September 22, 2008

Molecular Imaging Research Update
Radiology Today
Vol. 9 No. 19 P. 20

Editor’s Note: This article is compiled from information provided by the Society of Nuclear Medicine’s media relations staff at the 55th annual meeting held in June in New Orleans.

Research Report on First Semiconductor-Based PET
Evaluations of the first prototype PET brain scanner that uses semiconductor detectors suggest that the scanner could advance the quality and spatial resolution of PET imaging, according to researchers with Hitachi Ltd in Tokyo.

According to study results, the prototype scanner has already proven successful in better characterizing partial epilepsy and nasopharyngeal cancer. Eventually, the technology could be used to provide early-stage diagnoses of other cancers, neurological disorders, and cardiovascular disease; assess patients’ responses to therapies; and determine the efficacy of new drugs.

“This is an exciting development in the field of nuclear medicine,” said Yuichi Morimoto, senior researcher for the Central Research Laboratory of Hitachi Ltd and lead researcher of the study, “Performance of a Prototype Brain PET Scanner Based on Semiconductor Detectors.”

“Our research indicates semiconductor scanners show great potential because of their high energy resolution and flexibility in both sizing and fine arrangement of detectors. These characteristics should lead to improved PET images and, in turn, major advances in the practice of nuclear medicine.”

Semiconductor-based detectors could improve PET imaging capabilities because the smaller, thinner semiconductors are easier to adjust and arrange than conventional scanners. The new technology allows for even higher spatial resolution and less “noise,” or irrelevant images. The prototype semiconductor brain scanner also employs a depth of interaction detection system, which reduces errors at the periphery of the field of view.

Researchers evaluated the scanner’s physical performance and studied the technology’s clinical significance in patients suffering from partial epilepsy and nasopharyngeal cancer, a relatively rare form of cancer that develops at the top of the throat behind the nose. The results suggest that the PET scanner is feasible for clinical use and has good potential for providing the higher spatial resolution and quantitative imaging required in nuclear medicine.

This device, which has been installed in Hokkaido University Hospital, is a result of Hitachi’s collaboration with staff from the nuclear medicine department at Hokkaido University in Sapporo, Japan.


Using PET to Track Cells Injected Into the Body
A new technique has been developed that will enable more accurate noninvasive PET imaging of new cells injected into the body, according to researchers at the University of California (UC), Davis. The new technique, which involves engineering antibody fragments to act as reporter genes (markers that signal cells of interest for PET imaging purposes) could significantly advance the study of genetically engineered cells to treat diseases.

“Genetic cell engineering is the focus of intense research in almost all areas of medicine and shows great promise for treatment of common illnesses such as heart disease, diabetes, and Parkinson’s disease and other neurodegenerative disorders,” said Wolfgang Weber, MD.

However, despite intense efforts, researchers have few solid, noninvasive methods for accurately tracking the location, function, and viability of small numbers of transplanted cells.

“Our research shows that using antibodies as reporter genes in PET imaging provides these capabilities and could contribute to improved treatment of a number of potentially devastating diseases,” said Weber, who was lead researcher of the study, “Cell Surface Expression of an Engineered Antibody as a PET Reporter Gene for In Vivo PET Imaging.” The study was performed in UCLA’s molecular and medical pharmacology department in collaboration with UC Davis’ chemistry department. Weber is now professor of nuclear medicine at the University of Freiburg in Germany.

To improve PET imaging in this area, researchers have been studying the use of reporter gene-probe combinations. With this technique, cells are created to synthesize a protein that binds to or metabolizes radioactive reporter probes that are injected into the body and detected with PET. However, most available reporter gene combinations are not aptly sensitive or specific and have significant limitations in terms of tracking the cells of interest.

In this new research, Weber and his team explored using cell surface-bound antibody fragments as reporter genes. These engineered antibody fragments developed at UC Davis bind irreversibly to low–molecular-weight antigens, which act as reporter probes. Cell culture and animal studies demonstrated an intense and highly specific uptake of the probes in cells expressing the antibody fragment on the cell surface. These data indicate that antibody-based reporter genes represent a promising new platform for the development of new reporter gene and probe combinations.

Antibody-based reporter genes have several potential advantages over other combinations. For example, the reporter probe’s pharmacokinetics can easily be optimized, and probes can identify antibodies with much higher specificity, thus improving the accuracy of PET imaging. In addition, the number of antibodies that can be used as reporter genes is virtually unlimited compared with available viral or mammalian reporter genes. Antibody-based reporter genes have low immunogenicity and are better suited for imaging the expression of several genes.


Targeting Viral Cancers With Radioimmunotherapy
Radioimmunotherapy targeting viral antigens offers a novel option to treat, or possibly even prevent many viral cancers, by targeting cancer cells expressing viral antigens or infected cells before they convert into malignancy.

 “There is an urgent need to find new approaches to treating and preventing viral cancers,” said Ekaterina Dadachova, PhD, an associate professor of nuclear medicine, microbiology, and immunology at Albert Einstein College of Medicine in New York City. “The magnitude and global health burden associated with viral cancers is only now being realized.” Dadachova was lead researcher of the study, “Viral Antigens as Novel Targets for Radioimmunotherapy of Viral Cancers.”

It is estimated that up to 25% of all cancers are currently linked to existing viral infections. Most of these cancers are extremely difficult to treat and cannot successfully be reduced or removed using conventional therapies or treatments. Viral cancers include cervical cancers caused by infection with a human papillomavirus, a sexually transmitted disease; hepatocellular carcinoma, a cancer of the liver; various lymphomas and sarcomas in patients with AIDS/HIV; and other cancers.

According to Dadachova, this study was the first time that researchers have attempted to target viral antigens on cancers, although the use of radioimmunotherapy for cancer treatment has been under development for 30 years. However, the targets of  radioimmunotherapy to date have included only “self” human antigens, which are overexpressed on the tumors but also expressed on normal tissues. Viral antigens, however, are expressed only on the tumors.

The idea to perform the study was suggested by Arturo Casadevall, MD, PhD, chair of the department of microbiology and immunology at Albert Einstein College of Medicine, who collaborates with Dadachova on developing radioimmunotherapy for infectious diseases and cancers. The study involved treating experimental cervical cancer and hepatocellular carcinoma in nude mice with antibodies to respective viral antigens expressed on these tumors. The antibodies were radiolabeled with 188-Rhenium, a powerful beta-emitting radionuclide.

“This study demonstrates a real possibility for more specifically targeted cancer treatments,” Dadachova said. “Targeting those antigens with radiolabeled molecules offers exquisite specificity and will hopefully allow us to significantly increase the efficacy of treatment by administering more individualized doses while avoiding toxicity.

“Nuclear medicine and molecular imaging offer the ability to target disease on a truly molecular level that is unmatched by any other imaging or therapeutic modality,” she added. “Targeting viral antigens with radiolabeled antibodies (or also with specific peptides or aptamers) will allow the extremely precise diagnosis of such cancers and their effective therapy. Furthermore, this approach will make possible ‘molecular prevention’ of viral cancers, when infected cells will be targeted before they become cancerous.”


Tracking Stem Cells in Tumors Could Advance Cancer Treatments
Using noninvasive molecular imaging technology, a method has been developed to track the location and activity of mesenchymal stem cells (MSCs) in the tumors of living organisms, according to molecular imaging research at Stanford University. Tracking these MSCs could lead to advances using stem cell therapies to treat cancer.

“Stem cell cancer therapies are still in the early stages of development, but they offer great promise in delivering personalized medicine that will fight disease at the cellular level,” said Hui Wang, PhD, a postdoctoral fellow from the molecular imaging program group of Xiaoyuan Chen, PhD, in Stanford University’s radiology department. Chen was the lead researcher of the study, “Trafficking the Fate of Mesenchymal Stem Cells In Vivo.”

“Our results indicate that molecular imaging can play a critical role in understanding and improving the process of how stem cells migrate to cancer cells,” Wang said. “Eventually, this technique could also be used to determine if gene-modified stem cells are effective in fighting cancer.”

MSCs are adult stem cells that have the ability to transform into many different types of cells, such as bone, fat, or cartilage. Many scientists believe that stem cells show promise for treating different types of diseases, and a few stem cell therapies are already used to fight some types of cancer. For other types of cancer, researchers are experimenting with modifying stem cells that could be engineered to deliver chemotherapy more precisely to specific tumor sites.

For these types of treatments to be successful, the ability to track what happens to stem cells after they are injected into a living organism is essential. Currently, three different tracking techniques are used: radiolabeling, which consists of using a radioactive substance to tag the cells; magnetic labeling, or using magnetic nanoparticles to tag cells for MRI; and reporter gene tracking, which involves engineering genes that can adhere to cells and be tracked with molecular imaging technologies. Of these, reporter gene techniques are highly sensitive and able to monitor cell migration, survival, and proliferation over time in living organisms.

In their research, Wang and her team isolated stem cells from adult mice and engineered a reporter gene that would be both luminescent and green under a special microscope. Two tumor models were also tagged with reporter genes that were luminescent and red. The tumor cells were injected into live mice either intravenously or under the skin, followed days later by injection of the engineered stem cells.

The study produced solid evidence that the injected stem cells migrate to the tumors and don’t begin to differentiate into other types of cells until they are at the tumor sites. In some of the mice, the breast cancer cells had begun to spread to the lungs. Researchers found that the injected stem cells also migrated to the lung cancer tumors. In addition, the stem cells that migrated to lung tumors differentiated into bone cells, while the stem cells that migrated to breast cancer tumors differentiated into fat cells.

The results indicate that stem cells can migrate both to breast cancer cells and their lung metastases. In addition, the MSCs differentiate into distinctly different cells. “The next logical step of this study is to incorporate therapeutic genes into MSCs and use multimodality molecular imaging techniques to follow the distribution, homing, survival, proliferation, and cell/gene therapy efficacy of the MSC platform,” said Wang.