background: Women with history of chest irradiation for Hodgkin lymphoma are at increased risk of developing bilateral breast cancer, although contralateral breast cancer risk estimates in this population remain undefined. Methods: We queried the SEER database for women treated with radiation therapy for Hodgkin lymphoma prior to age 30 years an...

Mutations in genes encoding cytochrome c oxidase (COX; mitochondrial complex IV) subunits and assembly factors (e.g., SCO1, SCO2, COA6) are linked to severe metabolic syndromes. Notwithstanding that SCO2 is under transcriptional control of tumour suppressor p53, the role of mitochondrial complex IV dysfunction in cancer metabolism remains obscure....

Background/purpose: Type 2 diabetes and obesity increase the risk of developing colorectal cancer. Metformin may reduce colorectal cancer but the mechanisms mediating this effect remain unclear. In mice and humans, a high-fat diet (HFD), obesity and metformin are known to alter the gut microbiome but whether this is important for influencing tumor...

Metabolic scaling, the inverse correlation of metabolic rates to body mass, has been appreciated for more than 80 years. Studies of metabolic scaling have almost exclusively been restricted to mathematical modeling of oxygen consumption. The possibility that other metabolic processes scale with body size has not been studied. To address this gap in...

Background: Elevated bodyweight is a risk factor for breast cancer development in women who carry a mutation in the DNA repair enzymes BRCA1 and BRCA2. However, the mechanistic basis for this association is unknown. Breast adipose tissue undergoes significant changes in the setting of weight gain and obesity, including elevation in aromatase expres...

Background: Women with a history of chest radiation for Hodgkin lymphoma are at an increased risk of developing breast cancer. Although mastectomy has historically been recommended for surgical treatment of breast cancers in women with prior radiation exposure, surgical management trends and contralateral breast cancer risk in this population remai...

Background: Few prospective studies have examined biomarkers of glucose homeostasis or inflammation with prostate cancer risk by tumor stage or grade. Methods: We conducted a case-cohort study to examine associations of pre-diagnosis hemoglobin A1c (HbA1c), c-peptide, and c-reactive protein (CRP) with prostate cancer risk overall and stratified...

The National Cancer Institute (NCI) Division of Cancer Prevention (DCP) convened the "Translational Advances in Cancer Prevention Agent Development (TACPAD) Workshop on Immunomodulatory Agents" as a virtual 2-day workshop on September 13 to 14, 2021. The main goals of this workshop were to foster the exchange of ideas and potentially new collaborat...

Background Childhood and young adult survivors of Hodgkin lymphoma (HL) are at elevated risk of developing breast cancer, yet little data exist on the tumor characteristics that develop in this high‐risk patient population. Methods The National Cancer Institute's Surveillance, Epidemiology, and End Results database was used to identify breast canc...

Background Experimental and epidemiologic evidence supports the role of circulating IGF-1 levels with the risk of prostate cancer. Most circulating IGF-1 is bound to specific binding proteins, and only about 5% circulates in a free form. We explored the relation of free IGF-1 and other components of the IGF system with lethal prostate cancer. Meth...

Molecular mechanisms linking obesity to prostate cancer involve steroid hormone and insulin/insulin-like growth factor-1 (IGF-1) pathways. We investigated the association of circulating serum markers (e.g., androgens and IGFs/IGFBPs) with BMI and in modifying the association of obesity with prostate cancer risk. Data and specimens for this nested c...

Objective: To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR). Research design and methods: We used a large-scale two-sample MR study, using cis genetic determinants (protein quantitative trait loci [pQTL]) of up to 1,611 circulating proteins from five large genome-wide association stud...

Metabolic rewiring and redox balance play pivotal roles in cancer. Cellular senescence is a barrier for tumorigenesis circumvented in cancer cells by poorly understood mechanisms. We report a multi-enzymatic complex that reprograms NAD metabolism by transferring reducing equivalents from NADH to NADP⁺. This hydride transfer complex (HTC) is assembl...

Obesity is a risk factor for the development of post-menopausal breast cancer. Breast white adipose tissue (WAT) inflammation, which is commonly found in women with excess body fat, is also associated with increased breast cancer risk. Both local and systemic effects are likely to be important for explaining the link between excess body fat, adipos...

Background Adipocyte-derived adiponectin may play a role in the host inflammatory response to cancer. We examined the association of plasma adiponectin with the density of tumor infiltrating lymphocytes (TILs) in colon cancers, and with vitamin D, clinicopathological features and patient survival. Methods Plasma adiponectin and 25-hydroxyvitamin D...

p>Background Experimental and epidemiologic evidence supports the role of plasma IGF-1 and risk of prostate cancer. About 5% of IGF-1 circulates in a free or bioavailable form, and is only weakly correlated with total IGF-1; we hypothesized that higher levels of free IGF-1 would be associated with risk of lethal prostate cancer. Methods Lethal pro...

Bioenergetic perturbations driving neoplastic growth increase the production of reactive oxygen species (ROS), requiring a compensatory increase in ROS scavengers to limit oxidative stress. Intervention strategies that simultaneously induce energetic and oxidative stress therefore have therapeutic potential. Phenformin is a mitochondrial complex I...

567 Background: Childhood and young adult survivors of Hodgkin Lymphoma are at an increased risk of developing breast cancer, although little data exist on the characteristics and biologic subtype of breast cancers that develop in this high-risk population. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identif...

3591 Background: Adiponectin is a peptide hormone exclusively secreted by adipocytes that plays a role in immune regulation and in the host inflammatory response to cancer. We examined postsurgical adiponectin levels in relationship to tumor infiltrating lymphocytes (TILs), clinicopathological features, vitamin D status, and patient survival in par...

Malignant transformation and tumor progression are accompanied by significant perturbations in metabolic programs. As such, cancer cells support high ATP turnover to construct the building blocks needed to fuel neoplastic growth. The coordination of metabolic networks in malignant cells is dependent on the collaboration with cellular signaling path...

To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s...

Notwithstanding that high rates of glucose uptake and glycolysis are common in neoplasia, pharmacological efforts to inhibit glucose utilization for cancer treatment have not been successful. Recent evidence suggests that in addition to classical glucose transporters, sodium-glucose transporters (SGLTs) are expressed by cancers. We therefore invest...

Insulin-like growth factor-I (IGF-I) and its binding proteins (BPs) have been associated with breast cancer risk, especially high IGF-I concentrations and the biologically active fraction estimated as the IGF-I/IGFBP-3 molar ratio. The relation of circulating IGF-I and IGFBP-3 concentrations with risk of breast cancer recurrence has been less docum...

Obesity is associated with an increased risk of breast cancer in post-menopausal women and decreased risk in pre-menopausal women. Conversely, in BRCA1/2 mutation carriers, pre-menopausal obesity is associated with early-onset breast cancer. Here we show that obese, pre-menopausal BRCA1/2 mutation carriers have increased levels of aromatase and inf...

Excess body fat and sedentary behavior are associated with increased breast cancer risk and mortality, including in normal weight women. To investigate underlying mechanisms, we examined whether adiposity and exercise impact the breast microenvironment (e.g., inflammation and aromatase expression) and circulating metabo-inflammatory factors. In a c...

Observational studies report that physical activity and metformin are associated with improved clinical outcome in patients with cancer. Inflammation is one biological mechanism hypothesized to mediate these associations. In this phase II, multi-center, 2x2 factorial trial, 139 patients with breast and colorectal cancer who completed standard thera...

Background Energy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study. Methods Baseline plasma insulin-like growth factor (IGF)-I, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at ti...

Background Li-Fraumeni Syndrome (LFS) is a highly penetrant autosomal dominant cancer predisposition disorder caused by germline TP53 pathogenic variants. Patients with LFS have increased oxidative phosphorylation capacity in skeletal muscle and oxidative stress in blood. Metformin inhibits oxidative phosphorylation, reducing available energy for c...

Background: Thyroid hormone has been shown to be involved in carcinogenesis via its effects on cell proliferation pathways. The objective of this study is to determine the association between subclinical hypothyroidism (SCH) and the risk of incident cancer and cancer mortality via systematic review. Methods: A systematic search was performed on...

Aims Previous studies suggest that the use of low‐dose aspirin before a colorectal cancer (CRC) diagnosis may be associated with a decreased risk of CRC progression. Data supporting this association, however, have been inconsistent. We evaluate whether the use of prediagnostic low‐dose aspirin is associated with a lower risk of metastases and all‐c...

Cancer cells display metabolic plasticity to survive stresses in the tumor microenvironment. Cellular adaptation to energetic stress is coordinated in part by signaling through the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Here, we demonstrate that miRNA-mediated silencing of LKB1 confers sensitivity of lymphoma cells to m...

Background: Pancreatic cancer is the third leading cause of cancer death in the United States, and 80% of patients present with advanced, incurable disease. Risk markers for pancreatic cancer have been characterized, but combined models are not used clinically to identify individuals at high risk for the disease. Methods: Within a nested case-co...

Immune checkpoint blockade therapy provides substantial benefits for subsets of patients with advanced cancer, but its utility for cancer prevention is unknown. Lynch syndrome (MIM 120435) is characterized by defective DNA mismatch repair and predisposition to multiple cancers. A variant of Lynch syndrome, Muir–Torre syndrome (MIM 158320), is chara...

Background: Energy balance-related factors such as body mass index (BMI), diet, and physical activity may influence colorectal cancer (CRC) etiology through inter-connected metabolic pathways, but their combined influence is less clear. Methods: We used reduced rank regression to derive three energy balance scores that associate lifestyle factor...

Cancer cells display metabolic plasticity to survive metabolic and energetic stresses in the tumor microenvironment, prompting the need for tools to target tumor metabolism. Cellular adaptation to energetic stress is coordinated in part by signaling through the Liver Kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Reducing LKB1-AMPK s...

Obesity is associated with risk of colorectal adenoma (CRA) and colorectal cancer (CRC). The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in ApcMin/+ mice via metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPK, decreased pmTOR/mTOR ratio, and decreased pS6Ser235/S6Ser235 ratio...

Epidemiological studies suggest that metformin may reduce the incidence of cancer in patients with diabetes and multiple late phase clinical trials assessing the potential of repurposing this drug are underway. Transcriptomic profiling of tumour samples is an excellent tool to understand drug bioactivity, identify candidate biomarkers and assess fo...

Background: Non-muscle-invasive bladder cancer (NMIBC) is the most common neoplasm of the urinary tract and requires life-long invasive surveillance to detect disease recurrence. Currently, there are no effective oral therapies that delay disease recurrence or progression. We recently demonstrated that in mice, metformin accumulates unchanged in t...

Background: Observational data support inverse relationships between exercise or metformin use and disease outcomes in colorectal and breast cancer survivors, although the mechanisms underlying these associations are not well understood. Methods: In a phase II trial, stage I-III colorectal and breast cancer survivors who completed standard thera...

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited treatment options. Although metabolic reprogramming is a hallmark of many cancers, including PDA, previous attempts to target metabolic changes therapeutically have been stymied by drug toxicity and tumour cell plasticity. Here, we show that PDA cells engage an eIF4F-depende...

Purpose: The microenvironment of metastatic breast cancer is incompletely characterized, despite prior evidence that it plays a key role in the biology of metastasis. A major component of the tumor stroma is the carcinoma-associated fibroblast (CAF), which has been shown to communicate with other stromal and cancer cells to create a protumorigenic...

Background: Ewing sarcoma (EWS) manifests one of the lowest somatic mutation rates of any cancer, leading to a scarcity of druggable mutations and neoantigens. Immunotherapeutics targeting differentially expressed cell surface antigens could provide therapeutic benefit for such tumors. Pregnancy-associated plasma protein A (PAPP-A) is a cell membr...

Background: Hyperinsulinemia, high insulin-like growth factor 1 (IGF1) levels, and low IGF binding protein 1 (IGFBP1) levels have been implicated in the relationship between obesity and increased risk of colorectal cancer (CRC). However, it remains inconclusive whether circulating biomarkers of insulin and the IGF axis are associated with conventi...

Abstract Background Mammographic density (MD) is a strong breast cancer risk factor that reflects fibroglandular and adipose tissue composition, but its biologic underpinnings are poorly understood. Insulin-like growth factor binding proteins (IGFBPs) are markers that may be associated with MD given their hypothesized role in breast carcinogenesis....

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 r...

Inflammation is often suggested as major pathway by which lifestyle influences the development of colorectal cancer (CRC). In the present analysis, we empirically derived an inflammatory lifestyle score (ILS) based on associations of nine lifestyle factors with serum levels of high-sensitivity C-reactive protein (hsCRP) and subsequently examined it...

Background: Type 2 diabetes (T2DM) is associated with a lower risk of prostate cancer especially low-grade and localized prostate cancer. The association with aggressive prostate cancer is inconclusive. Few studies have directly examined the associations of diabetes biomarkers with prostate cancer risk. Methods: Among a cohort of 13,994 men who wer...

Cancer behavior is determined by cancer metabolism. Abnormalities in cancer cell metabolism are determined in part by intrinsic or autonomous characteristics of each cancer cell, which relate to in part to genetic alterations in oncogenes and cancer suppressor genes, and in part to host effects, which are mediated in large part by hormones and grow...

p>Inflammation is often suggested as major pathway by which lifestyle influences the development of colorectal cancer (CRC). In the present analysis, we empirically derived an inflammatory lifestyle score (ILS) based on associations of nine lifestyle factors with serum levels of high-sensitivity C-reactive protein (hsCRP) and subsequently examined...

Background: Type 2 diabetes (T2DM) is associated with a lower risk of prostate cancer especially low-grade and localized prostate cancer. The association with aggressive prostate cancer is inconclusive. Few studies have directly examined the associations of diabetes biomarkers with prostate cancer risk. Methods: Among a cohort of 13,994 men who wer...

Self-reported type 2 diabetes mellitus (T2DM) is convincingly associated with higher risks of liver, pancreatic, colon, rectal, female breast, and endometrial cancers, and may also be associated with higher risks of ovarian, bladder and kidney cancers. This evidence largely relies on self-reported T2DM, which does not properly classify the many ind...

3035 Background: Energy balance-associated biomarkers such as insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) have been associated with risk and prognosis of various malignancies. Their relationship to disease progression and mortality in metastatic colorectal cancer (mCRC) requires further study. Methods: In a prospective coho...

Insulin‐like growth factors (IGFs) and insulin‐like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross‐sectional associations of these exposures...

Background: There is evidence linking metformin to improved prostate cancer-related outcomes. Patients and methods: Twenty-five men with metastatic castration-resistant prostate cancer and prostate-specific antigen (PSA) progression while receiving treatment with abiraterone from 3 Swiss centers were included in this single-arm phase 2 trial bet...

Background & aims: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors a...

Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time point...

There is increasing interest in therapeutically exploiting metabolic differences between normal and cancer cells. We show that kinase inhibitors (KIs) and biguanides synergistically and selectively target a variety of cancer cells. Synthesis of non-essential amino acids (NEAAs) aspartate, asparagine, and serine, as well as glutamine metabolism, are...

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 th...