Monitoring of tumor response to therapy by 18F-ML-10, a novel small-molecule PET tracer for apoptosis: From preclinical to clinical studies
Authors: Anat Shirvan, Hagit Grimberg, Galit Levin, Avi Cohen, Ayelet Reshef, Ayelet Akselrod-Balin, Aaron Allen, Eyal Fenig, Adam Steinmetz, David Groshar, Edna Inbar, Yulia Kundel, Eyal Mishani, Ilan Ziv
Journal: Clinical Cancer Research (2008)

ED04-02    Background:  Apoptosis is a key mechanism of cell death associated with most anticancer treatments, including radiotherapy and chemotherapy. Non-invasive  in vivo  imaging of apoptosis may therefore allow early and real time assessment and optimization of treatment based on the biological tumor response in individual patients.  18 F-ML-10 is a novel, compact PET tracer (α-methyl  18 F-alkyl-dicarboxylic acid, MW=206) for apoptosis, that selectively accumulates in apoptotic cells from early stages of apoptosis, while being excluded from viable or necrotic cells. In preclinical studies in xenograft models in mice, upon intravenous systemic administration of the tracer  in vivo , marked and selective accumulation of ML-10 was observed in tumors treated with irradiation or with various chemotherapeutic agents. Increased uptake of ML-10 was associated with tumor shrinkage, and confirmed histologically with apoptotic markers of DNA fragmentation, caspase-3 activation, and membrane phospholipid scrambling. Bio-distribution studies  in vivo  showed increased uptake and accumulation of ML-10 specifically in the tumor in comparison with other organs or the blood, with rapid clearance of the tracer from non-target sites. Specificity of binding was demonstrated by competitive blocking with excess of non-labeled “cold” compound. In a Phase I clinical trial in healthy volunteers,  18 F-ML-10 showed favorable safety, biodistribution, dosimetry, stability and clearance profiles. Efficacy studies indicated selective accumulation of  18 F-ML-10 in sites of high physiological apoptotic targets, such as the testes of healthy volunteers and in sites of pathological apoptosis, such as cerebral infarct in patients with acute cerebral stroke, creating a clear image of the target. We report here the results of the first study assessing the suitability of  18 F-ML-10 for early detection of tumor response to radiation therapy in patients with brain metastases, and the respective correlation with subsequent alterations in tumor size.   Methods:  Patients with brain metastases, scheduled for whole brain radiation therapy (WBRT) underwent  18 F-ML-10 imaging prior to (baseline), during and immediately upon completion of WBRT. Changes in  18 F-ML-10 uptake relative to baseline were compared with clinical tumor response, as detected by Gd-enhanced MRI images, performed before and at 6-8 weeks after completion of treatment, and as assessed according to the RECIST criteria.   Results:  In 6 patients (out of 10 planned), 16 metastatic lesions were detected by Gd-MRI. Baseline  18 F-ML-10 images demonstrated specific uptake in all lesions, with regions of various uptake intensities, in alignment with sporadic endogenous apoptosis within these tumors, naturally-occurring even before its augmentation by radiotherapy. Dynamic analysis showed accumulation and retention of  18 F-ML-10 in the target lesions with time, while being cleared from the blood, supporting the specificity of uptake. So far 5 patients completed WBRT, and in all patients, the comparison of the baseline and post treatment  18 F-ML-10 PET images showed substantial treatment-related changes in uptake of  18 F-ML-10 within the tumor. A Voxel-based characterization of alterations in the uptake map of  18 F-ML-10 indicated changes in the intensity, in the extent of tumor volume exhibiting apoptotic response and in distribution of apoptotic areas within the target lesion. Such changes are quantitatively represented both graphically and visually. Complete follow-up is available for one patient, in whom the  18 F-ML-10 uptake increased by 30%-60% after treatment, which was subsequently found to correspond to a 27-30% reduction of tumor size per Gd-MRI at 6 weeks post treatment.   Conclusions : PET imaging of apoptosis with  18 F-ML-10 may have an important clinical role in monitoring the effect of radiation therapy in individual patients, providing early assessment of tumor response, and thus assisting in treatment optimization for the individual patient.