Monitoring response to Hydroxychloroquine (HCQ) in xenograft mouse model with [18F] ML-10 apoptosis molecular imaging probe.

Objectives Autophagy is a catabolic process involving the degradation of cellular components through lysosomal machinery and plays a central role in cell growth, development, and homeostasis. The balance between apoptosis ("programmed cell death") and autophagy ("programmed cell survival") is important in tumor development and response to therapy. There is increasing evidence suggesting that inhibiting autophagy in cancer cells is associated with increased apoptotic cell death. HCQ inhibits autophagy, eventuating in either apoptotic or necrotic cell death. Our study is aimed at providing an index of apoptotic cell death in response to therapy with HCQ with novel PET apoptosis tracer [18F] ML-10¹.

Methods Tumor xenograft model was used (n=6) in which Panc02 murine cells were implanted in the shoulder of albino hairless C57BL/6 mice. PET imaging was performed at baseline and after treatment with HCQ using the Siemens Inveon PET/CT scanner, after injection with 300 uCi of [18F] ML-10 (Univ. of Pittsburgh). Qualitative and quantitative evaluation of tumor uptake was performed using Inveon Research Workplace (IRW) software. Calculated SUVmax per body weight was standardized to liver, muscle and blood pool.

Results Increase in size of tumors from baseline to post treatment was noted. PET showed a heterogeneous radiotracer uptake in the tumors post treatment compared to baseline (attached table).

Conclusions Targeting autophagy has increased the antitumor effects of anticancer therapies in preclinical trials^2-6. In our study an increase in [18F] ML-10 uptake was observed, most likely in response to apoptotic cell death by HCQ, suggesting that [18F] ML-10 shows promise for monitoring apoptosis in response to therapy and also for monitoring autophagy. Histology studies to correlate apoptosis in tumors by tunnel staining with the imaging data are underway.

Research Support This work was support by the US National Institutes of Health research grant U01 CA140230, as well as the UPCI shared resources award P30CA047904 and Depart of Energy Grant DE SC0008833.