Hedgehog inhibitor Sonidegib potentiates 177Lu-octreotate therapy of GOT1 human small intestine neuroendocrine tumors in nude mice

• Background: 177Lu-octreotate is commonly used for treatment of patients with somatostatin receptor (SSTR) expressing neuroendocrine (NE) tumors. It is a highly successful treatment in animal models (e.g. the human midgut carcinoid cell line GOT1 transplanted to nude mice) although clinical studies have still only demonstrated low cure rates. In order to overcome treatment resistance, combination therapy has been proposed and some studies have shown synergistic effects (radiosensitizing). The Hedgehog signaling pathway is involved in normal embryo development, and remains important in the adult. Abnormal activation of the hedgehog pathway has been implicated in the development of cancers in various organs. Hedgehog inhibitors have previously shown therapeutic effect in NE tumors and might be one venue to enhance the effect from 177Lu-octreotate therapy. The aim of this study was to determine the therapeutic effect of combination therapy of GOT1 tumors using 177Lu-octreotate and the hedgehog signalling pathway inhibitor Sonidegib. Methods: GOT1 bearing BALB/c nude mice were divided into three groups with five mice in each group. The groups were treated with either Sonidegib (80 mg/kg twice a week via oral gavage), or 30 MBq 177Lu-octreotate i.v., or a combination of both. Tumor size was measured twice a week using calipers. Animals were killed 41 days after injection and tumors were excised. Samples from each tumor were snap frozen and total RNA was extracted and subjected to microarray analysis. Gene expression patterns and associated biological functions were compared to untreated controls using Nexus Expression 3.0, IPA, and Gene Ontology terms. Results: The mean tumor volume was clearly reduced after 177Lu-octreotate and combination treatment, while Sonidegib treatment alone resulted in a stable mean tumor volume over time. This difference was statistically significant up to more than 20 days after injection, when the tumors in the 177Lu-octreotate and combination treatment groups began to re-grow. The microarray analysis demonstrated a more profound effect on transcript regulation in the combination treatment group than in the other treatment groups. Conclusions: Comparisons between treatment groups show that combination therapy could be beneficial to patients with NE-tumors. Substantial differences in gene expression suggest a synergistic effect on cellular tumor functions at late time points following combination therapy. Further studies should be performed to optimize protocols for combination therapy with these drugs.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

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