Development of Targeted Therapeutics
David Krag completed a Surgical Oncology Research Fellowship at UCLA in 1984. Following medical school and Residency training he taught at University of California at Davis. He joined UVM in 1991. In this capacity he provides surgical oncologic care to cancer patients with an emphasis on breast cancer and malignant melanoma. Through the active process of patient care he provides education to medical students and surgical residents. David Krag fits into the category of a "translational researcher". This is direct bench to bedside delivery of new options for cancer care identified in the research lab.
David Krag currently runs a lab and clinical trials group of 9 people. As of 2005 funding is from 3 R01 grants from NCI and a Department of Defense grant IDEA Award. David Krag is also recipient of an endowed professorship which supports his research efforts.
Dr. Krag developed a radioactive tracer method for identification of lymph nodes that are the first to receive metastases from a primary tumor. This research went 3 steps:initial development of the technique, validation of the procedure at several institutions, phase 3 prospective randomized trial in breast cancer patients comparing conventional surgical removal of all lymph nodes to just the targeted nodes. This has been the worlds largest surgical breast cancer trial and completed enrollment in 2004. Tracking of patient outcomes is ongoing.
Research in the Krag lab is:
1. DEVELOPMENT OF TARGETED THERAPEUTICS. The lab emphasizes the use of phage display technologies to screen for tumor-binding ligands. The immediate goal is to develop the process by which a set of customized tumor-binding ligands can be rapidly obtained for any patient. The longer term goal is to apply these ligands in a therapeutic manner. The methods include a variety of screening strategies that range from 1- purified targets, eg cell membrane receptor such as ErbB2 or signal transduction molecules such as Grb2 or Grb7, 2- whole cells in an in vitro manner but freshly obtained from a cancer patient, to 3- cancer patients.
The lab has been continuously funded for this research effort for about a decade.
2. DEVELOPMENT OF IMPROVED METHODS FOR DETECTION OF RARE DISSEMINATED TUMOR CELLS. After surgical resection of most breast cancers or malignant melanoma and the patient has no evidence of metastatic disease most patients are cured. However, a significant portion, even without evidence of metastatic disease, will ultimately die of their cancer from cells which had already spread to distant organs. Our ability to detect such "occult" metastases is poor. We are evaluating methods to detect rare disseminated cells in the peripheral blood or in the bone marrow of breast cancer patients. The potential benefits from successful outcome of this research will be improved staging of patients for optimization of adjuvant therapies and importantly a better understanding of the nature of disseminated tumor cells. It is likely that the majority of cells released from a primary site are not clonogenic and evaluation of the primary tumor is less likely to yield important information compared to evaluation of the actual disseminated cells.
3. IMPROVED SURGICAL METHODS FOR TARGETING DISSIMINATED TUMOR CELLS IN REGIONAL LYMPH NODES. This has been an active project for about 12 years in which methods to identify the lymph nodes most likely to first receive cancer cells from a primary tumor have been developed. A radioactive tracer is injected into or around the primary tumor and the uptake in lymphatics is monitored. The first draining lymph node becomes radioactive and can be identified with a gamma detector for guiding surgical resection. If that lymph node is negative for cancer then the other regional nodes are almost always negative. The Krag lab developed the tracer technique, trained a large number of surgeons validating the procedure, and conducted a phase III randomized prospective trial comparing this newer method to conventional surgery.
Tanaka, S. et al. A specific peptide ligand for Grb7 signal transduction protein inhibits invasion and metastasis of pancreatic cancer. Manuscript in progress.
Krag, DN, et al. The detection of isolated tumor cells in bone marrow comparing bright-field immunocytochemistry and multicolor immunofluorescence. Annals of Surgical Oncology, 2005; 12(9):753-760.
Shukla, GS and Krag, DN. Phage display selection for cell-specific ligands: Development of a screening procedure suitable for small tumor specimens. Journal of Drug Targeting, 2005; 12(1):7-18.
Shukla, GS and Krag, DN. A sensitive and rapid chemiluminescence ELISA for filamentous bacteriophages. Journal of Immunoassay & Immunochemistry, 2005; 26:89-95.
Harlow, SP et al. Prerandomization surgical training for the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 trial: A randomized phase III clinical trial to compare sentinel node resection to conventional axillary dissection in clinically node-negative breast cancer. Ann Surg, 2005: 241(1):48-54.
Shukla, GS and Krag, DN. Selection of tumor-targeting agents on freshly excised human breast tumors using a phage display library. Oncology Reports, 2005; 13:757-764.
Sato, K., et al. Optimal particle size of radiocolloid for sentinel node identification in breast cancer-election microscopic study and clinical comparison. Breast Cancer, 2004; 11(3):256-263.
* indicates equal contribution
SD Ireland Professorship of Surgical Oncology Endowed professorship. (2001 through present)
Department of Surgery
Office: Given E309
Lab: Given E309
Leah Novinger, CMB Student
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