Targeted delivery of Lu-177 to tumor vasculature

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Our goal is to develop a targeted anti-cancer 177Lu radiotherapeutic agent that localizes to a tumor via receptor- mediated uptake by endothelial cells in the tumor vasculature. Due to beta emission (1.5 mm max depth) 177Lu radiopharmaceutical is expected to be cytotoxic to the host endothelial cells and to surrounding tumor cells, but not to surrounding healthy tissue. In addition, targeted destruction of tumor vasculature can bring starvation to tumor areas outside of uptake areas, further amplifying the cytotoxic effects of the proposed radiopharmaceutical. To achieve selective accumulation of 177Lu in the tumor vasculature, we will target it to the receptors for vascular endothelial growth factor (VEGFR). These receptors are overexpressed in tumor vasculature and their critical role in tumor angiogenesis is underscored by the massive drive to develop drugs that selectively inhibit VEGFR activity. Although the significance of targeting VEGFR stems from their role in tumor angiogenesis, the "inhibition approach" has, so far, only achieved a modest success. Approved anti-angiogenic drugs (Avastin, Sunitinib, Sorafenib) in combination with established chemo- or radiotherapy prolong life only for several months in a small and unpredictable set of patients. Because of these issues, we propose a different approach to VEGFR- targeted therapy. Instead of inhibiting these receptors, we propose to use VEGFR for targeted delivery of therapeutic radionuclides. We hypothesize that combination of destruction of tumor vasculature and bystander killing of tumor cells will provide for a significantly larger therapeutic effect than VEGFR inhibition alone. For the targeting of 177Lu to the tumor vasculature, we will use a proprietary VEGFR ligand, an engineered single-chain (sc) VEGF developed in our company. According to our published data, scVEGF can be site- specifically derivatized with PEGylated chelators for VEGF receptor mediated delivery of imaging and therapeutic radionuclides to tumor vasculature. Our preliminary results indicate that such conjugates can be radiolabeled with 177Lu to a specific radioactivity that is sufficient for therapeutic efficacy in tumor models. Furthermore, these studies indicated several pathways to optimize the chemical design of scVEGF/177Lu radiopharmaceutical. In Phase I of this project we propose to optimize the composition of scVEGF/177Lu, calculate the dosimetry of optimized scVEGF/177Lu, and perform an initial test of single or divided dose treatment regimens. These are the critical tasks because the viability of any potential radiotherapeutic agent is determined by its therapeutic window, the balance between its therapeutic efficacy and non-specific radiotoxicity. In Phase II of the project we will test optimized scVEGF/177Lu in metastatic models of breast cancer and models of poorly treatable liver, pancreatic, and brain cancer. The second major Phase II task will be the development of GMP production of scVEGF conjugate optimized in Phase I. PUBLIC HEALTH RELEVANCE: The developing a targeted radiotherapeutic agent for delivery of 177Lu to tumor vasculature. We expect that this therapeutic agent will be internalized by tumor endothelial cells and will be cytotoxic to such cells and surrounding tumor cells. In Phase I of this project, we will optimize targeted radiotherapeutic agent, establish its radiotoxicity and therapeutic efficacy mouse model of breast cancer. The results of Phase I will provide a rational basis for clinical development of targeted radiotherapeutic agent in Phase II.
StatusFinished
Effective start/end date9/24/098/31/14

ASJC

  • Medicine(all)