Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the United States today. Accurate preoperative assessment of local, regional and distant metastatic spread is critical for optimal management. Positron emission tomography scanning is a more sensitive technique for identifying mediastinal nodal metastases, but has the disadvantage of expense and lack of availability. Our approach to the development of a sensitive, more readily available imaging test is to explore a more appropriate carrier molecule, which is key in achieving delivery of a radiopharmaceutical probe to the desired target issue. To do this, we have capitalized on radioiodinated phospholipid either analogs (PLE) as potential diagnostic imaging agents. These lipid analogues are selectively retained in tumor membranes due to their inability to become metabolized and cleared. In preclinical studies, we have shown these molecules have high levels of selective accumulation in a wide variety of murine and human tumors including a human NSCLC model (A549) in SCID mice. The objective of this proposal is to generate preliminary human data regarding the use of the second-generation PLE analog, NM-404 in imaging patients with NSCLC.
The specific aims of this proposal are to: 1) Determine the optimal imaging characteristics of radiolabeled I-131 NM-404 in ten patients with NSCLC. The pharmacokinetics, radiation dosimetry, biodistribution, and optimal imaging times will be determined. 2) Determine the specific tumor accumulation and metabolic fate of NM-404 in NSCLC tumors collected in five patients undergoing resection. 3) Collect preliminary data on imaging NSCLC tumors in ten patients with evaluable disease. Due to favorable efficacy, toxicity (two animal species at 200 times the anticipated imaging dose), and dosimetry results, an IND was recently filed to evaluate NM-404 in human prostate cancer patients. The results of this exploratory study will provide the preliminary data for a larger study designed to more accurately estimate the predictive power of NM-404 for staging and/or following response to therapy in NSCLC.
| Pinchuk, Anatoly N; Rampy, Mark A; Longino, Marc A et al. (2006) Synthesis and structure-activity relationship effects on the tumor avidity of radioiodinated phospholipid ether analogues. J Med Chem 49:2155-65 |
