Biomedical Engineering, Radiology, Pharmacy
Keck School of Medicine
School of Pharmacy
Viterbi School of Engineering
- Cell Cycle
- Growth & Proliferation
- Membranes & Transport
- Gene Therapy
- Drug Design
Research OverviewTumor Metabolism
The objective is to develop a method that will measure the growth rates of tumors. This will enable both improved cancer diagnosis as well as early assessment of tumor response to therapy. PET is the most appropriate approach because of the changes in metabolism that occur in cancer. Since these changes often precede changes in anatomy that can be observed by CT or MRI scanning, PET should be the most sensitive technique for assessing growth rates and whether that growth rate has changed after anti-cancer therapy. Cell division is one of the most basic pathophysiologic processes of tumors and is a direct measure of growth. We have pioneered the use of PET for the determination of cell division using a new PET compound, [11C]thymidine, a radioactive analogue of one of the building blocks of DNA.
Our research has also shown that while the use of [11C] thymidine works, its use is limited due to normal breakdown of the body's enzymes. Very recently, we developed a different analogue that is left intact in the body. We are one of only a handful of facilities in the entire country studying this, so rapid completion of our efforts is critical to the improvement of cancer therapies.
Tumor Incorporation of Chemotherapeutic Agents
One facet of the PET research program focuses on the development and use of radioactively-labeled chemotherapy agents as tools for better defining drug delivery and optimizing treatment plans. Current therapy programs are applied generically across wide populations of patients. The long-range goal of our research is to develop a method that would support the design of individualized therapy strategies. The unique information about drug distribution and action would provide a rational basis for application of an individualized therapy protocol based on measurements made in the patients themselves. One outgrowth of our work in this regard is the study of specific chemotherapy drugs to further the understanding of how the drugs work and why tumor resistance may occur. To date, we have focused on the study of 5-fluorouracil (5-FU), which is used to treat a wide variety of cancers. We have demonstrated tumor uptake of a radioactive 5-FU and an improvement in uptake when it is administered with other drugs which alter 5-FU metabolism. This modulation of metabolism may improve the usefulness of drugs such as 5-FU by increasing tumor uptake.
Effectiveness of Gene Therapy in Cancer
Gene therapy has recently been developed as a selective means of delivering the "silver bullet" treatment to cells that have been transformed by a genetic intervention. Early efforts with gene therapy have been encouraging, but researchers have encountered many roadblocks. A promising approach to evaluate the delivery and expression of a given gene in cancer patients is with PET. Radiolabeled antiviral drugs, which selectively localize in changed tumor cells, have been developed. One of these well-studied gene therapy techniques involves the incorporation of a herpes virus, HSV-tk. Many antiviral drugs are known to localize only in these virus-infected cells, including ganciclovir and penciclovir. Radiolabeled analogues of these drugs would be a potential means of imaging genetically transduced tumor cells to see if the "silver bullet" had been delivered, and to monitor if transduced cells remain after gene therapy of these cancer patients. Our group has radiolabeled these two antiviral agents, [18F]-FHPG or [18F]-FHBG. Initial testing show that these compounds have promise in assessing gene therapy.
Improved Detection of Tumors
PET has been shown to be very useful in detecting cancer. Technical features of the equipment and current computer image reconstruction methods limits the total number of lesions that can be detected to those larger than 1/2 a millimeter in size. Background activity in normal cells may also prevent very small or marginally active lesions from being detected by the human eye. Research to develop computerized, intelligent systems to supplement the visual interpretation of an image may improve the total number of abnormalities that can be detected with PET, or may enable them to be seen even earlier in their development. Using image reconstruction methods first perfected for military defense purposes, tumors that cannot be seen visually on a PET scan may be detectable. The more we can see, the better our ability to treat disease and potentially cure it.