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A preclinical and clinical study of lithium in low-grade neuroendocrine tumors
Sam J Lubner1, Muthusamy Kunnimalaiyaan, Kyle D Holen
1University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA. sjlubner@medicine.wisc.edu
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.
Insights
Lithium chloride did not show radiographic responses in patients with low-grade neuroendocrine tumors (NETs). Further research is needed to explore effective, less toxic therapies for NETs.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Low-grade neuroendocrine tumors (NETs) exhibit poor response to chemotherapy, necessitating novel therapeutic strategies.
- Glycogen synthase kinase (GSK)-3β plays a role in NET growth and hormone production.
- Preclinical studies indicated lithium chloride suppressed carcinoid tumor growth and reduced GSK-3β levels.
Purpose of the Study:
- To assess the efficacy of lithium chloride in patients diagnosed with low-grade neuroendocrine tumors.
- To evaluate the impact of lithium chloride on tumor response, survival, and GSK-3β inhibition in NET patients.
Main Methods:
- A single-arm, open-label, phase II clinical trial was conducted.
- Lithium chloride was administered orally at 300 mg three times daily, with dose titration to achieve serum levels of 0.8-1.0 mmol/L.
- Objective tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST), with secondary endpoints including survival and GSK-3β phosphorylation.
Main Results:
- Fifteen patients with low-grade NETs were enrolled; median age was 58 years.
- The median progression-free survival was 4.50 months, with no objective radiographic responses observed.
- The study was closed early due to the absence of responses, and two patients discontinued due to side effects.
Conclusions:
- Lithium chloride demonstrated ineffectiveness in achieving radiographic responses in patients with low-grade NETs.
- Lithium chloride did not significantly inhibit GSK-3β at the tested serum levels.
- Development of effective and less toxic therapies for NETs remains a critical unmet need.
