Abstract This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT- CA-20-012. High attrition rates—particularly at the late stage of drug development—contribute to the estimated $2.0B cost of bringing a drug to the market. Furthermore, many of the drugs that reach the market. including anti- angiogenics, benefit only a subset of patients. Companion diagnostics (CDs) that identify patients who are likely to respond these drugs are not available. This adds significant costs to the healthcare system through the unnecessary treatment of patients that are not likely to respond to specific therapies. Our overall strategy is to develop VEGF-3S (a VEGF antagonist) as a novel anti-angiogenic theranostic agent for cancer therapy, where VEGF-3S will be the therapeutic and [18F] cVEGF-3S will be the corresponding PET CD to stratify patients that would benefit from the drug. We believe that our novel approach will have significant clinical advantages to benefit these patients because patients selected with positive [18F] cVEGF-3S PET tumor signals are expected to be most responsive to VEGF-3S, making it a highly efficient therapy. This will help reduce the cost to the healthcare system of treatment. Our currently funded SBIR Phase I feasibility studies to develop the CD, [18F] cVEGF-3S, to be used during the late preclinical and clinical development of VEGF-3S, have evolved rapidly. In order to accelerate our progress, we will need to conduct a supplementary study to determine clinical targets for VEGF-3S. This will help position our project for a stronger Phase II application and generate further interest from private strategic partners. A defined clinical target is necessary for the clinical study design for the IND studies of the CD, [18F] cVEGF-3S. In other words, identifying which cancer is ideal for VEGF-3S treatment in the clinic will make us more competitive for Phase II. That can only be achieved by evaluating the in vivo efficacy of VEGF-3S in multiple tumor models. Therefore, we propose here to measure in vivo efficacy of VEGF-3S in mouse models of breast, colon and lung cancer. Accomplishing this goal will provide the evidence-based foundation for selecting a clinical target for VEGF-3S. Pairing our completed Phase I results—which will establish the feasibility of [18F] cVEGF-3S as a novel PET imaging-based CD—with the selection of a clinical target for VEGF-3S will be the quantitative milestones to progress to Phase II for IND enabling studies. These combined results will make us highly competitive for our Phase II application and will accelerate the development of the SBIR product to advance it toward commercialization. Since our unique product will fulfill a major unmet medical need, allowing for more personalized treatment for patients, we believe that it will be attractive to our private sector partners as well.