Peptide-drug conjugates targeting EGFR for improved efficacy of chemotherapy

/ ABSTRACT Chemotherapy is the treatment of choice for many cancers, including triple-negative breast cancer (TNBC). However, it is rarely curative and mostly ineffective due to intolerable off-target toxicities of the chemotherapeutic agents. TNBC is an aggressive subtype of breast cancer with a poor prognosis, and chemotherapy is the first- line treatment for TNBC. We engineered a novel peptide, peptide 31, that specifically binds to EGFR in TNBC cells and is internalized via EGFR-mediated endocytosis. We further prepared a peptide 31-doxorubicin conjugate that showed selective toxicity to TNBC cells and displayed no toxicity toward normal breast cells. In this proposal, we aim to advance preliminary work by developing novel peptide-drug conjugates (PDCs) that link chemotherapeutic agents, such as doxorubicin or exatecan, to linear peptide 31, its cyclic analogue, or bispecific cancer cell-binding peptides. Our central hypothesis is that PDCs targeting TNBC cells via EGFR will enhance the therapeutic efficacy of chemotherapy. The rationale behind this proposal is that PDCs, which selectively target TNBC cells, will deliver higher concentration of drug to cancer cells while sparing normal cells and tissues from the toxic effects of chemotherapy. This work will also investigate the interactions between EGFR and peptide 31 in TNBC cells using a peptide affinity probe to elucidate the specificity of PDCs for targeting TNBC. We will test the central hypothesis through three specific aims: 1) Evaluate PDCs consisting of linear or cyclic peptide 31 for targeting TNBC, 2) Evaluate PDCs consisting of a bispecific peptide for targeting TNBC and 3) Mechanistic insights into EGFR-mediated uptake of PDCs in TNBC. To achieve these objectives, we will utilize a combination of solid-phase peptide synthesis, characterization techniques, cell-based assays, and mouse TNBC xenograft models. To ensure the lack of on-target off-tumor toxicities, we will also test the PDCs on normal cells, including normal mammary cells, cardiomyocytes, and mouse heart tissue. Evaluation using the in vitro and in vivo systems will ensure that our results are robust and reproducible, and the proposed conjugates succeed toward TNBC treatment ultimately benefiting Women’s Health. Overall, these studies will have a major positive impact as they lay the foundation for developing a new modality for targeted cancer treatment. Project Number: 1R15CA309584-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Kamaljit Kaur | Institution: CHAPMAN UNIVERSITY, ORANGE, CA | Award Amount: $534,925 | Activity Code: R15 | Study Section: Special Emphasis Panel[ZRG1 CDPT-E (80)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11291213