Abstract
The investigational drug PR610, which is activated in tissues with low levels of oxygen, will be tested in people with non–small cell lung cancer containing the T790 mutation that is resistant to the EGFR inhibitor erlotinib.
A phase I/II trial has begun to test the safety and efficacy of a new cancer drug called PR610 that is activated in tissues with low levels of oxygen. After dose escalation studies, the drug will be examined in people with non–small cell lung cancer containing the T790 mutation that is resistant to the EGFR inhibitor erlotinib.
Called hypoxia-activated prodrugs, PR610 and others like it mask an active drug with a deactivating trigger, typically a nitroheterocyclic compound that has an affinity for electrons. When the prodrug encounters hypoxic tissue, which is found inside some tumors, the addition of an electron cleaves the trigger and releases the active drug. The electron is provided by enzymes present in all tissues but only fragments the trigger in hypoxic conditions.
For years, researchers have struggled to create effective hypoxia-activated prodrugs. “You're trying to design something that is extremely stable and durable and has excellent tissue distribution properties, but when it reaches a cell with sufficiently low oxygen, it falls apart,” says Jeff Smaill, PhD, senior research fellow at the Auckland Cancer Society Research Center at the University of Auckland. “It's quite a difficult design challenge.”
“Medicinal chemists are being more clever in the way they design these drugs than in the past,” says Glen Weiss, MD, who is leading the trial at Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare in Scottsdale, AZ, a partnership with the Translational Genomics Research Institute in Phoenix.
For example, PR610 takes advantage of the way that regions of tumor under hypoxic conditions change. It is the first hypoxia-activated prodrug to have a long enough lifespan to remain in tumor tissues for several days, the investigators say. “It just sits and waits for hypoxia to happen,” says Adam Patterson, also a senior research fellow at the University of Auckland. “So we get a slow and steady release of the drug throughout the tumor.”
Fluorescence microscopy with small-molecule hypoxia probes shows changes in oxygenation patterns over 24 hours in an A431 cell line xenograft (red at start, green at end, yellow both). The prodrug PR610, licensed to Proacta, can exploit the way that regions of tumor under hypoxic conditions change.
Fluorescence microscopy with small-molecule hypoxia probes shows changes in oxygenation patterns over 24 hours in an A431 cell line xenograft (red at start, green at end, yellow both). The prodrug PR610, licensed to Proacta, can exploit the way that regions of tumor under hypoxic conditions change.
Further, PR610 is only activated at very low levels of oxygen, so the drug is unlikely to be activated outside of the tumor. In animal studies, co-inventors Smaill and Patterson found approximately 1% of the active drug in circulation. “Only time will tell what side effects the drug may have in humans,” says Weiss.
Weiss also led the phase I trial of another promising hypoxia-activated prodrug, TH-302 from Threshold Pharmaceuticals in South San Francisco, CA, and he and his co-investigators found unanticipated dose-limiting skin and mucosal side effects in patients with advanced solid tumors. However, TH-302 is now in phase III trials for soft tissue sarcoma and Threshold recently entered a co-development deal with Merck KGaA.
PR610, licensed to Proacta of San Diego, releases an irreversible multikinase inhibitor. TH-302 is converted into a nitrogen mustard drug.
For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
