Preclinical evaluation and clinical translation of novel bispecific toxins that t

University Of Minnesota, Minneapolis MN

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Abstract

DESCRIPTION (provided by applicant): My goal is to become an independent translational researcher devoted to the development of novel targeted therapeutics for cancer patients. My background in veterinary and comparative oncology provides a unique opportunity to leverage companion animals as models to accelerate such development, and this project is designed to facilitate my transition to independence through a structured program under the guidance of an exceptional mentoring team. Mentored Research Phase: I will lead a phase I clinical study in dogs with spontaneous cancer to evaluate safety and efficacy of a bispecific ligand targeted toxin we have named EGFuPA. This compound is designed to deliver Pseudomonas exotoxin by targeting epidermal growth factor receptors (EGFR) and urokinase receptors (uPAR) expressed by tumors and associated vasculature. I will test three independent hypotheses: (1) EGFuPA is a safe and effective adjunct to standard chemotherapy for highly metastatic, chemoresistant hemangiosarcomas in dogs, (2) measurements of circulating tumor cells (CTCs) will provide an accurate, non- invasive, real-time assessment of disease status that will correlate with progression-free survival (PFS) and overall survival (OS), and (3) targeted therapy with EGFuPA is applicable to human tumors expressing EGFR and uPAR, and CTCs can be used as a surrogate of disease in human patients with sarcomas. To extend the approach to humans, we will use banked samples and tissue microarrays to identify types of sarcomas where clinical outcomes clearly identify therapeutic gaps and which are likely to be efficiently targeted by EGFuPA. The mentoring objectives are to hone skills for translating basic findings into clinical outcomes in a novel mode (dogs with spontaneous cancer) using rigorous criteria that can support an IND application. Transition to Independence Phase: The data from the mentored phase will be used to design a phase II clinical study in dogs with spontaneously occurring sarcomas. We will evaluate EGFR and uPAR expression in primary and metastatic tumor samples and in CTCs. Dogs will receive EGFuPA as adjuvant to the accepted standard of care to establish the prognostic value of EGFR and uPAR expression patterns on PFS and OS for this treatment. Both the prognostic and the predictive value of CTC levels will be assessed. This will set the stage to validate CTCs as treatment-specific biomarkers in human sarcoma patients and accelerate the translational development and approval of this unique drug by defining Absorption, Distribution, Metabolism, Elimination, Toxicity (ADMET) criteria that would be challenging to establish using laboratory animal models or human clinical trials alone. I will complete my training and transition by preparing an IND application for this drug, and subsequently apply this training for example, taking advantage of R01 as well as R21 and R33 support mechanisms, to develop and refine innovative tools that will help accelerate cancer drug development.