ACCOMPLISHMENTS AND FUTURE PLANS
Bioanatomic Imaging
Bioanatomic Imaging is based on the use of anatomic, biologic, physiologic, and functional imaging of cancer and normal tissues for the brain, breast, and prostate cancer as well as other solid tumors. Bioanatomic imaging has potential applications for screening, early detection, diagnosis, staging, treatment planning, and post-treatment follow-up. Supporting the Cancer Center’s research activities in bioanatomic imaging is the WFUHS Center for Biomolecular Imaging (CBI). A tremendous amount of Institutional resources (~$20 million over the last funding period) have been spent on state-of-the-art imaging equipment for molecular, cellular, small animal, medium-large animal, and human imaging. The CBI is now equipped with a 7 Tesla micro-MR scanner and a micro-PET scanner for small animal imaging, dedicated research CT, MR, and PET scanners for medium-large animal imaging, and recently acquired devices for dedicated human oncologic imaging including a 3 Tesla short bore MRI scanner and a hybrid CT/PET scanner, located in the new Outpatient Cancer Center's Department of Radiation Oncology.
Breast Cancer
Research in novel breast imaging has developed in three particular areas: positron emission mammography (PEM), MR spectroscopy of the breast, and cardiac MR in breast cancer chemotherapy patients who have received anthracyclines.
PEM is a high-resolution PET scan of the breast using the standard PET tracer F-18 FDG. Early clinical results suggest that PEM is particularly useful for detecting cancer in the fibrotic breast, identifying cancers not seen by conventional mammography, depicting ductal carcinoma in-situ, and finding residual disease post lumpectomy. The clinical application of PEM as an imaging modality for screening and early detection of breast cancer originated at Wake Forest, being developed during the previous CCSG funding period with collaboration among a number of clinicians including Edward Levine, M.D. (chief of surgical oncology at Wake Forest and a Clinical Research Program member), and Rita Freimanis, M.D. (mammographer at Wake Forest). Drs. Levine, Freimanis, Edward Staab, M.D. (section head of nuclear medicine at Wake Forest), Perry Shen, M.D. and John Stewart M.D. (surgical oncologist and member of the Clinical Research Program) are now leading the PEM research effort at Wake Forest. Dr. Stewart is another example of the importance given by the CCCWFU to targeted faculty recruitment. Dr. Stewart is a clinician-scientist recruited in 2004 following a surgical oncology fellowship at the NCI with Dr. Steven Rosenberg. A participant in Wake Forest’s junior faculty mentoring program, Dr. Stewart will resubmit a K 23 application that focuses on pharmacoproteomic
modeling of combined modality treatment response in breast and colorectal cancer. Jian-Ming Zhu, Ph.D., MR physicist and member of the Clinical Research Program, is conducting a DOD supported study entitled “Fast and accurate MR spectroscopic imaging for early detection of breast cancer”. Highly spectral-selective radiofrequency pulses have been designed and implemented into pulse sequences that have effectively suppressed the spectral contamination from large water and lipid signals, allowing the spectra from cellular metabolites of low concentration to be accurately detected. The breast phantom is being constructed and eventually, 10 patients with positive mammograms will be recruited for 3D MRSI. Future plans for bioanatomic breast research will combine PEM and 3D MRSI with conventional and digital mammography in a variety of settings (screening/early detection, post-treatment follow-up) based on the hypothesis that multi-modality imaging of the breast will be superior to (i.e., more sensitive and specific than) conventional/digital mammography.
A third area of imaging in breast cancer patients, the use of cardiac MRI to assess the toxicity of multimodality therapy of cancer, particularly breast cancer, is led by Greg Hundley, M.D., cardiologist and member of the Clinical Research Program. Early work in this area was funded by an American Heart Association grant, and Dr. Hundley has recently been awarded two NCI R21 grants. Dr. Hundley's research focuses on the cardiovascular toxicity associated with the administration of combined modality therapy (particularly anthracycline and taxane chemotherapy as well as herceptin) for breast cancer. To date, he has utilized advanced imaging techniques with ultrasound and MRI to characterize the structural and functional components of the left ventricle throughout the course of chemotherapy administration. In humans, he has collected data that suggest noninvasive imaging markers identify individuals at risk to develop congestive heart failure in the setting of systemic therapy administration. This is particularly important for women who may undergo adjuvant therapy for breast cancer in which newer regimens including doxorubicin, paclitaxel, and herceptin can lead to a complete cure, but cause cardiotoxicity in 2% to 20% of patients. Dr. Hundley has developed an animal model in Sprague-Dawley rats for study of this process. Using this model, he can compare histopathologic data with image data, the subject of one of his R21 grants. Future research plans for bioanatomic imaging research in breast cancer includes examining the role of computer modeling for identifying those patients at risk for developing cardiotoxicity during their course of treatment.
Prostate Cancer
Initially funded by an R21 grant, Dr. Pradeep Garg, Director, PET Imaging Center, established the feasibility of synthesizing a 18F-androgen based PET tracer, thereby facilitating androgen receptor mediated detection of prostate cancer in vitro and in a murine model in vivo. Dr. Garg has recently received R01 funding to extend this work. The major goals of the grant are to optimize the synthesis of the fluorinated testosterone based PET tracer, assess its binding efficiency to androgen receptors, determine its in vivo distribution properties in normal as well as tumor-bearing rodents, and eventually, perform PET images of the new tracer in non-human primates as a final step prior to future bioanatomic prostate research, which will focus on human fluorinated testosterone based PET imaging of prostate cancer for staging, response assessment, and early detection of recurrence.
Upper Aerodigestive Tract Cancers
Locally advanced esophageal cancer is a relatively common clinical problem seen at Wake Forest. The standard of care includes the use of chemo-/radiotherapy, either as preoperative or definitive treatment. In2002, Edward Levine, M.D., chief of surgical oncology and a member of the Clinical Research Program, was awarded an R21 grant to assess the predictive value of 18F-FDG PET (and esophageal ultrasound) staging inpatients with locally advanced esophageal cancer. With co-investigator William Blackstock, M.D., radiation oncologist and member of the Clinical Research Program, a Phase II clinical trial was designed in which patients had pre-treatment CT/PET as well as esophageal ultrasound (EUS), and then underwent 5FU/cisplatinand radiation therapy, followed by restaging with the same modalities and then esophagectomy. The major findings of the grant/study are being published in the Annals of Surgery and International Journal of Radiation Oncology, Biology, and Physics.
Future plans for bioanatomic esophagus cancer research includes a 4/06 R01 grant submission by Drs. Blackstock and Levine in this same patient population, again utilizing PET and esophageal ultrasound staging, but with a preoperative regimen of oxaliplatin (hypothesized to be a superior radiosensitizer based on preclinical data from the Blackstock lab), radiation therapy, and the targeted agent ZD 1839 (Tarceva), given the high degree of EGFR positivity in esophageal cancer. Bioanatomic imaging based grant submissions are also being planned in head and neck cancer as well as non-small cell lung cancer.