Precision Radiotheranostics Targeting Oncogenic Mutations - Project Summary This proposal outlines a five-year career development program for Paul Klauser, PhD, to prepare him for an independent research career at the intersection of radiopharmaceutical sciences, protein engineering, and cancer biology. Dr. Klauser will conduct his postdoctoral training at Memorial Sloan Kettering Cancer Center (MSK), a premier institution for cancer research and translational oncology and an outstanding environment in which to complete the proposed research and deepen his expertise in radiochemistry, molecular imaging, protein engineering, and cancer immunology. Dr. Klauser’s mentorship and support team, including Drs. Lewis, Lareau, Scheinberg, Solit, and Lyashchenko, will offer complementary technical expertise covering all aspects of the proposal, along with strong track records in guiding trainees to independence. Additionally, Dr. Klauser will leverage MSK’s world-class resources, including core facilities dedicated to radiochemistry and molecular imaging, pathology, antitumor assessment, and small animals, as well as the Office of Postdoctoral Affairs. The robust research infrastructure within his mentors’ labs will support the efficient execution of his proposed scientific aims, facilitate specialized training, and prepare him for a successful transition to independence. The goal of this proposal is to develop next-generation targeted radiopharmaceuticals by combining intelligent protein engineering with nuclear imaging and therapy. Current radiopharmaceutical approaches often lack sufficient specificity and retention at tumor sites, limiting their efficacy. By leveraging covalent binding strategies and protein-based chelators, this work seeks to enhance selectivity, tumor retention, and therapeutic potency. In Aim 1 (K99), Dr. Klauser will develop covalent antibody fragments targeting extracellular oncogenic mutations, evaluating their potential for imaging and therapy. In Aim 2 (K99), he will extend this approach to intracellular oncogenic mutations present on MHC peptide complexes, integrating radiopharmaceuticals for tumor-specific theranostics. Upon transitioning to a faculty position in Aim 3 (R00), he will expand this platform by engineering genetically encoded protein-based chelators for PET imaging and targeted radiotherapy, improving radiometal delivery for clinical applications. Murine xenograft and patient-derived xenograft models will be essential for evaluating parameters that cannot be adequately assessed in vitro: biodistribution, tumor targeting, therapeutic efficacy, and safety in vivo. These studies will provide critical preclinical data to support clinical translation. This research program will establish a new paradigm for high-specificity radiopharmaceutical development, addressing critical challenges in cancer diagnostics and therapy. The resulting tools will have broad applications across oncology. All data and methodologies developed during this work will be openly shared with the scientific community. This proposal not only advances radiopharmaceutical science but also serves as a comprehensive training plan to equip Dr. Klauser with the expertise, mentorship, and career development necessary to launch an independent research program as a tenure-track investigator.
