Bladder cancer ranked as the 12th most common cancer in the world in 2018 and was the 7th most prominent cancer in men. Current treatment options for non-muscle invasive bladder cancer do not include radiation therapy, as the bladder is a mobile organ and adjacent to many sensitive tissues. Standard of care treatment (BCG) is effective in only 60-70% of the patient population and the nonresponsive patients eventually require more radical treatment options. Given that 30-40% of the bladder cancer patients are not effectively treated, together with the high cost of more radical approaches, there is a huge need for new bladder cancer treatments. One option could be adding targeted radiation therapy delivered inside the bladder with standard of care BCG could improve the response rate for this cancer type, while lowering cost and possible complications. Thus, our hypothesis was that bladder cancer could be safely and effectively treated using alpha-particle therapy with Pb-214/Bi-214-labeled trastuzumab/cetuximab. A supportive prior pilot study demonstrated that alpha particle therapy was safe and effective in muscle-invasive bladder cancer patients, using intravesical Bi-213-cetuximab antibody. We first determined the EGFR1 and EGFR2 levels for 6 human bladder cancer cell lines in vitro and binding affinities of Tc-99m-[Trastuzumab] and Tc-99m-[Cetuximab] to the human bladder cancer cells. The purity of the radionuclide bound antibodies was determined using instant Thin Layer Chromatography, and specific binding of the radiolabeled antibodies to target receptors was measured. Next, we attached Pb-214/Bi-214, the novel radioactive agent emitting alpha particles, to the FDA-approved antibodies (Cetuximab and Trastuzumab) that target the EGFR1 and EGFR2 receptors expressed on bladder cancer cells. Then, Pb-214/Bi-214-labeled Trastuzumab and Pb-214/Bi-214-Cetuximab was demonstrated to provide efficient killing of the bladder cancer cells. Addition of increasing concentrations of radiolabeled antibodies resulted in 5-20% reduction in cell numbers after 24 hours. These effects were often statistically significant, but the overall effects were modest at 24 hours. However, cell viability was significantly reduced at 72-hour post treatment. Overall, the results at 72 hours after treatment suggest that higher doses of Pb-214/Bi-214-trastuzumab/cetuximab were effective in killing EGFR1/EGFR2-expressing human bladder cancer cells. This research demonstrated a new targeted radiation treatment for bladder cancer is was effective and cost-efficient. This work developed methods for moving the new bladder cancer treatment strategy forward to a phase I clinical trial.
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