Preclinical to Clinical 18F-FLT PET Imaging Moving from Mice to Men

One of the most promising radiopharmaceuticals is the proliferation marker 3'-deoxy-3'-[18F] fluorothymidine (18F-FLT). Here we discuss examples that could begin to move into clinics over the next two years or more to better predict early response to treatment in ovarian cancer and gliomas, evaluate bone marrow transplant and visualize stem cells in the brain.

Predicting early response to treatment: Ovarian cancer & glioma

	18F-FLT PET Imaging of Response to Cetuximab in Mice Representative pre-treatment and post-treatment coronal maximum-intensity projection PET images from mice with head and neck squamous cell carcinoma xenografts treated with cetuximab or placebo. Image source: Jann N. Sarkaria, MD, Associate Professor of Radiation Oncology, Mayo Clinic, Rochester, Minn.

Tumors can become resistant to drugs. One potential way to overcome drug cisplatin resistance is to target the mammalian target of the rapamycin (mTOR) pathway. In a study published in the October 2010 issue of the Journal of Nuclear Medicine, 18F-FLT was been able to predict early response to the mTOR inhibitor everolimus in a cisplatin-resistant ovarian cancer in mice. “18F-FLT PET imaging could be used very early after treatment initiation, i.e. at a time when conventional criteria based on tumor size measurements are useless,” says Nicolas Aide, MD, of the Centre for Molecular Imaging at the Peter MacCallum Cancer Centre, East Melbourne, Australia.

In another study published in the June 2010 issue of Molecular Imaging and Biology, the potential of 18F-FLT PET to detect early treatment response was shown in human glioma cells stably transduced with genes yielding therapeutic activity and implanted subcutaneously into nude mice. “In this study, we have demonstrated that FLT-PET is able to non-invasively detect and quantify the antiproliferative effect of a gene therapy paradigm within three days after onset of treatment,” says Andreas H. Jacobs, MD, director of the European Institute for Molecular Imaging at the University of Münster and the head of the laboratory for gene therapy and molecular imaging at the Max-Planck-Institute for Neurological Research in Cologne, Germany. The fact that treatment response can be detected very early should be easily translatable to clinical practice in the next two years, predicts Jacobs.

Imaging stem cell responses in the brain

Endogenous neural stem cells in the adult brain have raised much scientific interest and the hope of new therapies for neurological diseases. 18F-FLT PET imaging gives us the opportunity to monitor both the “where” and “when” of stem cell mobilization in the living brain, shares Michael Schroeter, MSc, senior consultant, department of neurology, University Hospital Cologne, Germany. In experimental animals, stem cells responses are usually assessed by immunocytochemical staining of brain sections. By contrast, 18F-FLT PET imaging can look at stem cell responses in a living brain and the results of the study were published in the May 2010 issue of the Journal of Neuroscience. “We are able to envisage the stem cells niche in a longitudinal fashion, before and after the treatment under investigation, or compare 18F-FLT PET of groups of placebo versus treated animals in a prospective fashion, a study design that parallels clinical trial in humans,” Schroeter adds.

Evaluation of bone marrow transplant

Another study using a rat model predicts that 18F-FLT PET could be used in the evaluation of bone marrow transplant. The study was performed by Vibhudutta Awasthi, PhD, associate professor in pharmaceutical sciences at the University of Oklahoma Health Science Center, College of Pharmacy, Oklahoma City and colleagues and published in the February 2010 issue of Nuclear Medicine Communication. There are two important advantages of using whole-body 18F-FLT PET to evaluate bone marrow injury and recovery. There is no current non-invasive imaging tool to evaluate bone marrow after transplant and it is possible to see the entire bone marrow population instead of just the site of biopsy using whole-body 18F-FLT PET imaging. 18F-FLT PET imaging also can change the course of intervention earlier by reducing the wait time for biopsy in patients after bone marrow transplant.

The cost and limited availability involved in using 18F-FLT in routine clinical practice is obviously a challenge for clinical translation, according to the researchers. “But where there costs of treatment are high and progression or regression on conventional imaging may be slow, early readouts of efficacy may actually reduce costs and avoid morbidity in patients who aren't responding,” Aide notes. Cost-benefit studies of 18F-FLT PET in the framework of clinical trials are needed to address this.