A novel, cancer-selective proteasome inhibitor has shown early promise for treating multiple myeloma (MM) and breast cancer, according to researchers.
The drug, known as VR23, is a quinoline-sulfonyl hybrid proteasome inhibitor.
In preclinical experiments, VR23 preferentially targeted MM cells and breast cancer cells, demonstrated synergy with bortezomib or paclitaxel, and shrank both MM and breast cancer tumors in mice.
Hoyun Lee, PhD, of the Advanced Medical Research Institute of Canada (AMRIC) in Sudbury, Ontario, and his colleagues described these experiments in Cancer Research.
The team noted that VR23 is structurally distinct from other known proteasome inhibitors, and it “potently inhibits” the activities of trypsin-like proteasomes, chymotrypsin-like proteasomes, and caspase-like proteasomes.
In several experiments, VR23 proved active against breast cancer.
In experiments with MM cell lines, VR23 exhibited activity as a single agent and demonstrated synergy with bortezomib. VR23 proved more effective against bortezomib-resistant cells than bortezomib-naïve cells.
When the researchers introduced treatments to bortezomib-naïve RPMI-8226 cells, they found the cell growth rate was 79.3% with VR23, 12.5% with bortezomib, and 1.6% with both drugs. In bortezomib-resistant RPMI-8226 cells, the cell growth rate was 47% with VR23, 109.7% with bortezomib, and -8.6% with both drugs.
In KAS6/1 cells, the cell growth rate was 65% with VR23, 92% with bortezomib, and 26.5% with both drugs. In bortezomib-resistant ANBL6 cells, the cell growth rate was 94% with VR23, 102.9% with bortezomib, and 48.9% with both drugs.
The researchers also tested VR23 in mice engrafted with RPMI-8226 MM cells. At 24 days after treatment, the tumor volume for VR23-treated mice was 19.1% that of placebo-treated mice.
The team noted that VR23 selectively killed cancer cells via apoptosis. Cancer cells exposed to the drug underwent an abnormal centrosome amplification cycle caused by the accumulation of ubiquitinated cyclin E.
Dr Lee and his colleagues are now planning to work with the US National Cancer Institute to test VR23 in additional cancers. The team is hoping to progress to clinical trials with the drug in the next 3 years.
AMRIC has applied for international intellectual property protection for VR23 and licensed commercial rights to Ramsey Lake Pharmaceutical Corporation (www.ramseylakepharma.com), an operation of AMRIC.
