Cell signaling is often perturbed in pathological states. For example, in a number of cancers, there is an overexpression of receptors involved in signaling and transport. Additionally, in some cases the receptors are mutated, changing downstream signaling properties. We have approached receptor imaging through the use of radiolabeled small molecules, peptides, and larger proteins, as well as fluorescent and magnetically labeled binding ligands. We image a broad range of receptors in both murine models and humans.

 


 

Somatostatin receptors (SSTR) are highly expressed in well-differentiated neuroendocrine tumors (NET). Octreotide, an SSTR agonist, has been used to suppress the production of vasoactive hormones and relieve symptoms of hormone hypersecretion with functional NETs. In a clinical trial, an empiric dose of octreotide treatment prolonged time to tumor progression in patients with small bowel neuroendocrine (carcinoid) tumors, irrespective of symptom status. However, there has yet to be a dose optimization study across the patient population, and methods are lacking currently to optimize dosing of octreotide therapy on an individual basis.

68Ga-DOTATOC is a PET tracer that binds to SSTR. We used the quantitative nature of 68GaDOTATOC PET imaging to develop a technique that allows one to compute the receptor density in a tumor volume and monitor the fraction that is occupied with agonist treatment at a given time, based on changes in the available (unbound) receptor density. In combination with another positron-emitting radiotracer, 18F-fluoro-3’-deoxy-3’-L-fluorothymidine (18F-FLT), a proliferation marker we were able to correlate the changes in unoccupied SSTR with proliferation status in an animal model. The imaging techniques and quantitation methods we have developed have the potential to be readily translated to patients with NETs to more effectively monitor treatment and improve dosing regimens.

 

FIGURE LEGEND: Imaging of AR42J tumors using static 68Ga-DOTATOC (A-D), 18F-FLT (E-H) and staining for Ki-67 in tumors samples (I-L) in 4 groups of mice treated with vehicle, 1.25, 2.5, or 10 mg/kg. There is high 68Ga-DOTATOC and 18F-FLT uptake as well as 25% cells stained for Ki-67 in tumors in the control group; there is a graded decreaseacross all the biomarkers with increased dose of octreotide treatment. The 10 mg/kg octreotide dose shows near background levels of 68Ga- DOTATOC and 18F-FLT uptake and 5% staining for Ki-67.

Heidari P, Wehrenberg-Klee E, Habibollahi P, Yokell DL, Kulke MH, Mahmood U. Free somatostatin receptor fraction predicts the antiproliferative effect of octreotide in a neuroendocrine tumor model: implications for dose optimization. Cancer Res. 2013 Oct 1. [Epub ahead of print] PubMed