In a preclinical study, the investigational drug CX-5461, which blocks the protein RNA polymerase I, extended survival in mouse models of highly aggressive acute myeloid leukemia and multiple myeloma refractory to standard therapy.

In a preclinical study, the investigational drug CX-5461, which inhibits RNA polymerase I (Pol I), extended survival in mouse models of highly aggressive acute myeloid leukemia (AML) and multiple myeloma refractory to standard therapy. In addition, the effect was independent of p53 status, according to data presented at the American Association for Cancer Research special conference Hematologic Malignancies: Translating Discoveries to Novel Therapies, held in Philadelphia, PA, in September.

In earlier work, Ross D. Hannan, PhD, head of the Oncogenic Signalling and Growth Control Program and a professor at the Peter MacCallum Cancer Centre in Melbourne, Australia, and his colleagues demonstrated that hyperactivated Pol I transcription is a “rate-limiting step” in ribosome biogenesis. Because cancer cells are “far more dependent on ribosome biogenesis that we expected,” the team thought inhibition of Pol I, considered a housekeeping protein because of its role in cell proliferation and survival, could be an effective therapeutic strategy.

“There is an urgent need for new drugs that can treat patients with these cancers that have relapsed on standard therapy, which is why we chose to study the effects of CX-5461 in mouse models of these diseases,” Hannan explained.

In a mouse model of highly aggressive AML (the MLL/ENL + Nras model) refractory to standard therapy, Hannan said that CX-5461 significantly extended survival. Median survival was 17 days for mice treated with vehicle with no drug and 21 days for mice treated with a standard chemotherapy regimen of cytarabine and doxorubicin. However, median survival for mice treated with CX-5461 was 36 days.

CX-5461 significantly prolonged survival in the V-kappa-MYC–driven model of multiple myeloma, too. Median survival was 103.5 days for mice treated with vehicle with no drug, compared with 175 days for mice treated with CX-5461.

Notably, the effect of CX-5461 was independent of p53 status; in previous studies of the drug in B-cell lymphoma, cell death was dependent on the presence of wild-type p53. The reason why is not clear.

In addition, therapeutic doses of CX-5461 had little effect on normal cells in the experiments. “Prior to these studies, few people would have guessed that such a therapeutic window could be obtained by targeting a so-called housekeeping protein that is essential to all cells for survival,” said Hannan, who dubbed the compound “a smart man's cytotoxic drug.”

Based on these results, as well as previously published data, researchers launched a phase I clinical trial of CX-5461 in patients with a variety of advanced hematologic malignancies, including AML and multiple myeloma.

©2014 American Association for Cancer Research.
2014