Principal Investigator

Victoria Lin
Bae-Jump
Awardee Organization

Univ Of North Carolina Chapel Hill
United States

Fiscal Year
2023
Activity Code
R37
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Obesity-driven Metabolic and Molecular Biomarkers of Metformin Response in Endometrial Cancer

Obesity, diabetes and insulin resistance are associated with increased risk and worse outcomes for endometrial cancer (EC). Metformin is a biguanide that is widely used in the treatment of type 2 diabetes. Epidemiological and preclinical data suggest that metformin may have anti-tumorigenic activity, due to its indirect effects within the metabolic milieu (↓insulin, ↓glucose) and direct effects on tumor cells through AMPK activation/mTOR inhibition and suppression of fatty acid/lipid biosynthesis. Metformin is dependent on cation-selective transporters for entry into cells, and the multi-drug and toxin extrusion transporters, MATE1 and 2, are expressed in human EC cell lines and tumors. Thus, metformin may break the link between obesity and EC, emerging as a metabolically targeted agent for this disease. Within The Cancer Genome Atlas database, endometrioid ECs arising in obese versus non-obese women have distinguishing patterns of gene expression, including upregulation of lipoprotein lipase and modulators of the insulin/insulin growth factor-1 (IGF-1) pathway. These findings suggest that ECs arising in obesity may have distinct metabolic vulnerabilities that could be targeted for treatment. In a phase 0 clinical trial of obese EC patients, short-term metformin treatment reduced proliferation and decreased expression of the IGF-1 receptor and targets of the mTOR pathway within the endometrial tumor tissues. Responders to metformin had higher pre-treatment levels of fatty acids/glycolipids in their serum and MATE2 in their ECs, suggesting that these biomarkers might predict metformin response. Lastly, in the LKB1fl/flp53fl/fl EC mouse model, diet-induced obesity led to a doubling of tumor size, accompanied by increases in energy metabolism and lipid biosynthesis. Importantly, metformin had increased efficacy against EC in obese versus lean mice and reversed the detrimental metabolic effects of obesity in the ECs, via shunting fatty acids to beta-oxidation as opposed to lipid production. The overall goal of this proposal is to assess the contribution of indirect effects (via downregulation of insulin/IGF-1 signaling) and direct effects (via transporter-dependent cell entry, activation of AMPK/inhibition of mTOR signaling, blunting of fatty acid/lipid biosynthesis) of metformin (+/- chemotherapy) to its overall anti-cancer efficacy in (i) a clinically relevant EC mouse (obese/lean) model and (ii) an ongoing randomized phase 2/3 clinical trial evaluating metformin versus placebo, in combination with standard of care paclitaxel/carboplatin for the treatment of EC [through the NRG Oncology Group]. Our central hypothesis is that predictors of metformin response (+/- chemotherapy) will include both molecular and metabolic biomarkers, specifically obesity, insulin resistance, upregulation of insulin/IGF1 signaling, heightened fatty acid/lipid biosynthesis and higher MATE 1/2 expression. The proposed research will rigorously test this hypothesis in parallel pre-clinical and clinical studies and support it with diverse measurements of metabolic and molecular markers associated with obesity and modulated by metformin treatment. This strategy should delineate the interplay of metformin’s indirect and direct effects on tumor growth, identify metabolic and molecular biomarkers predictive of response to metformin, and define the role of this agent in obesity-driven EC treatment.

Publications

  • Chaib M, Sipe LM, Yarbro JR, Bohm MS, Counts BR, Tanveer U, Pingili AK, Daria D, Marion TN, Carson JA, Thomas PG, Makowski L. PKC agonism restricts innate immune suppression, promotes antigen cross-presentation and synergizes with agonistic CD40 antibody therapy to activate CD8+ T cells in breast cancer. Cancer letters. 2022 Apr 10;531:98-108. Epub 2022 Jan 21. PMID: 35074498
  • Zhang Y, Huang Y, Yin Y, Fan Y, Sun W, Zhao X, Tucker K, Staley A, Paraghamian S, Hawkins G, Prabhu V, Allen JE, Zhou C, Bae-Jump V. ONC206, an Imipridone Derivative, Induces Cell Death Through Activation of the Integrated Stress Response in Serous Endometrial Cancer In Vitro. Frontiers in oncology. 2020 Oct 20;10:577141. doi: 10.3389/fonc.2020.577141. eCollection 2020. PMID: 33194693
  • Sipe LM, Chaib M, Pingili AK, Pierre JF, Makowski L. Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti-tumor immunity. Immunological reviews. 2020 May;295(1):220-239. PMID: 32320071
  • Guo H, Kong W, Zhang L, Han J, Clark LH, Yin Y, Fang Z, Sun W, Wang J, Gilliam TP, Lee D, Makowski L, Zhou C, Bae-Jump VL. Reversal of obesity-driven aggressiveness of endometrial cancer by metformin. American journal of cancer research. 2019 Oct 1;9(10):2170-2193. eCollection 2019. PMID: 31720081
  • Chaib M, Chauhan SC, Makowski L. Friend or Foe? Recent Strategies to Target Myeloid Cells in Cancer. Frontiers in cell and developmental biology. 2020 May 19;8:351. doi: 10.3389/fcell.2020.00351. eCollection 2020. PMID: 32509781
  • Pierce SR, Fang Z, Yin Y, West L, Asher M, Hao T, Zhang X, Tucker K, Staley A, Fan Y, Sun W, Moore DT, Xu C, Tsai YH, Parker J, Prabhu VV, Allen JE, Lee D, Zhou C, Bae-Jump V. Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer. Journal of experimental & clinical cancer research : CR. 2021 Feb 8;40(1):61. PMID: 33557912
  • Wilson MR, Skalski H, Reske JJ, Wegener M, Adams M, Hostetter G, Hoffmann HM, Bernard JJ, Bae-Jump VL, Teixeira JM, Chandler RL. Obesity alters the mouse endometrial transcriptome in a cell context-dependent manner. Reproductive biology and endocrinology : RB&E. 2022 Nov 24;20(1):163. PMID: 36424602
  • Zhao X, Kong W, Tucker K, Staley A, Fan Y, Sun W, Yin Y, Huang Y, Fang Z, Wang J, Sen S, Dugar S, Zhou C, Bae-Jump VL. SPR064, a pro-drug of paclitaxel, has anti-tumorigenic effects in endometrial cancer cell lines and mouse models. American journal of translational research. 2020 Aug 15;12(8):4264-4276. eCollection 2020. PMID: 32913503
  • Regner MJ, Wisniewska K, Garcia-Recio S, Thennavan A, Mendez-Giraldez R, Malladi VS, Hawkins G, Parker JS, Perou CM, Bae-Jump VL, Franco HL. A multi-omic single-cell landscape of human gynecologic malignancies. Molecular cell. 2021 Dec 2;81(23):4924-4941.e10. Epub 2021 Nov 4. PMID: 34739872
  • Buckingham L, Hao T, O'Donnell J, Zhao Z, Zhang X, Fan Y, Sun W, Zhang Y, Suo H, Secord AA, Zhou C, Bae-Jump V. Ipatasertib, an oral AKT inhibitor, inhibits cell proliferation and migration, and induces apoptosis in serous endometrial cancer. American journal of cancer research. 2022 Jun 15;12(6):2850-2862. eCollection 2022. PMID: 35812065
  • Pingili AK, Chaib M, Sipe LM, Miller EJ, Teng B, Sharma R, Yarbro JR, Asemota S, Al Abdallah Q, Mims TS, Marion TN, Daria D, Sekhri R, Hamilton AM, Troester MA, Jo H, Choi HY, Hayes DN, Cook KL, Narayanan R, Pierre JF, Makowski L. Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer. Cell reports. 2021 Jun 22;35(12):109285. PMID: 34161764
  • Fang Z, Wang J, Clark LH, Sun W, Yin Y, Kong W, Pierce SR, West L, Sullivan SA, Tran AQ, Prabhu VV, Zhou C, Bae-Jump V. ONC201 demonstrates anti-tumorigenic and anti-metastatic activity in uterine serous carcinoma in vitro. American journal of cancer research. 2018 Aug 1;8(8):1551-1563. eCollection 2018. PMID: 30210923
  • Bateman NW, Teng PN, Hope E, Hood BL, Oliver J, Ao W, Zhou M, Wang G, Tommarello D, Wilson K, Litzy T, Conrads KA, Hamilton CA, Darcy KM, Casablanca Y, Maxwell GL, Bae-Jump V, Conrads TP. Jupiter microtubule-associated homolog 1 (JPT1): A predictive and pharmacodynamic biomarker of metformin response in endometrial cancers. Cancer medicine. 2020 Feb;9(3):1092-1103. Epub 2019 Dec 6. PMID: 31808620
  • Rana M, Kansal R, Chaib M, Teng B, Morrrison M, Hayes DN, Stanfill AG, Shibata D, Carson JA, Makowski L, Glazer ES. The pancreatic cancer immune tumor microenvironment is negatively remodeled by gemcitabine while TGF-β receptor plus dual checkpoint inhibition maintains antitumor immune cells. Molecular carcinogenesis. 2022 Jun;61(6):549-557. Epub 2022 Mar 23. PMID: 35319799
  • Staley A, Tucker K, Yin Y, Zhang X, Fan Y, Zhang Y, Fang Z, Sun W, Suo H, Zhao X, Zhao Z, Prabhu VV, Allen JE, Zhou C, Bae-Jump VL. Highly potent dopamine receptor D2 antagonist ONC206 demonstrates anti-tumorigenic activity in endometrial cancer. American journal of cancer research. 2021 Nov 15;11(11):5374-5387. eCollection 2021. PMID: 34873466
  • Sipe LM, Chaib M, Korba EB, Jo H, Lovely MC, Counts BR, Tanveer U, Holt JR, Clements JC, John NA, Daria D, Marion TN, Bohm MS, Sekhri R, Pingili AK, Teng B, Carson JA, Hayes DN, Davis MJ, Cook KL, Pierre JF, Makowski L. Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgery. eLife. 2022 Jul 1;11. PMID: 35775614