Optimization of Early Response Monitoring and Prediction of Cancer Antiangiogenesis Therapy via Noninvasive PET Molecular Imaging Strategies of Multifactorial Bioparameters

Abstract

Objective: Antiangiogenesis therapy (AAT) has provided substantial benefits regarding improved outcomes and survival for suitable patients in clinical settings. Therefore, the early definition of therapeutic effects is urgently needed to guide cancer AAT. We aimed to optimize the early response monitoring and prediction of AAT efficacy, as indicated by the multi-targeted anti-angiogenic drug sunitinib in U87MG tumors, using noninvasive positron emission computed tomography (PET) molecular imaging strategies of multifactorial bioparameters.Methods: U87MG tumor mice were treated via intragastric injections of sunitinib (80 mg/kg) or vehicle for 7 consecutive days. Longitudinal MicroPET/CT scans with 18F-FDG, 18F-FMISO, 18F-ML-10 and 18F-Alfatide II were acquired to quantitatively measure metabolism, hypoxia, apoptosis and angiogenesis on days 0, 1, 3, 7 and 13 following therapy initiation. Tumor tissues from a dedicated group of mice were collected for immunohistochemical (IHC) analysis of key biomarkers (Glut-1, CA-IX, TUNEL, ανβ3 and CD31) at the time points of PET imaging. The tumor sizes and mouse weights were measured throughout the study. The tumor uptake (ID%/gmax), the ratios of the tumor/muscle (T/M) for each probe, and the tumor growth ratios (TGR) were calculated and used for statistical analyses of the differences and correlations.Results: Sunitinib successfully inhibited U87MG tumor growth with significant differences in the tumor size from day 9 after sunitinib treatment compared with the control group (P < 0.01). The uptakes of 18F-FMISO (reduced hypoxia), 18F-ML-10 (increased apoptosis) and 18F-Alfatide II (decreased angiogenesis) in the tumor lesions significantly changed during the early stage (days 1 to 3) of sunitinib treatment; however, the uptake of 18F-FDG (increased glucose metabolism) was significantly different during the late stage. The PET imaging data of each probe were all confirmed via ex vivo IHC of the relevant biomarkers. Notably, the PET imaging of 18F-Alfatide II and 18F-FMISO was significantly correlated (all P < 0.05) with TGR, whereas the imaging of 18F-FDG and 18F-ML-10 was not significantly correlated with TGR.Conclusion: Based on the tumor uptake of the PET probes and their correlations with MVD and TGR, 18F-Alfatide II PET may not only monitor the early response but also precisely predict the therapeutic efficacy of the multi-targeted, anti-angiogenic drug sunitinib in U87MG tumors. In conclusion, it is feasible to optimize the early response monitoring and efficacy prediction of cancer AAT using noninvasive PET molecular imaging strategies of multifactorial bioparameters, such as angiogenesis imaging with 18F-Alfatide II, which represents an RGD-based probe.

18F-Alfatide II PET/CT for Identification of Breast Cancer: A Preliminary Clinical Study

“…Second, lymph node and other distant metastases were not evaluated due to the limited number of metastatic lesions in these patients. Third, immunohistochemistry tests were not performed to assess the correlation between integrin a v b 3 expression and alfatide II uptake, which has been demonstrated in several animal and clinical studies (12,16,39). Further investigations are still required in the future to elucidate the role of 18 F-alfatide II in breast cancer management.…”

“…Because of the superiority of PET molecular imaging technique, RGD tracers labeled with positron-emitting radionuclides such as 18 F, 64 Cu, 68 Ga, and 89 Zr have attracted much attention (7)(8)(9)(10). As a PET tracer based on dimeric RGD peptide, 18 F-alfatide II has been recently proven to possess excellent clinical translational potential in several studies (11)(12)(13)(14)(15)(16). Consequently, it warrants further promotion in clinical applications.…”

PET response assessment in apatinib-treated radioactive iodine-refractory thyroid cancer

“…Till now, there has been no specific tool to predict the prognosis after TKI therapy targeting VEGF/VEGFR pathway. Bao et al used 18 F-Alfatide II to monitor the early response in U87MG tumour mice (Bao et al 2016). Hence, it would be a useful tool if RGD imaging could reveal the response and prognosis in patients treated with TKI.…”

Radiolabelled Peptides for Positron Emission Tomography and Endoradiotherapy in Oncology

“…A variety of preclinical studies have demonstrated the potential to monitor response to antiangiogenesis therapies in murine tumour models [199][200][201][202][203]. All studies, using different antiangiogenic pharmaceuticals including Endostar, sunitinib, ZD4190, linifanib, and dasatinib, already showed a reduction of uptake within 3 days after treatment start, where tumour size was only slightly affected and [ 18 F]FDG did not reveal significant changes in uptake.…”