Probes challenge hegemony of FDG

The reign of F-18 FDG as the only relevant PET radiopharmaceutical for cancer imaging is about to end, as promising alternative agents approach clinical readiness. Rather than simply improving upon FDG, new probes based on molecular discoveries are expanding the role of PET into cancer treatment monitoring, according to Dr. David A. Mankoff, director of nuclear medicine at the University of Washington, Seattle.

"These new approaches will help oncologists by making sure they've chosen the correct therapy," he said.

Target expression recognition will be the key to using nuclear imaging to measure the in vivo effect of drug therapy, Mankoff said at the Academy of Molecular Imaging meeting in March.

"If you have a treatment that affects receptor antagonism or changes target expression, then serial imaging should be able to tell you that," he said.

By measuring estrogen receptor (ER) patterns, F-18 fluoroestradiol (FES), for example, can discriminate between ER-positive and ER-negative breast cancers, a distinction that indicates whether hormonal therapy will effectively treat the disease.

F-18 FES imaging can help assess heterogeneous estrogen reception by mapping specific variations in spatial and temporal heterogeneity in breast cancer. This capability enables the oncologist to individualize treatment planning, he said.

Dr. Johannes Czernin, director of the Ahmanson Biological Imaging Center at the University of California, Los Angeles, affirmed in the same AMI session that FDG is here to stay as a mainstay of PET imaging. But he argued that conventional nuclear imaging is otherwise so inherently flawed that new probes are needed.

Czernin envisions a role for radiopharmaceutical agents based on cyclo-oxygenase-2 (COX-2) inhibitors for imaging the therapeutic responses to lung, breast, and colorectal cancer treatment. COX-2 inhibitors target the COX-2 enzyme, which is crucial to prostaglandin synthesis. Suppression of the COX-2 enzyme may slow tumor cell proliferation, encourage tumor cell apoptosis, and inhibit metastatic cell migration.

Because COX-2 expression reaches its peak early during pathogenesis, the timing of COX-2 inhibitors as a cancer treatment is crucial, he said. F-18-labeled COX-2-inhibitor analogs may eventually identify suspicious lesions at an early stage of pathogenesis to calculate when COX-2 inhibitors can do the most good.

New Drug Design Strategy

The thought process behind this strategy is indicative of how new radiopharmaceutical imaging agents are now conceived, according to Czernin. Researchers are tapping into the drug discovery process for promising imaging targets. The resulting imaging probes are tested on small animals to determine their biophysiological characteristics before testing in human trials.

Other new radiopharmaceutical agents will find a place in nuclear imaging because of their ability to measure biochemical processes that show whether cancer therapy is working, according to Mankoff. These include the following:

- F-18 fluoromisonidazole (FMISO). FMISO detects hypoxia and predicts its effect on radio- and chemotherapies. Hypoxia alters cell cycle kinetics, raising cancer's resistance to therapy. Dr. Joseph Rajendran, an assistant professor of nuclear medicine at the University of Washington, presented results at the 2003 Society of Nuclear Medicine meeting confirming that hypoxia rates vary with FMISO uptake.

- F-18 FLT. Carbon-11 thymidine is the gold standard for tracking DNA proliferation. Although it is not practical for clinical use, work on this agent inspired the development of F-18 fluorodeoxythymidine (FLT), F-18 2´-fluoro-5-methyl-1-Beta-D-arabinofuranosyluracil (FMAU), and analogs with a longer half-life, such as iodine-124 iodo-2´-deoxyuridine (UdR). F-18 FLT could become the next big thing in PET radiopharmacology. FLT's ability to detect changes in cell proliferation seems to complement FDG's ability to measure glucose metabolism. FLT does not detect DNA division, the source of C-11 thymidine's predictive power, but proliferation marker Ki-67 histopathology tests have shown that FLT can track cancer cell division. The probe may gain acceptance for monitoring treatment because cancer cell proliferation slows almost immediately after the disease begins to respond positively to radio- or chemotherapy.

F-18 FLT is also high on Czernin's list because of its potential to complement FDG imaging. But transporting FLT from bench to bedside hasn't been easy, he said. Human studies, such as those performed by Dr. Andreas K. Buck at the University of Ulm, Germany, found that FDG uptake was consistently twice that of FLT in lung tumors, despite the strong association between FLT uptake and cell proliferation. Such results led Czernin to conclude that FLT may be best suited for treatment monitoring.

- Annexin V. Annexin V has exhibited the ability to track apoptosis, another key genetic-based cancer-killing strategy drawn on the natural inclination of normal cells to destroy themselves when they sense mutations. Apoptosis would provide an early measure of cell death in response to therapy, according to Mankoff.

Agents cited by Czernin include the following:

- Choline. Paired with C-11 or F-18 radioisotopes, choline shows promise for diagnosing recurrent prostate cancer and bladder cancer and for improving the specificity of solitary pulmonary nodule characterization. Four studies published in 2003 found that C-11 choline accurately stages pelvic lymph nodes and is highly sensitive, although somewhat unspecific, for detecting local recurrence after surgery and differentiating prostate cancer from hyperplastic disease, Czernin said.

- F-18 DOPA. F-18 dihydroxyphenylalanine (DOPA) improves on surface receptor-based octreotide and other agents designed for SPECT imaging of neuroendocrine tumors.

- Whole-body F-18 fluoride. This may eventually replace technetium-99m-MDP SPECT as the method of choice for bone imaging. Dual F-18 FDG/F-18 fluoride PET/CT may be the ideal test for identifying osteolytic and sclerotic lesions, although multicenter trials are needed to verify its efficacy.