Development of EGFR-Based Imaging Agents for Breast Cancer

Institution: Lawrence Berkeley National Laboratory
Investigator(s): Henry VanBrocklin, Ph.D. -
Award Cycle: 1998 (Cycle IV) Grant #: 4IB-0059 Award: $69,580
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Imaging, Biomarkers, and Molecular Pathology: improving detection and diagnosis

Initial Award Abstract (1998)
The aim of this project is to develop new radioactively labeled pharmaceuticals (radiopharmaceuticals) for the early detection of breast cancer using nuclear medicine imaging methods. The nuclear medicine procedure involves the injection of a radiopharmaceutical that is attracted to and preferentially accumulates in the breast tumor. The patient is then placed in an imaging device called a scanner to show the physician where the radiopharmaceutical has gone. In this case we are looking for accumulation in tumors that have a special receptor called the epidermal growth factor receptor. Only 45% of breast cancers have epidermal growth factor receptors, however, tumors with these receptors are harder to treat and do not respond to conventional hormonal treatment. Therefore, it is important that the earlier these tumors are detected the sooner any treatment can begin. Nuclear Medicine imaging agents can provide information about the tumor faster than biopsy, is less invasive than a biopsy and uses no more radiation than an ordinary X ray.

This research is intended to address the earlier detection of breast cancer CBCRP priority issue. The development of these radiolabeled pharmaceuticals relates directly to an approach towards a more sensitive, less invasive technological advance for breast cancer detection. These pharmaceuticals are intended to be used with positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging devices.

This project is perhaps the first of its kind that is seeking to develop an imaging agent to target epidermal growth factor receptors in breast cancer. We have brought together a multidisciplinary team of scientists and physicians to perform the research on these new radiopharmaceuticals. We have chemists and biochemists from LBNL to make these new radiopharmaceuticals and a molecular pharmacologist from Purdue University in Indiana and physicians from UCSF to help provide the expertise and experiments to test them.

There are three aspects to the translation potential of this proposal. First, the radiopharmaceuticals we are developing may be used for diagnosis and monitoring treatment. Second, information about how the radiopharmaceuticals behave in a living system is important for developing new chemotherapeutic or radiotherapeutic drugs. Third, the systematic approach that we are proposing for the development of these radiopharmaceuticals may be applied to the development of radiopharmaceuticals for other breast tumor receptors.

Finally, nuclear medicine techniques have a positive impact on the reduction of human and economic costs of breast cancer. These techniques are non-invasive and can provide localization information as well as some clinical evaluation of the type of disease in a single procedure, thus reducing the need for separate detection and biopsy procedures. This has both human and economic benefits by providing reliable, fast detection and diagnostic information. This in turn can have a positive impact on survivability by fostering rapid treatment response.

Final Report (2000)
The overall objective of this effort was to develop new, radioactively labeled pharmaceuticals (radiopharmaceuticals) for the detection of epidermal growth factor receptors (EGFR) in breast cancer. These radiopharmaceuticals would be used in nuclear medicine imaging methods such as positron emission tomography (PET) or single photon emission computed tomography (SPECT). The EGF receptors are proteins found in the membranes of some breast tumor cells. These receptors, when stimulated, initiate a cascade of cellular events that leads to tumor proliferation.

Our approach involved i) evaluating new non radioactive compounds for their ability to interact and specifically target the EGF receptor, and ii) radioactive labeling of promising candidate radiopharmaceuticals for further studies on their ability to accumulate in cells and tumors which have EGF receptors. We studied five new compounds. Four out of the five inhibited the biological activity of the EGF receptor. Three out of those four preferentially inhibited the biological activity of the EGF receptor over two other similar receptors. This preference demonstrates the specificity and selectivity of the new compounds. We developed a new assay to determine the extent of the binding interaction of the compounds with the receptor. All of the compounds bind to the receptor with high affinity. Based on these tests one iodine and one fluorine containing compound were selected for labeling with a radioactive isotope. We labeled one with iodine 125 and another with fluorine 18. The iodine 125 compound went to the receptor site of EGFR containing cells. The fluorine 18 compound went to tumor tissue in a small animal breast cancer model. The fluorine molecule went to other tissues as well. Over time the amount of fluorine in the other tissues decreased faster than the fluorine in the tumor indicating that the fluorine compound was sticking to the receptors. In spite of this distribution, the tumor-to-background ratios at 2 hours after administration was only 1.5 to 1, not high enough for imaging.

The information derived from these studies has established the foundation for future work in developing an EGFR based imaging agent. We will continue to screen new compounds using many of the techniques perfected here to find an optimal radiopharmaceutical to detect EGFR in breast cancer. As 45% of breast tumors have EGFR and these tumors are harder to treat, an EGFR based radiopharmaceutical has the potential to provide early, fast, reliable diagnostic information that can in turn positively impact treatment and survivability.