Abstract A230: Exploring novel PET agents for support of experimental cancer therapy: Selecting patient cohorts and monitoring response to therapy
Authors: Krohn Kenneth A. , Eary Janet F. , Linden Hannah M. , Link Jeanne M. , Mankoff David A. , Muzi Mark , O'Sullivan Finbarr , Spence Alexander M. 
Published: June 2012

The time course of biodistribution of PET radiopharmaceuticals, when analyzed by appropriate models, can be used to image molecular differences between tumors and normal tissues. Understanding important molecular differences and how they change during treatment should lead to better characterization of tumor biology and ultimately better treatment outcome. Four examples will show the value of PET to image specific aspects of the tumor phenotype.

Proliferation imaging started with [C-11]-thymidine and later with our development of [F-18]-FLT. The salvage pathway provides a robust measure of the growth rate of tumors. As an example, standard therapy for newly diagnosed glioblastoma multiforme is 60 Gy RT plus concurrent temozolomide. Many patients who complete therapy show MRIs consistent with tumor progression but they improve on continued TMZ. This pseudoprogression is an important problem; clinicians armed with MRI alone may wrongly conclude that standard treatment is failing. Misdiagnosing tumor progression could risk entering patients into trials of new agents, leading to falsely positive outcomes. FLT PET may help clarify this dilemma since preliminary studies have shown promise in distinguishing radionecrosis from recurrent disease. In these studies, we assessed FLT flux and transport as well as SUV and MRI and found that only FLT flux was an independent variable to distinguish the two groups.

Anthracycline based therapy continues to be a mainstay for solid cancers but many of these tumors have variable levels of multiple drug resistance. Pglycoprotein is a membrane pump to exclude anthracyclines from intracellular accumulation. We use PET to quantify Pgp activity using a transporter substrate, [C-11]-verapamil. Pilot studies of sarcoma patients showed a range of uptake kinetics in tumors before treatment compared with after exposure to chemotherapy. Our initial data shows that the extent of acquired MDR measured by PET correlates with survival.

Hypoxia is an important resistance factor in treatment. [F-18]-FMISO is an imaging agent that accumulates in hypoxia but not in necrosis. In outcomes studies of patients with brain tumors, FMISO was an independent predictor of outcome. Glioma patients with hypoxic volumes &gt;15 cc had a median survival of ∼4 mo while patients with less hypoxia had a median survival of ∼15 mo compared to 12–14 mo with current standard therapy. These data argue that better treatments directed at hypoxic disease deserve serious attention. We have also imaged recurrent malignant gliomas before and after treatment with bevacizumab plus irinotecan and correlated FMISO changes with survival. Our preliminary results argue that anti-angiogenic therapy may reduce hypoxia and lower resistance to radiotherapy and chemotherapy.

We are imaging estrogen receptors using [F-18]-fluoroestradiol to select breast cancer patients for targeted therapy. FES predicts response to endocrine therapy in metastatic breast cancer. It shows a pharmacodynamic difference between two ER blocking agents, tamoxifen and fulvestrant. We are beginning to explore the value of FES PET in novel therapy intended to re-express ER in breast cancer tumors refractory to endocrine therapy using a HDAC inhibitor.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A230.