Since the late 1960s, one of the most successful cancer-fighting drugs on the market has been doxorubicin, commonly known as “dox,” an anti-cancer agent widely used to treat leukemia, lymphoma, soft-tissue sarcomas and some types of breast cancers, among others. But dox has one rather ominous downside: It has a limited lifetime dose before the drug itself does more harm than good.
“The trouble is, the more dox you give someone, the more their chances of developing cardiotoxicity, which basically means they’re at risk of developing untreatable cardiovascular failure,” explained Ken Cornell, an associate professor of chemistry who is himself a cancer survivor. “This is especially dangerous in cases where cancer reoccurs.”
For the past three years, Cornell has teamed up with fellow chemistry associate professor Don Warner and Gem Pharmaceuticals to develop a dox analogue that doesn’t provoke cardiotoxicity.
To understand their research, it first helps to understand how dox works: The medication is a DNA intercalating agent, which means it inserts itself into the double-stranded DNA, and in doing so it can block DNA replication. It also inhibits an enzyme called toposiomerase, which also is required to replicate DNA.
Cancer cells replicate rapidly and they’ve frequently lost the ability to correct errors in their DNA replication. So when cancer is treated with a drug that blocks replication – like dox – the next generation of cancer cells no longer have viable coding DNA.
“It basically causes errors in a process that leads to nonviable cancer cells,” Cornell explained.
Gem Pharmaceuticals has been working on developing new dox analogues for the past 20 years, with some success: “We’re on the second generation of analogues and we’re seeing patients who don’t show cardiotoxicity,” Cornell said. “The downside is the drug also isn’t as potent, so you have to administer more of it.”
Several years ago, “a representative from Gem approached me about synthesizing a new compound,” Warner explained. “I realized that once it was prepared, a series of experiments would need to be conducted to evaluate the new drug’s anticancer activity. Originally, I think Gem intended to conduct these experiments elsewhere, but I convinced them that Boise State had the required expertise – through Ken – and facilities.”
Cornell and Warner have been working on creating and testing a third generation of dox in their Boise State labs, as well as actively pursuing grant funding and submitting patent applications. “In this generation, we’ve engineered in some aspects of the drug that ought to improve its activity so the amount of drug we need will go down. Our lab research has shown that this drug is as active as or nearly as good as dox but doesn’t have the cardiotoxicity,” Cornell said.
Soon, Warner added, the duo will be seeking to publish their results.
The drug currently is in pre-clinical trials, which means the duo, along with student researchers, have tested the drug against a large panel of different types of cancer cells, using animal models of soft-tissue sarcoma. “So far, it’s worked,” Cornell said. “We’ve shown that drug treatment significantly reduced tumor volume.”
As a 30-year cancer survivor, Cornell said he stayed away from cancer-related research for a long time. But when Warner approached him about working on the project, he saw the work as both challenging and rewarding. “We’re talking about helping patients without any other choice,” Cornell said, referring to patients currently participating in the dox second-generation drug trial. “You agree to clinical trials when you’re out of options. We want to help those people.”
What started as a side project has become one of the main projects in Cornell’s lab – and likely will continue to be for many years. “What people don’t realize about drug development is that it is a long-term career path,” he said. “There are almost no drugs that go to market in five years. Most drugs have more like a 20-year cycle.”
BY: CIENNA MADRID PUBLISHED 1:16 PM / SEPTEMBER 28, 2016