Reference Detail

Ref Type

Journal Article

PMID

(26921394)

Authors

Liu Z, Yokoyama NN, Blair CA, Li X, Avizonis D, Wu XR, Uchio E, Youssef R, McClelland M, Pollak M, Zi X

Title

High Sensitivity of an Ha-RAS Transgenic Model of Superficial Bladder Cancer to Metformin Is Associated with ∼240-Fold Higher Drug Concentration in Urine than Serum.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	15	3	2016 Mar	430-8	Mol Cancer Ther

URL

Abstract Text

While pharmacoepidemiologic and laboratory studies have supported the hypothesis that the antidiabetic drug metformin may be useful in treating or preventing cancer, there is limited evidence to suggest which specific cancer sites may be particularly sensitive. Sensitivity likely is determined both by features of tumor pathophysiology and by pharmacokinetic factors. We used UPII-mutant Ha-ras transgenic mice that develop hyperplasia and low-grade, papillary urothelial cell carcinoma to determine whether metformin has activity in a model of superficial bladder cancer. Metformin significantly improved survival, reduced urinary tract obstruction, reduced bladder weight (a surrogate for tumor volume), and led to clear activation of AMP α kinase and inhibition of mTOR signaling in neoplastic tissue. We investigated the basis of the unusual sensitivity of this model to metformin, and observed that following oral dosing, urothelium is exposed to drug concentrations via the urine that are approximately 240-fold higher than those in the circulation. In addition, we observed that bladder cancer cell lines (RT4, UMUC-3, and J82) with homozygous deletion of either TSC1 or PTEN are more sensitive to metformin than those (TEU2, TCCSUP, and HT1376) with wild-type TSC1 and PTEN genes. Our findings provide a strong rationale for clinical trials of oral metformin in treatment of superficial bladder cancer.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN del	urinary bladder cancer	sensitive	Metformin	Preclinical	Actionable	In a preclinical study, bladder cancer cells with PTEN deletion were sensitive to Glucophage (metformin) in culture, resulting in inhibition of cell growth (PMID: 26921394).	26921394
HRAS mutant	urinary bladder cancer	sensitive	Metformin	Preclinical	Actionable	In a preclinical study, mouse models of bladder cancer harboring an HRAS mutation were sensitive to Glucophage (metformin), resulting in tumor growth reduction and prevention of hyperplasia regression (PMID: 26921394).	26921394
TSC1 del	urinary bladder cancer	sensitive	Metformin	Preclinical	Actionable	In a preclinical study, bladder cancer cells harboring a deletion of TSC1 were sensitive to Glucophage (metformin) in culture, resulting in cell growth inhibition (PMID: 26921394).	26921394