Preclinical Study of ¹⁸F-ML-10 to Evaluate Early Target Therapy Response of Novel MDM2-p53 Antagonist APG115 in Dedifferentiated Papillary Thyroid Carcinoma: A Comparison with ¹⁸F-FDG PET

Purpose: Molecular imaging of cell apoptosis may detect the cellular response to novel target therapies and determine treatment efficacy early on, assisting in the design of individualized therapy. 2-(5-fluoro-pentyl)-2-methyl-malonic acid (¹⁸F-ML-10) PET/CT imaging, as lately developed molecular imaging of cell apoptosis, can selectively target cells undergoing apoptosis. Previous study has reported that novel MDM2-p53 antagonist APG115 could induced cell apoptosis in dedifferentiated papillary thyroid carcinoma(DePTC). Hereby, we compared the predictive ability of cell apoptosis imaging using ¹⁸F-ML-10 with the current gold standard ¹⁸F-FDG for treatment response assessment after targeted therapy with this novel antagonist.

Methods: Early targeted therapy response evaluation was investigated by ¹⁸F-ML-10 and ¹⁸F-FDG PET imaging in treatment-sensitive TPC-1 and treatment-resistant B-CPAP human DePTC xenografts 48 h after a single increasing doses of APG115 or vehicle control. Radiotracer uptake was counted ex vivo by γ-counting and autoradiography and compared with Z-DEVD-aminoluciferin bioluminescent imaging of activated caspase-3/7 and DNA fragmentation (TdT-mediated dUTP nick-end labeling [TUNEL]).

Results: TPC-1 subcutaneous xenograft tumors uptake of ¹⁸F-ML-10 were dose-dependent augmented from baseline in vehicle-treated control mice (P < 0.001), correlated well with bioluminescent detection of apoptosis (Caspase-3/7, r ²= 0.8256, and TUNEL, r ²= 0.8616; P < 0.001). No notable uptake change was gauged in bearing B-CPAP xenograft tumors. ¹⁸F-FDG uptake was not significantly increased from baseline in TPC-1 vehicle-treated control mice and B-CPAP xenograft mice (P = 0.272 and 0.534, respectively) and did not correlate with immunohistochemical detection of apoptosis. Conclusion: Preliminary data showed that ¹⁸F-ML-10 specifically bound to apoptotic tumor cell in which ¹⁸F-FDG was not able to distinguish responding from non-responding tumor lesions early after novel MDM2-p53 antagonist APG115 treatment. ¹⁸F-ML-10 demonstrates its potential role as a noninvasive PET imaging probe for early evaluation of apoptosis induced by novel target agents in the clinic.