We propose to develop novel anobioconjugates for the treatment of breast cancer by inhibiting angiogenesis and stimulating the host immune system simultaneously. The nanobioconjugates are based on a biodegradable and non-toxic polymalic acid nanoplatform with covalently attached anti-transferrin receptor (TfR) monoclonal antibody for delivery through the endothelial system of the tumor vasculature, antisense oligonucleotides (AON) to inhibit angiogenesis, and/or potent immunostimulatory antibody-cytokine fusion proteins specific for the breast cancer antigen HER2/neu. We hypothesize that the new nanobiopolymers when used alone or in combination would be capable of a multi-pronged attack against cancer cells by inhibiting tumor angiogenesis with the subsequent induction of apoptosis and by activating innate and adaptive immune responses resulting in long-term anti-tumor immunity not only against HER2/neu but also against other tumor antigens. In addition, the nanobioconjugates would exhibit superior tumor targeting as a consequence of the combination of transcytosis mediated by TfR overexpressed on the endothelial cells of the tumor neovasculature, targeting of HER2/neu or TfR overexpressed by the tumor, and the enhanced permeability and retention (EPR) effect exhibited by nanopolymers. The anti-angiogenic effect would be achieved using AON to inhibit the expression of vascular protein laminin-411 and/or vascular endothelial growth factor (VEGF), critical factors produced by the cancer cells needed to develop new vasculature that supports the tumor. In addition, to achieve HER2/neu targeting and immunoactivation we will use the potent immunostimulatory cytokines interleukin-2 (IL-2) or interleukin-12 (IL-12) that would be delivered into the tumor by an anti-HER2/neu IgG3-cytokine fusion protein as part of the nanobiopolymer. We will also explore the effect of combining free antibody-cytokine fusion proteins with the anti-angiogenic nanopolymer. Importantly, IL-12 is also an anti-angiogenic cytokine increasing the anti-angiogenic effect of AON. The proposed nanobiopolymers represent novel and unique molecules in terms of structure and mechanisms of action. To the best of our knowledge, neither the proposed therapeutic nor other molecules with similar mechanisms of action have either been described or are under development.
The specific aims of this project are:
Aim 1. Synthesis and in vitro characterization of nanobiopolymers, Aim 2. Initial pharmacokinetic and toxicological studies of the nanobiopolymers, and Aim 3. Examine the ability of nanobiopolymers to inhibit tumor growth and investigate the mechanism responsible for anti-tumor protection and immunological memory. The proposed nanobiopolymers represent the starting point for a new generation of cancer therapeutics and are expected to be effective against aggressive breast cancer tumors such as those overexpressing HER2/neu. A novel nanobiopolymer-based therapy against HER2/neu expressing cancer cells with sufficient capacity to inhibit angiogenesis and orchestrate an anti-tumor immune response should make a significant clinical impact.

Public Health Relevance

Despite significant improvement in breast cancer therapy, relapse remains a major problem and once the disease has disseminated it is practically incurable. Since breast cancer prognosis is especially poor when tumors express HER2/neu protein we proposed to develop novel nanobiopolymers with conjugated anti-cancer drugs and combine them with immune response stimulators;this strategy is expected to result in a multi-pronged attack against breast cancer expressing HER2/neu. Combining tumor-specific delivery of anti-cancer drugs and avoiding side effects while inducing a robust tumor-specific immune response would efficiently destroy tumor cells and contribute to a decrease in the human and economic cost associated with breast cancer, which is the leading cause of cancer death in women worldwide.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
3R01CA136841-05S1
Application #
8830616
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Lin, Alison J
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Ding, Hui; Helguera, Gustavo; Rodriguez, Jose A et al. (2013) Polymalic acid nanobioconjugate for simultaneous immunostimulation and inhibition of tumor growth in HER2/neu-positive breast cancer. J Control Release 171:322-9
Ding, Hui; Portilla-Arias, Jose; Patil, Rameshwar et al. (2013) Distinct mechanisms of membrane permeation induced by two polymalic acid copolymers. Biomaterials 34:217-25
VanderWall, Kristina; Daniels-Wells, Tracy R; Penichet, Manuel et al. (2013) Iron in multiple myeloma. Crit Rev Oncog 18:449-61
Ljubimova, Julia Y; Portilla-Arias, Jose; Patil, Rameshwar et al. (2013) Toxicity and efficacy evaluation of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment. J Drug Target 21:956-67
Inoue, Satoshi; Patil, Rameshwar; Portilla-Arias, Jose et al. (2012) Nanobiopolymer for direct targeting and inhibition of EGFR expression in triple negative breast cancer. PLoS One 7:e31070
Inoue, Satoshi; Ding, Hui; Portilla-Arias, Jose et al. (2011) Polymalic acid-based nanobiopolymer provides efficient systemic breast cancer treatment by inhibiting both HER2/neu receptor synthesis and activity. Cancer Res 71:1454-64