Intermittent fasting entails restricting food intake during specific times of day, days of the week, religious practice, or surrounding clinically important events. Herein, the metabolic and circadian rhythm mechanisms underlying the proposed benefits of intermittent fasting for the cancer population are described. We summarize epidemiological, preclinical, and clinical studies in cancer published between January 2020 and August 2022 and propose avenues for future research. An outstanding concern regarding the use of intermittent fasting among cancer patients is that fasting often results in caloric restriction, which can put patients already prone to malnutrition, cachexia, or sarcopenia at risk. Although clinical trials do not yet provide sufficient data to support the general use of intermittent fasting in clinical practice, this summary may be useful for patients, caregivers, and clinicians who are exploring intermittent fasting as part of their cancer journey for clinical outcomes and symptom management.

Obesity, an established risk and progression factor for at least 13 cancer types, is highly prevalent globally, and effective strategies to mitigate the burden of obesity-related cancer are urgently needed. We investigated whether tirzepatide, a widely used incretin-mimetic drug that induces substantial weight loss, offers anticancer benefits. Across 3 tumor models, we demonstrate that chronic tirzepatide treatment reverses diet-induced increases in body weight and fat mass, systemic metabolic perturbations, and tumor growth. We also showed that the anticancer activity of tirzepatide does not involve direct effects on the neoplastic cells used, which lack incretin receptor expression. The anticancer actions of tirzepatide require the reversal of both the metabolic dysregulation and hyporesponsiveness of CD8+ tumor infiltrating lymphocytes evident in obesity. Our findings establish tirzepatide as a promising compound for intercepting obesity-related cancers.

Several cancers, including breast cancers, show dependence on glutamine metabolism. The purpose of the present study was to determine the mechanistic basis and impact of differential glutamine metabolism in nonmetastatic and metastatic murine mammary cancer cells. Universally labeled ¹³C₅-glutamine metabolic tracing, qRT-PCR, measures of reductive–oxidative balance, and exogenous ammonium chloride treatment were used to assess glutamine reprogramming. Results show that 4 mM media concentration of glutamine, compared with 2 mM, reduced viability only in metastatic cells, and that this decrease in viability was accompanied by increased incorporation of glutamine-derived carbon into the tricarboxylic acid (TCA) cycle. While increased glutamine metabolism in metastatic cells occurred in tandem with a decrease in the reduced/oxidized glutathione ratio, treatment with the antioxidant molecule N-acetylcysteine did not rescue cell viability. However, the viability of metastatic cells was more sensitive to ammonium chloride treatment compared with nonmetastatic cells, suggesting a role of metabolic reprogramming in averting nitrogen cytotoxicity in nonmetastatic cells. Overall, these results demonstrate the ability of nonmetastatic cancer cells to reprogram glutamine metabolism and that this ability may be lost in metastatic cells.

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.

Triple-negative breast cancers (TNBCs) lack targeted therapies, leaving surgery and systemic chemotherapy as current standard approaches for treatment. However, chemotherapy resistance is a major clinical challenge. Stimulation of receptor tyrosine kinases such as insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) activates the protein kinase A (PKA), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling cascades. Activation of these pathways is observed in the majority of TNBC tumors and promotes pro-proliferative signaling. Thus IGF-1R/IR are potential therapeutic targets in TNBC, but clinical trials of anti-IGF-1R/IR therapies have consistently shown minimal and often heterogeneous therapeutic responses. Our objective was to determine whether metabolic reprogramming achieved by combination regimens, specifically the IGF-1R/IR inhibitor BMS-754807 and/or treatment with the platinum-based chemotherapeutic agent, carboplatin, promotes autophagy induction and sensitizes cancer cells to autophagy inhibition. Cytotoxicity of BMS-754807, alone or in combination with carboplatin and/or the autophagy inhibitor, hydroxychloroquine, was assessed in murine (E0771, metM-Wnt^lung, B6C3TAg 2.51) and human (MDA-MB-231, MDA-MB-468) models of TNBC using MTT assays. Analysis of mitochondrial mass was measured in cells stained with MitoTracker Green FM using flow cytometry. Autophagic flux was measured with an mCherry-EGFP-LC3B tandem fluorescent protein. BMS-754807 (10μM) significantly induced 22-51% cytotoxicity in all cell lines tested, with E0771 cells showing the strongest response. Treatment with BMS-754807 (2.5µM) significantly increased mitochondrial mass (31%) compared to untreated cells. In addition, co-treatment with BMS-754807 and carboplatin further suppressed cell viability and regulated phosphorylation of the double-stranded DNA damage response proteins γ;-H2AX and Chk2. Co-treatment with BMS-754807 and carboplatin also altered the GFP/RFP ratio in LC3-expressing cells, suggesting modulation of autophagic flux. Finally, the addition of the autophagy inhibitor hydroxychloroquine further induced cytotoxicity when coupled with BMS-754807 and carboplatin. This work indicates that IGF-1R/IR inhibition remodels metabolism in TNBC cells, potentially synergizing with carboplatin to induce double stranded DNA damage. Moreover, the combination of IGF-1R/IR and carboplatin can further collaborate with autophagy inhibition to strongly suppress TNBC cell growth. We conclude that inhibiting nutrient-sensing metabolic pathways such as IGF-1R/IR in combination with chemotherapy and/or autophagy inhibition warrants additional study as a strategy to improve therapeutic responses in women with TNBC. Citation Format: Alyssa N. Ho, Violet A. Kiesel, Scott P. Connelly, Michael F. Coleman, Stephen D. Hursting. Targeting metabolic pathways through pharmacological and chemotherapeutic interventions to improve triple-negative breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3010.