Peptides Targeting Metastatic Tumor Cells as Probes for Cancer Detection and Vehicles for Therapy Delivery
Abstract
An overarching challenge in breast oncology is the lack of effective treatments against metastatic breast cancer. This is a particularly grave concern for patients with triple-negative breast cancer, which accounts for up to 40% of breast cancer mortality in the U.S. Lumpectomy, combined with hormonal or radiation therapy, typically enables control of the primary tumor. However, once the cancer has metastasized, the likelihood of lethality is dramatically increased. Patients with metastatic breast cancer are treated with chemotherapy, which initially impedes disease progression. However, at that stage, cancer often relapses due to acquired chemoresistance. In addition, systemic toxicity of chemotherapy adversely affects the quality of life. To date, molecular targets of aggressive cancer cells remain unidentified. Biomarkers of metastatic cells are lacking, and probes that could be used for their detection and therapy targeting would be highly valuable. Our group has documented expertise in the design of molecules targeting cancer cells. Our technology is based on peptides we select in vivo from combinatorial phage display libraries. Using this approach, we have previously isolated peptides that selectively home to receptors on cells of tumors, as well as other tissues, and used them for targeted drug delivery. In a series of preclinical studies, we have demonstrated that cytotoxin-conjugated peptides can be used as effective experimental targeted therapeutics and validated their safety in clinical trials. This project is based on the hypothesis that metastatic cancer cells express cell surface receptors that can be harnessed for identification of molecules homing to metastases. In preliminary studies, we screened a combinatorial library in a mouse model of spontaneous breast tumor metastasis to isolate cyclic peptides with tropism for cancer cells disseminated to the lung. Radiolabeled peptides were validated as selective probes enabling non-invasive detection of lung metastases in mice. We also designed peptides inducing apoptosis upon cell internalization and demonstrated that these hunter-killer peptides ablate cancer cells and suppress metastatic burden in vivo. Our objective is to develop this project to advance applications of metastasis-homing peptides. Specific Aims of this study are to: 1. Validate metastasis homing of peptides in mouse models of murine and human chemoresistant breast cancer. 2. Optimize the approach to non-invasive metastasis detection with radiolabeled peptide probes. 3. Test the approach to suppressing breast cancer with hunter-killer peptides targeting chemoresistant cells. 4. Identify the cellular receptors of chemoresistant metastasis-homing peptides. We expect to complete the study with at least one experimental drug that can significantly suppress metastatic dissemination and growth. Our collaborator, Dr. Ueno, is a medical oncologist involved in a number of clinical trials who will be instrumental in subsequent clinical translation of our invention. Our preliminary data suggest that at least some of the compounds we will develop will be effective against chemoresistant metastatic cells in breast cancer types other than triple-negative. Future studies will test that and, if necessary, similar screens can be performed to identify cancer type-tailored therapies. Developing such drugs will be pivotal for cancer medicine, as they would enable targeting the mortality-responsible cell population with minimal off-side effects. The ultimate applicability of this research will depend on the identity of the cellular receptors of the peptides and on our established collaboration enabling generation of antibodies against these receptors. The projected time it may take to achieve a patient-related outcome is likely to be at least 5 years, since this study is based on preclinical models. However, provided the track record of UTHealth Therapeutic Antibody Core in humanized antibody develo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211002
Entities
People
- Mikhail Kolonin
Organizations
- United States Army
- University of Texas Health Science Center at Houston