Lung cancer is the leading cancer killer in worldwide. The outcome of a lung cancer diagnosis is often bleak, with the 5-year survival rate for someone diagnosed with stage 1 small cell lung cancer (SCLC) at 31%, decreasing to only 2% at stage IV. For non-small cell lung cancers (NSCLC) the 5-year survival rate of stage I is 68-92%, which decreases to only 1-10% at stage IV. An earlier diagnosis will vastly improve survival. Chest x-rays and CT scans find over 1 million pulmonary nodules of indeterminate significance annually in the U.S. Although most of these nodules are benign, a missed early lung cancer diagnosis dramatically effects survival outcomes, so these nodules cannot be dismissed without further scrutiny. Currently, this is by using 18F- fluorodeoxyglucose positron emission tomography (18F-FDG-PET), dynamic contrast enhanced-computer tomography, or biopsy. Since 18F-FDG accumulates in regions with high metabolic rates, infection, inflammation and cancer can all cause a positive result. Thus, higher specificity as well as sensitivity are desired for diagnostic imaging. This Phase 1 proposal utilizes PET imaging in animal models to determine if hJAA-F11, our patented highly specific humanized antibody to the tumor associated Thomsen-Friedenreich antigen (TF-Ag), can achieve higher sensitivity and specificity for detection of lung cancer without the confounding detection of inflammation. Immunohistochemical analysis indicates that JAA-F11 reacts with ~84% of human lung cancers (both NSCLC and SCLC) and other carcinomas but not specifically with normal tissues. Use of hJAA-F11 imaging will be an innovative technology to differentially detect lung cancer, where biomarker specific antibodies aren?t currently used. Successful completion of the proposed preclinical aims will support the future clinical application of 124I-hJAA-F11 in the differential diagnosis of patients with lung cancer, to distinguish non-malignant causes of positive 18F-FDG-PETimages from those associated with malignant tumors.
Aim 1 will conduct in vivo biological specificity analysis using microPET tumor localization with 18F- FDG and 124I hJAA-F11 imaging and tissue biodistribution of 124I-hJAA-F11 in orthotopic and non-orthotopic murine xenograft models of human lung cancer as well as a syngeneic breast cancer mouse model that develops metastatic tumors in the lung, and healthy controls.
Aim 2 will conduct these studies in an influenza induced mouse lung inflammation model.
Aim 3 will assess dosimetry, false negative and false positive results and clearance rates of 18F-FDG and 124I-hJAA-F11 using imaging, biodistribution data and histopathology analysis of lung tissues from the mice in above Aims, at 3 to 8 days after administration of 124I-hJAA-F11. Successful SBIR Phase I studies will be followed by an SBIR Phase II study optimizing the isotope and linkage for patient use and performing pharmacologic characterizations. These data, coupled with toxicology studies and cGMP antibody produced in our recent partnership with the NCI Experimental Therapeutics Program (NExT), will allow Clinical Phase I Radiopharmaceutical Diagnostic Drug testing with radiolabeled hJAA-F11.
Lung cancer is the leading cancer killer in the U.S. and worldwide, and although new treatments are providing some improvement to survival rates, earlier clinical diagnosis will vastly improve survival. Chest x-ray and CT scans can aid in this earlier diagnosis, but these methods are plagued with findings of indeterminate lesions wherein inflammatory lesions due to infection are difficult to differentiate from cancer. We hypothesize that the tumor specific biomarker antibody, hJAA-F11, which reacts with 84% of all lung cancer types, can be radiolabeled and used in PET imaging to differentiate pulmonary tumors from inflammation, and that this will allow earlier treatment of cancer patients and less invasive analysis for patients with inflammation due to infection.
