Pretargeting Bacterial Therapy of HER2+ Breast Cancer
Abstract
The major goal of the project is development of specifically targeted therapy for HER2-positive breast cancer using functionalized bacteria, as therapeutic agent. Bacterial therapy is a long-standing concept in cancer management that has been originally proposed in the late 19th century, and currently there is a renewed interest with novel advancements. Bacteria-mediated tumor therapy is orthogonal to standard anticancer therapies and therefore can overcome some of their limitations, such as limited efficacy, development of drug resistance, as well as severe side effects. The major premise of bacterial cancer therapy is that the systemically injected bacteria can home to the tumor, penetrate, invade, colonize, and eventually destroy the tumor. In this project, we intend to develop a novel strategy of bacterial therapy for HER2-positive breast cancer that is based on (i) specific targeting of bacteria to the tumor by pretargeting of the HER2 receptors expressed on cancer cells; (ii) non-pathogenic form of E. coli bacteria will be engineered to produce a specific enzyme bacterial cytosine deaminase that can convert a non-toxic compound 5-fluorocytosine to a standard cytotoxic chemotherapeutic drug 5-fluorouracil (5-FU); and (iii) bacterial colonization of the target tumor will be monitored in vivo by noninvasive PET imaging. Real-time imaging will allow precise evaluation of the tumor bacterial load, as well as immediate termination if an uncontrolled proliferation of bacteria in non-tumor body locations is detected. This proof-of-concept study will be performed in preclinical mouse models of breast cancer. By exploring a new strategy for pretargeting bacterial therapy, the project has high relevance to developing novel forms of breast cancer therapy and is specifically responsive to Breast Cancer Research Program (BCRP) overarching challenges: 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. Breast cancer is the most commonly detected non-dermatologic cancer in women in the United States with an estimated 290,000 new cases diagnosed per year and approximately 43,780 deaths. HER2-positive breast cancer has an aggressive clinical phenotype with generally unfavorable prognosis. While several first- and second-line targeted therapies including novel forms of immunotherapy exist for this cancer type exist, the cancer ultimately becomes resistant. Eventually, the stage IV metastatic breast cancer is incurable and fatal. Therefore, new, efficient, and less toxic treatment strategies are urgently needed to improve outcomes in patients with HER2-positive breast cancer. We envision that future clinical applications of bacterial cancer therapy will be initially tested and will show efficacy in patients who have already been treated with multiple therapies and likely have partly suppressed immune system and drug refractory HER2-positive breast cancer. We anticipate that these clinically translatable technologies, membrane surface modified pretargeted bacteria, and complementary bacterial PET imaging could be used to assess colonization and safety of microbial-based therapy in clinical trials as well as a precision medicine approach for patient care. The current proposal is focused on the development and proof of principle of the pretargeting bacterial therapeutic strategy in preclinical models. If successful, future clinical translation would require additional validation and toxicity evaluation in small and large animals, for which we would seek additional funding. We estimate the projected time to achieve patient-related outcomes is within 5 to 10 years. BCRP’s mission to end breast cancer requires supported development of novel therapies that can be applied to the most dangerous metastatic cancers that escape local control and for which there is no current effective treatment options. Unf
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310467
Entities
People
- Dmitri Artemov
Organizations
- Johns Hopkins University
- United States Army