Currently available anti-angiogenic drugs inhibit VEGF/VEGFR signaling, which leads to transient vascular regression followed by rebound of drug-resistant vasculature, which significantly decrease the therapeutic efficacy of very expensive anti-angiogenic treatment. To overcome this problem, we are developing a cytotoxic 177Lu radiopharmaceutical, scVEGF/Lu. This radiopharmaceutical is based on engineered single-chain VEGF (scVEGF) and it accumulates in tumor endothelial cells via endocytosis mediated by overexpressed VEGFR-2. In Phase I we optimized the composition of scVEGF/Lu, assessed its radiotoxicity and dosimetry and performed initial therapeutic efficacy and mechanistic studies in orthotopic breast tumor models. Our results demonstrate that a single injection of a safe dose of scVEGF/Lu induces destruction of tumor vasculature sustainable for at least 30-35 days and a widespread apoptosis in tumor without significant overall radiotoxicity. In contrast, FDA-approved sunitinib and bevacizumab failed to induce sustainable destruction of tumor vasculature, suggesting potential advantages of scVEGF/Lu. In Phase II we will focus on late pre-clinical development of scVEGF/Lu as a novel component of anti- angiogenic therapy, using orthotopic mouse models of recurrent breast cancer, including a model of human triple negative breast cancer. First, we will establish the dose- and time-dependences for scVEGF/Lu-induced destruction of tumor vasculature and potential roles of overexpressed endogenous VEGF and immunocompetent environment in therapeutic efficacy of scVEGF/Lu. Next, we will establish optimal sequence for scVEGF/Lu-doxorubicin combination as adjuvant therapy for recurrent breast cancer. Considering that scVEGF is a physiologically active protein, we will also establish the safety profile for scVEGF-PEG-DOTA conjugate. We expect that by the end of Phase II of the project we will have evidence-based indications for safe use of scVEGF/Lu in adjuvant anti-angiogenic therapy for breast cancer. We will also have a GLP-grade for dosimetry studies. This data will be used for filing IND or eIND with FDA for Phase I clinical trials with scVEGF/Lu in breast cancer. We believe that this novel targeted radiopharmaceutical may provide a new line of attack on breast cancer, and eventually will be explored for treatment of other cancers.

Public Health Relevance

To increase the efficacy anti-angiogenic therapy, it is necessary to sustain tumor vascular regression and to inhibit vascular rebound. For this, we develop a novel 177Lu radiopharmaceutical, scVEGF/Lu, which delivers lethal doses of 177Lu in tumor endothelial cells. In orthotopic models of breast cancer, scVEGF/Lu induces destruction of tumor vasculature and widespread apoptosis in tumor, without significant overall radiotoxicity. In this project we will evaluate the potential of scVEGF/Lu as a novel component of anti-angiogenic therapy that could make a significant impact on outcome of triple negative breast cancer. We expect that this study will provide evidence-based indications for safe use of scVEGF/Lu as a mono- or combination therapy as adjuvant therapy for breast cancer. We believe that this novel targeted radiopharmaceutical may provide a new line of attack on breast cancer and eventually will be explored for treatment of other cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44CA141806-03
Application #
8332296
Study Section
Special Emphasis Panel (ZRG1-OTC-R (11))
Program Officer
Kurtz, Andrew J
Project Start
2011-09-13
Project End
2014-08-31
Budget Start
2012-09-20
Budget End
2014-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$985,550
Indirect Cost
Name
Sibtech, Inc.
Department
Type
DUNS #
966566465
City
Brookfield
State
CT
Country
United States
Zip Code
06804