Targeting Brain-Metastatic Breast Tumors with HER3-Homing Bioparticles
Abstract
Targeted therapies act as molecular missiles that can hone-in on tumors that display distinguishing features, making them targets for these tumor-seeking missiles. However, triple-negative breast cancer (TNBC) lacks distinguishing features that allow it to be treated by targeted therapies. Worse yet, TNBC has a propensity to spread to distant sites, including the brain. Once established in the brain, these tumors are extremely difficult to treat: current clinical targeted therapies cannot enter the brain from the bloodstream and the only option is chemotherapy, which can damage normal healthy tissue while the tumors often gain resistance to the chemotherapy drugs. We have found that a cell-surface protein known as HER3 is prominently displayed on TNBC that spreads to the brain and on the barrier separating the brain from the bloodstream (known as the blood-brain barrier or BBB). We have produced a protein-based particle, or bioparticle, that can encapsulate therapeutic drugs and seek out TNBC that has spread to the brain because the bioparticle uses HER3 to ferry across the BBB and enter into TNBC tumors in the brain. In the current project, we are using the bioparticle to deliver novel compounds known as corroles to these tumors. What is unique about the particular corrole molecules being tested in this study is that they are toxic to tumors but can protect the health of non-tumor tissue, in contrast to chemotherapy agents that are unable to distinguish tumor and non-tumor cells, and thus may damage heart, blood vessel, and brain tissue. The missile-like targeting of the bioparticle facilitates this distinction, as the protective action of corroles occurs through antioxidant activity at very small amounts that might be present in normal off-target tissue after bioparticle delivery whereas the high tumor accumulation afforded by the bioparticle targeting enables the corrole drug to accumulate to tumor-toxic levels. Mice will serve as models of brain metastatic TNBC. Two types of scenarios of late-stage breast cancer will be modeled: TNBC tumors that are highly metastatic and spread to distant sites including the lung and brain, and TNBC tumors that have already established in the brain. We will test our bioparticles on these models for their ability to reduce tumor growth, sustain health of non-tumor tissue, and improve survival. By monitoring specific activities of the bioparticle and the therapeutic corrole cargo, we can make adjustments to the bioparticle design and treatment regimen to optimize therapeutic efficacy. This new biotargeted therapy has the potential to revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival; and eliminate mortality associated with metastatic breast cancer. If successful, this novel therapeutic could provide an effective treatment for patients with late-stage metastatic, including brain-metastatic, cancer for which there are few if any treatment options. The risks inherent in any new biologic is the potential for toxicity to non-tumor tissue and adverse immunostimulatory effects, which is why this project will include careful assessments of the impact on normal tissue, including the immune system, that can enable design adjustments and thorough re-testing before advancing the biotherapeutic to the next stage of translational development. If the goals of this study are successfully achieved, a patient-related outcome could be realized within 5-8 years and could make a breakthrough in offering a viable option for patients with late-stage metastatic, including brain-metastatic breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210953
Entities
People
- Lali K Medina-Kauwe
Organizations
- Cedars-Sinai Medical Center
- United States Army