Interdisciplinary Initiatives Program Round 5 – 2010
Edward Graves, Radiation Oncology
Amato Giaccia, Radiation Oncology
Jennifer Cochran, Bioengineering
Ovarian cancer continues to be a major global health problem, due to both the aggressive nature of this disease as well as the fact that it is commonly first detected in patients at an advanced stage where tumor cells have disseminated throughout the abdomen. Therefore, there is a tremendous clinical need for methods to identify ovarian cancer at an early stage where current treatments can control it, as well as for new therapies that can eradicate both primary ovarian tumors and the distant metastases for patients who present with advanced disease. A collaboration between the Graves, Giaccia, and Cochran laboratories has identified the protein AXL as a key mediator of ovarian tumor progression and metastasis. Furthermore, in preliminary animal studies therapies inhibiting AXL have demonstrated potent antitumor activity, both in the treatment of primary and disseminated ovarian cancers.
The aim of this project is to develop methods to image AXL non-invasively using radiopharmaceuticals detectable by positron emission tomography (PET). We are engineering several candidate radiopharmaceticals for this purpose, including radiolabeled antibodies and protein fragments as well as synthetic AXL-binding peptides selected from a library screen. Candidate imaging probes will be evaluated in mouse models of ovarian cancer, in terms of both their ability to diagnose and stage primary and metastatic ovarian tumors as well as their ability to quantitatively measure response to conventional and anti-AXL ovarian cancer chemotherapies. Currently the candidate radiopharmaceuticals are being developed through peptide library screens and engineering of recombinant AXL ligand fragments. With these agents in hand, radiolabeling will be conducted using established labeling protocols with the positron-emitting isotope fluorine-18. Animal models for ovarian cancer have been developed and studied by the Giaccia, Cochran, and Graves laboratories in terms of their response to anti-AXL therapies as well as their imaging characteristics when interrogated with PET using the clinical standard agent fluorodeoxyglucose (FDG). We are therefore well-positioned to complete the proposed aims within the second year of the project as anticipated. This project represents a new collaboration between Edward Graves, Amato Giaccia, and Jennifer Cochran, and one that effectively leverages the expertise of each investigator. The introduction of AXL imaging into clinical oncology may provide a much-needed step forward in the diagnosis and treatment of ovarian cancer.