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18[F]FDG small animal PET study of sorafenib efficacy in lymphoma preclinical models
V Ambrosini1, C Quarta, P L Zinzani
1Department of Nuclear Medicine, Policlinico S. Orsola-Malpighi, Bologna University Hospital, Bologna, Italy.
Aim:
Kinase inhibitors have been proposed as novel therapeutic agents in different forms of solid tumours. The Food and Drug Administration (FDA) approved the use of Sorafenib, an oral multikinase inhibitor, for advanced renal carcinoma and unresectable hepatocellular carcinoma. On-going studies are investigating the efficacy of Sorafenib in other solid tumours such as melanoma and non-small cells lung carcinoma and pre-clinical models showed the efficacy of treatment with Sorafenib in murine models of renal cells carcinoma, breast cancer, colon carcinoma and melanoma. To our knowledge, Sorafenib has never been employed in human lymphoma. The aim of the present study was to assess the efficacy of Sorafenib in murine models of human anaplastic large cells lymphoma (ALCL) and Hodgkin lymphoma (HD).
Methods:
Sorafenib cytotoxicity was assessed in vitro and growth inhibition (IC50) was calculated. Cells were assayed for Caspase-3 to measure apoptosis. Human ALCL and HD xenografts in NOD/SCID mice were monitored by small animal positron emission tomography (PET) and computed tomography (CT) over time. Tumour bearing animals were randomly selected to receive treatment with Sorafenib or no treatment. Pathology was available in all cases.
Results:
Sorafenib efficacy on cells proliferation and apoptosis (IC50: HD=0.0343 mg/L; ALCL=0.319 mg/L) was confirmed in vitro. Caspase-3 production showed a dose-dependent trend reaching significantly higher values for 0.046 mg/L and 0.465 mg/L drug concentrations in both cell lines. In vivo experiments showed a progressive increase of tumour lesions metabolism and dimensions regardless treatment.
Conclusion:
Sorafenib showed a good cytotoxic effect in vitro especially on human HD cell line, but these findings were not confirmed in vivo. The strong discrepancy between in vitro and in vivo results suggests that further studies are needed to better acknowledge the biodistribution and metabolism of Sorafenib in NOD/SCID mice. Factors influencing drug availability at tumour site or differences in the downstream pathways may be responsible for the scarse effect of treatment.
Insights
Sorafenib effectively reduced cancer cell growth in laboratory tests but failed to inhibit lymphoma tumors in mice. Further research is needed to understand this discrepancy in Sorafenib efficacy.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Sorafenib, an oral multikinase inhibitor, is FDA-approved for advanced renal and hepatocellular carcinoma.
- Pre-clinical studies indicate Sorafenib's efficacy in various solid tumors, but its use in human lymphoma is unexplored.
Purpose of the Study:
- To evaluate the efficacy of Sorafenib in murine models of human anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HD).
Main Methods:
- In vitro cytotoxicity and apoptosis assays (Caspase-3) were performed.
- Human ALCL and HD xenografts in NOD/SCID mice were monitored using PET/CT.
- Tumor-bearing mice were randomized to receive Sorafenib or no treatment.
Main Results:
- Sorafenib demonstrated significant in vitro cytotoxicity and apoptosis induction, particularly in the HD cell line.
- In vivo studies showed progressive increases in tumor lesion metabolism and dimensions, irrespective of Sorafenib treatment.
Conclusions:
- Sorafenib exhibits potent in vitro cytotoxic effects against human lymphoma cell lines, especially HD.
- The lack of in vivo efficacy suggests potential issues with Sorafenib's biodistribution, metabolism, or downstream pathway activation in mice.
