UCLA researchers in the Department of Medicine–Hematology/Oncology have developed next-generation metformin analogs that show improved antitumor efficacy and tumor microenvironment remodeling in pancreatic cancer.
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related death in the U.S. with a 5-year survival of <11%. Despite recent advancements in therapies which target oncogenic mutations such as KRAS, chemotherapy remains among the primary 1st-line treatments of PDAC. Notably, KRAS mutations are correlated with over-activation of mTOR, resulting in increased cell proliferation and cancer progression. In addition to KRAS oncogene mutations, many PDAC patients also have deletion or silencing of the CDKN2A tumor-suppressor gene, which can activate CDK4/6 kinases, leading to uncontrolled cell division.
One of the biggest risk factors for PDAC is Type 2 diabetes mellitus (DM2), which has been shown to significantly increase the risk of developing PDAC. Furthermore, those PDAC patients with DM2 have significantly worse outcomes compared to PDAC patients without diabetes, potentially due to increased PI3K and MAPK signaling driven by compensatory high insulin levels in the setting of insulin resistance.
Despite the widespread use of chemotherapy such as FOLFIRINOX or gemcitabine plus nab-paclitaxel, the benefit of chemotherapy on overall survival remains modest, and results are even less durable in PDAC patients with a history of DM2. This opens a gap for combination therapies that specifically target the pathways disrupted in DM2 that are linked to worsened PDAC outcomes, especially in patient populations that are treatment- and immune-resistant.
Historically, metformin, a common DM2 treatment, has been shown to reduce the risk of PDAC, potentially due to indirect activation of cellular AMPK signaling, which downregulates mTOR; however, a major challenge impeding the ability to use metformin as an antitumor therapeutic is the high dosage required for such effects, which is not feasible to achieve in a clinical setting.
INNOVATION: Researchers at UCLA, led by Dr. Richard Pietras, in collaboration with Dr. Michael Jung’s laboratory have developed novel metformin analogs that effectively stimulate AMPK and inhibit downstream mTOR signaling, resulting in a dose-dependent reduction in PDAC cell progression. These analogs were tested directly against metformin and demonstrated up to 4x greater efficacy in vitro, as well as statistically significant reductions in tumor volume compared to metformin in an in vivo human xenograft mouse model.
In additional in vivo studies, these metformin analogs produced statistically significant reductions in immunosuppressive Tregs and myeloid-derived suppressor cells, along with broader improvements in tumor immune microenvironment remodeling. Additionally, these analogs have been evaluated in combination with CDK4/6 inhibitors, demonstrating statistically significant additive effects in reducing PDAC proliferation in vitro. Thus, these analogs may serve as promising novel PDAC therapies to be used alone or as combination therapies.
POTENTIAL APPLICATIONS:
- Treatment of pancreatic ductal adenocarcinoma (PDAC)
- Combination therapy with CDK4/6 inhibitors in PDAC
- Combination with chemotherapy in PDAC
- Combination with KRAS-targeted therapies (e.g. daraxonrasib) in PDAC
ADVANTAGES:
- Targets insulin-driven and metabolic signaling (AMPK–mTOR axis) linked to worsened PDAC outcomes, addressing a biologically defined high-risk patient subset (DM2-associated PDAC)
- Enhanced potency relative to metformin, with improved antitumor activity demonstrated in vitro and in vivo at lower, more clinically feasible doses
- Strong rationale for combination therapy, including additive effects with CDK4/6 inhibitors
DEVELOPMENT-TO-DATE: This technology has demonstrated significant reductions in PDAC tumor volume in an in vivo human xenograft mouse model, along with improved efficacy of CDK4/6 inhibitors in PDAC in vitro.
Related Papers (from the inventors only):
Emelyne Diers, Gang Deng, Diana Márquez-Garban, Richard J. Pietras, Michael E. Jung (2016). New Metformin Analogues for the Treatment of Triple-Negative Cancer. Proc Am Chemical Society Meeting 2016: 5412.
Burton, Lorena P et al. “Novel Metformin Analogues for Treatment of Pancreatic Cancer.” Journal of the Endocrine Society vol. 5,Suppl 1 A1027–A1028. 3 May. 2021, doi:10.1210/jendso/bvab048.2103
Diana C. Márquez-Garban, Gang Deng, Lorena P. Burton, Gaoyuan Ma, Vishaka Muhunthan, Begonya Comin-Anduix, Gabriela Llarena,Neda Moatamed, Jennifer Murphy, Nalo Hamilton, David Shackelford, Michael E. Jung, Richard J. Pietras. Abstract 510: Targeting metabolic vulnerabilities to reduce triple negative breast cancer health disparities. Cancer Res 1 April 2023; 83 (7_Supplement): 510.
Samantha A. Melendrez, Mario Morales Martinez, Eduardo Mauricio Gonzalez, Gang Deng, Timothy Donahue, Michael Jung, Jaydutt V. Vadgama, Richard Pietras, Diana C. Marquez-Garban; Abstract 826: Combination of CDK4/6 and CDK2/4/6 inhibitors with novel biguanides for pancreatic cancer treatment. Cancer Res 15 April 2025; 85 (8_Supplement_1): 826.
Mario Morales Martinez, Samantha Anne Melendrez, Eduardo Mauricio Gonzalez, Gang Deng, Linsey Stiles, Timothy Donahue, Michael E Jung, Jaydutt V Vadgama, Diana C. Marquez-Garban, Richard J Pietras. Targeting Mitochondrial Metabolism and Treatment Resistance in Pancreatic Cancers. Endocrine Society Annual Meeting Proceedings, Abstract, 2025.
Keywords: Metformin, Type 2 diabetes, diabetes, diabetes mellitus, PDAC, pancreatic ductal adenocarcinoma, KRAS, PI3K, mTOR, AMPK, oncology, cancer, analog, Treg, inflammation, DM2