Novel Anti-Bladder Cancer Therapeutics

Bladder cancer is the 4th most prevalent cancer in men, 11th in women and presents one of the highest rates of post-treatment recurrence (70%) among malignancies. Despite its impact on human health, therapeutic approaches against bladder cancer are of limited efficacy. 

We previously developed a strategy based on receptor micro-clustering (µC) to induce agent fast internalization by bladder tumor cells.  Importantly, µC effects can be elicited by different multivalent agents including anthrax toxin that clusters as heptamers at the plasma membrane inducing its own uptake. Further, and considering that bladder tumor cells express high levels of Epidermal Growth Factor (EGF) Receptor (EGFR), we used EGF to target this lethal toxin against cancer cells. 

Here we show that the EGF-toxin induces its own internalization and delivery into the cytosol of targeted cells within min of exposure. This agent was up to 1000 times more efficient that current anti-bladder cancer agents such as mitomycin C and Gemcitabine at eliminating bladder cancer cells. Further we also found that this agent was capable of eliminating Cancer Stem Cells of bladder and prostate origin. We established that under bladder instillation conditions, the toxin eliminated human, canine and mouse bladder cancer cells, including Her2-positive cells, with a LC50<1nM (<<intoxication dose ~1μM) and exposure time<3min.

Since µC enhances internalization of cargoes independently of receptor dimer formation, we found that this strategy was insensitive to known efficacy-decreasing factors to EGF-based approaches such as internalization interference by presence of Her2 or by endocytosis-limiting mutations. Further, dogs with spontaneous, treatment-resistant Her2-positive bladder cancer (closely mimicking the human condition) showed marked reduction in tumor mass when treated with EGF-toxin. Safety studies indicated no deleterious effects in normal and patient dogs.

These studies provide the foundation for an innovative and transformative anti-bladder cancer therapy. The EGF-toxin is a superior agent due to its high efficacy, fast action (minutes vs. current treatments requiring more than 2h retention of therapeutics in the bladder) and enhanced safety, but also due to its ability to target cancer stem cells and Her2-positive tumors. 
 

Learning Objectives:

1. Review the current impact of bladder cancer and the limitations of available treatment options.

2. Review the novel paradigms for the developments of more efficient and specific anti-bladder therapeutics.