Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived Xenografts

Abstract

There is currently tremendous interest in developing anti-cancer therapeutics targeting cell signaling pathways important for both cancer cell metabolism and growth. Several epidemiological studies have shown that diabetic patients taking metformin have a decreased incidence of pancreatic cancer. This has prompted efforts to evaluate metformin, a drug with negligible toxicity, as a therapeutic modality in pancreatic cancer. Preclinical studies in cell line xenografts and one study in patient-derived xenograft (PDX) models were promising, while recently published clinical trials showed no benefit to adding metformin to combination therapy regimens for locally advanced and metastatic pancreatic cancer. PDX models in which patient tumors are directly engrafted into immunocompromised mice have been shown to be excellent preclinical models for biomarker discovery and therapeutic development. We evaluated the response of four PDX tumor lines to metformin treatment and found that all four of our PDX lines were resistant to metformin. We found that the mechanisms of resistance may occur through lack of sustained activation of adenosine monophosphate-activated protein kinase (AMPK) or downstream reactivation of the mammalian target of rapamycin (mTOR). Moreover, combined treatment with metformin and mTOR inhibitors failed to improve responses in cell lines, which further indicates that metformin alone or in combination with mTOR inhibitors will be ineffective in patients, and that resistance to metformin may occur through multiple pathways. Further studies are required to better understand these mechanisms of resistance and inform potential combination therapies with metformin and existing or novel therapeutics.

Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer in�vitro and in�vivo

“…Previous studies have revealed that rapamycin therapy for PC patients was not effective and the efficacy of metformin in vivo was contradictory in many studies (30)(31)(32)(33)(34)(35)(36). The present study demonstrated the anti-tumor action of metformin and revealed the synergistic action of metformin and rapamycin in the treatment of PC cells by the downregulation of the mTOR signaling pathway.…”

Respiratory Capacity and Reserve Predict Cell Sensitivity to Mitochondria Inhibitors: Mechanism-Based Markers to Identify Metformin-Responsive Cancers

“…Sterilized water was used as placebo in the control group. Notably, the dose ranges of metformin in mouse studies have been well established, ranging from 50 to 400 mg/kg (34,35). Tumor volume was calculated as (length  width 2 /2) and measured every 2 days using calipers.…”

Metformin influences drug sensitivity in pancreatic cancer cells

“…Finally, some basic research studies with patient derived xenografts (PDX) in mice have indicated that metformin treatment did not inhibit the growth of the PDX in the four different PDX mouse models utilized in that study. The authors proposed that the PDAC cells may have become resistant to metformin by various mechanisms including lack of activation of AMPK or reactivation of mTOR (Lipner et al, 2016). Thus, while some clinicians, epidemiologists and basic scientists have concluded that metformin usage does not improve the survival of PDAC patients, there remains some open questions as to whether metformin can enhance the effects of other drugs which may be used in PDAC and other types of cancers.…”