Novel Mechanistic Insights into Arginine Deiminase Pharmacology Suggest 18F-FDG Is Not Suitable to Evaluate Clinical Response in Melanoma

Journal of Nuclear Medicine

Eric Rosenfeld¹  John S. Bomalaski¹  Michael J. Evans¹  Achim A. Jungbluth¹  Pat Zanzonico¹  Thomas Ku¹  Lars Stelter¹  Steven M. Larson¹  Gerd Ritter¹  Lloyd Old¹ 

关键词: arginine deiminase;    melanoma;    ¹⁸F-FDG;    PI3K;   

DOI  :  10.2967/jnumed.111.092973

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

Because of deficiencies in l-arginine biosynthesis, some cancers are susceptible to therapeutic intervention with arginine deiminase (ADI), an enzyme responsible for consuming the dietary supply of l-arginine to deprive the disease of an essential nutrient. ADI is currently being evaluated in several clinical trials, and fully realizing the drug's potential will depend on invoking the appropriate metrics to judge clinical response. Without a clear biologic mandate, PET/CT with 18F-FDG is currently used to monitor patients treated with ADI. However, it is unclear if it can be expected that 18F-FDG responses will indicate (or predict) clinical benefit. Methods: 18F-FDG responses to ADI therapy were studied in preclinical models of melanoma in vitro and in vivo. The molecular mechanism of response to ADI therapy was also studied, with a particular emphasis on biologic pathways known to regulate 18F-FDG avidity. Results: Although proliferation of SK-MEL 28 was potently inhibited by ADI treatment in vitro and in vivo, no clear declines in 18F-FDG uptake were observed. Further investigation showed that ADI treatment induces the posttranslational degradation of phosphatase and tensin homolog and the activation of the PI3K signaling pathway, an event known to enhance glycolysis and 18F-FDG avidity. A more thorough mechanistic study showed that ADI triggered a complex mechanism of cell death, involving apoptosis via poly (ADP-ribose) polymerase cleavageindependent of caspase 3. Conclusion: These findings suggest that some unexpected pharmacologic properties of ADI preclude using 18F-FDG to evaluate clinical response in melanoma and, more generally, argue for further studies to explore the use of PET tracers that target apoptotic pathway activation or cell death.

【 授权许可】

Unknown