Faculty Collaboration Database

A preclinical and clinical study of lithium in low-grade neuroendocrine tumors. Oncologist 2011;16(4):452-7

Date

03/12/2011

Pubmed ID

21393344

Pubmed Central ID

PMC3119207

DOI

10.1634/theoncologist.2010-0323

Scopus ID

2-s2.0-79955570598 (requires institutional sign-in at Scopus site)   25 Citations

Abstract

BACKGROUND: Low-grade neuroendocrine tumors (NETs) respond poorly to chemotherapy; effective, less toxic therapies are needed. Glycogen synthase kinase (GSK)-3β has been shown to regulate growth and hormone production in NETs. Use of lithium chloride in murine models suppressed carcinoid cell growth, reduced GSK-3β levels, and reduced expression of chromogranin A. This study assessed the efficacy of lithium chloride in patients with NETs.

DESIGN: Eligible patients had low-grade NETs. A single-arm, open-label phase II design was used. Lithium was dosed at 300 mg orally three times daily, titrated to serum levels of 0.8-1.0 mmol/L. The primary endpoint was objective tumor response by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included overall survival, progression-free survival, GSK-3β phosphorylation, and toxicity.

RESULTS: Fifteen patients were enrolled between October 3, 2007 and July 17, 2008, six men and nine women. The median age was 58 years. Patient diagnoses were carcinoid tumor for eight patients, islet cell tumor for five patients, and two unknown primary sites. Eastern Cooperative Oncology Group performance status scores were 0 or 1. Two patients came off study because of side effects. The median progression-free survival interval was 4.50 months. There were no radiographic responses. Because of an early stopping rule requiring at least one objective response in the first 13 evaluable patients, the study was closed to further accrual. Patients had pre- and post-therapy biopsies.

CONCLUSIONS: Lithium chloride was ineffective at obtaining radiographic responses in our 13 patients who were treated as part of this study. Based on the pre- and post-treatment tumor biopsies, lithium did not potently inhibit GSK-3β at serum levels used to treat bipolar disorders.

Author List

Lubner SJ, Kunnimalaiyaan M, Holen KD, Ning L, Ndiaye M, Loconte NK, Mulkerin DL, Schelman WR, Chen H

MESH terms used to index this publication - Major topics in bold

Aged
Antineoplastic Agents
Disease-Free Survival
Female
Glycogen Synthase Kinase 3
Glycogen Synthase Kinase 3 beta
Humans
Lithium Chloride
Male
Middle Aged
Neuroendocrine Tumors
Phosphorylation
Treatment Failure