A novel, safe, fast and efficient treatment for Her2‐positive and negative bladder cancer utilizing an EGF‐anthrax toxin chimera

Abstract

Bladder cancer is the sixth most common cancer in the United States, and it exhibits an alarming 70% recurrence rate. Thus, the development of more efficient antibladder cancer approaches is a high priority. Accordingly, this work provides the basis for a transformative anticancer strategy that takes advantage of the unique characteristics of the bladder. Unlike mucin‐shielded normal bladder cells, cancer cells are exposed to the bladder lumen and overexpress EGFR. Therefore, we used an EGF‐conjugated anthrax toxin that after targeting EGFR was internalized and triggered apoptosis in exposed bladder cancer cells. This unique agent presented advantages over other EGF‐based technologies and other toxin‐derivatives. In contrast to known agents, this EGF‐toxin conjugate promoted its own uptake via receptor microclustering even in the presence of Her2 and induced cell death with a LC50 < 1 nM. Furthermore, our data showed that exposures as short as ≈3 min were enough to commit human (T24), mouse (MB49) and canine (primary) bladder cancer cells to apoptosis. Exposure of tumor‐free mice and dogs with the agent resulted in no toxicity. In addition, the EGF‐toxin was able to eliminate cells from human patient tumor samples. Importantly, the administration of EGF‐toxin to dogs with spontaneous bladder cancer, who had failed or were not eligible for other therapies, resulted in ~30% average tumor reduction after one treatment cycle. Because of its in vitro and in vivo high efficiency, fast action (reducing treatment time from hours to minutes) and safety, we propose that this EGF–anthrax toxin conjugate provides the basis for new, transformative approaches against bladder cancer.

The Clinical Significance and Prognostic Value of HER2 Expression in Bladder Cancer: A Meta-Analysis and a Bioinformatic Analysis

“…T-DM1, a drug consisting of the HER2 antibody trastuzumab in combination with a cytotoxic agent, has been indicated to be superior to trastuzumab alone in breast cancer by Hayashi et al ( 48 ). A recent study pointed out that the conjugates of epidermal growth factor and anthrax toxin could be a new approach against BCa in dogs ( 49 ). Indoleamine 2, 3-dioxygenase and programmed death ligand-1 have been proved to be associated with HER2 protein.…”

Epidermal Growth Factor Based Targeted Toxin for the Treatment of Bladder Cancer

“…The immunotoxin was internalized within few minutes into BC cells of human, mouse or dog origin and killed them with LD 50 values of <1 nM. Moreover, the immunotoxin induced an about 30% average tumor reduction after one intravesical application cycle in dogs with BC (25).…”

Bacillus anthracis’ PA63 Delivers the Tumor Metastasis Suppressor Protein NDPK-A/NME1 into Breast Cancer Cells

“…Cell-type selectivity can be achieved by deleting the natural receptor binding capacity of PA 63 by single amino acid exchange in its B-domain (mPA 63 ) and fusing peptide ligands for receptors on the surface of certain cancer cells such as EGF or ZHER2, the ligand for HER2 receptor. This elegant approach was developed by the Collier group earlier and successfully applied in various studies In Vitro, ex vivo and In Vivo, without obvious immunological reactions caused by the PA-based delivery system [34][35][36][37][38]. Finally, the feasibility and efficacy of such approaches have to be validated in animal models for metastasis.…”