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BMH-21 “When we think about radiation therapy, it is high-tech, but the complexity of cancer requires that we have a better understanding of the biology,” says Marikki Laiho, the Willard and Lillian Hackerman Professor of Radiation Oncology and vice chair of research for the Department of Radiation Oncology and Molecular Radiation Sciences. “Now, we combine technology with biology, and that ultimately means improved treatments for patients.” This biological underpinning led Laiho to an exciting discovery that appears to stop cancer cells in their tracks.

She identified an unexpected target for cancer therapy and developed a drug that hits the target. The drug goes after a kind of cellular machinery called the RNA polymerase 1, or POL1. The genetic instructions in our DNA are read out by RNA polymerases. Cells have three main ways— POL 1, 2 and 3—to read the instruction manual that is our DNA and help convert those instructions into protein-based actions that are dictated by genes.

Errors in the genetic code, known as mutations, alter how proteins are formed and function, and ultimately how cells behave. POL2 is studied most in cancer because it executes the primary program that leads to the defective proteins related to the majority of cancer mutations identified to date. The other two polymerases, however, provide essential molecular tools that help make the actual proteins. “POL1 is fundamentally important for every cell, so it has not been considered an actionable target for cancer therapy. If you hit it, the thought was that you would harm every cell, not just cancer cells,” says Laiho.

Laiho proved that was not the case after developing a drug that targets POL1 and studying it in the laboratory. She found that cancer cells rely on it more than normal cells, so it was possible to interfere with the pathway without causing excessive damage to normal cells. “Cancer cells can’t survive without this program. They can’t function,” says Laiho. “Just as important, however, normal cells don’t take much notice.” She has spent the last three years deciphering how POL1 works and developing tools to measure its activity in cancer cells. Working with prostate cancer expert and pathologist Angelo De Marzo, Laiho used these tools, and a large Challenge Award from the Prostate Cancer Foundation, to develop a test that identifies prostate cancers that rely on POL1.

This was the first step to a clinical approach. Laiho discovered a drug called BMH-21 from a drug library screen and then worked with her research team to identify the target, POL1. Now Laiho is working with Johns Hopkins medicinal chemist James Barrow to refine it. She was surprised by how well the drug worked in preclinical proof-of-principle studies. “Without this transcription machinery, cancer cells couldn’t recover,” says Laiho. “They cannot function.” BMH-21 showed exceptional activity against cancer cells from many tumor types. In fact, in these studies, the drug functioned better against the cancer cells than many FDA-approved cancer drugs.

“We have been able to confirm that BMH-21 works by binding to DNA and are very near the optimal stage of drug development,” says Laiho. “Typically, many revisions to the lead molecule are required before it is ready for clinical studies. We are very excited because that is not the case with our drug, and that means we are closer to the clinic than we could have ever imagined.” With most of the science in place, the research could be translated into a new treatment in a little over a year.

Still, Laiho and team face some hurdles. She needs funding and a pharmaceutical partner to make the leap from laboratory to clinic. Bluefield Innovations, a Deerfield Management and Johns Hopkins University collaboration aimed at supporting the commercialization of early stage drug research at Johns Hopkins announced that it will take on Laiho’s drug as its first project. A prestigious Harrington Discovery Institute Scholars Innovator Award, the Patrick C. Walsh Prostate Cancer Research Fund and the Allegheny Health Network have also provided much-needed funding to help move her drug to the clinic. “It has taken a long time to get here because this was uncharted territory for me,” says Laiho. “From the day I had my molecule, I was walking around asking about how to do the molecular modeling, how to make derivatives, and how to do a PK experiment. I had an endless line of questions.” PK, refers to pharmacokinetics. Literally translated, it means movement of drugs—how a drug gets into the bloodstream and then travels to tissues and organs, how the body breaks the drug down, how long it stays in the body and how the body gets rid of it.

Experiments directed at understanding how a drug moves through the body and what it does are an essential part of new drug development. The collaborative nature of the Kimmel Cancer Center certainly worked in Laiho’s favor, and she found answers to her PK experiments questions and other questions by making connections with experts, but this took time. She believes Nelson’s vision for the drug discovery program in the Kimmel Cancer Center represents a complete package of all the necessary elements that would speed drug discovery and development. “We need financial support, but we also need knowledge support,” says Laiho. “The knowledge already exists here, so we’re one step ahead already. We just need to bring all of the elements together.”

As Laiho inches closer to moving her drug to patients, one of the things she is most excited about is its application across many cancer types. “Even though we are looking at prostate cancer and melanomas now, BMH-21 appears to work in many solid tumors with high dependency on the POL1 pathway,” says Laiho. “The more a tumor depends on this pathway, the better this treatment should work.” She hopes to be able to obtain enough support to soon launch clinical trials in prostate cancer patients who have exhausted all other treatment options and to make the necessary modifications to BMH-21 to expand studies to other cancers.

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