Early Prediction of Tumor Response to Treatment: Clinical Translation of [99mTc]-Duramycin

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Colorectal cancer (CRC) is one of the major health concerns in the western world and the second leading cause of cancer death in the USA. While the availability of novel active agents has improved the prognosis of patients with CRC, patients with metastatic disease have a 5-year overall survival rate of only 13%. The current treatment paradigm consists of the subsequent use of cytotoxic chemotherapy and/or selected targeted agents. Objective and accurate evaluation of the tumor response to therapy represents one of the biggest challenges in oncology. An early assessment of therapeutic ineffectiveness will avoid treatment related toxicity to the patient and could lead to improved survival by allowing earlier treatment intensification, discontinuation of ineffective therapy, or initiation of second-line therapy. In today's clinical practice treatment response evaluation is primarily based on anatomical imaging (MRI, CT, X-ray or ultrasound), and focuses on the volumetric and morphometric assessment of the tumor. Unfortunately, it usually takes a few weeks to months after start of the therapy before morphological changes become apparent. In that time span, non-responding patients are suffering from avoidable side-effects and can possibly be subject to disease progression. Consequently, there is a growing demand for non-invasive molecular imaging biomarkers that allow early monitoring of treatment efficacy. Phosphatidylethanolamine (PE), expressed only on apoptotic and dead cells, provides an attractive molecular biomarker for the detection of cell death. Duramycin, a naturally occurring peptide antibiotic that binds specifically to PE, has been successfully used as a probe for the imaging of cell death in several animal models. The main goals of this project are to conduct Phase 0 and early Phase I clinical studies of the proprietary imaging probe, [99mTc]duramycin, to ascertain its safety and ability to detect cancer therapy- induced cell death. By comparing a [99mTc]duramycin SPECT scan obtained early after onset of the therapy to a pretreatment scan clinicians should be able to distinguish responders versus non-responders sooner than with anatomical methods. The specific aims of this project include: 1) pre-clinical validation of [99mTc]duramycin for evaluation of response to the most novel treatment options in CRC, 2) the production of HYNIC-duramycin kits in compliance with cGMP, 3) the conduct of a GLP extended single-dose toxicology study, 4) the conduct of a first-in-human study in healthy volunteers to show safety, biodistribution and dosimetry, and 5) to evaluate the clinical value of [99mTc]duramycin for early treatment response in CRC patients. In summary, this research should show whether [99mTc]duramycin can detect the effectiveness of tumor therapy before conventional imaging techniques and enable its use in clinical practice.