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Preclinical Study Looks at RNA Polymerase I Inhibitor in Refractory AML and Multiple Myeloma

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Key Points

  • The investigational drug CX-5461 prolonged survival in mouse models of highly aggressive acute myeloid leukemia (AML) and multiple myeloma refractory to standard therapy.
  • CX-5461 was effective independent of p53 status.
  • A phase I clinical study of CX-5461 has been launched in patients with advanced hematologic malignancies, including AML and multiple myeloma.

A laboratory study of the investigational drug CX-5461, which blocks the inhibition of RNA polymerase I transcription, has found that it prolonged survival in mouse models of highly aggressive acute myeloid leukemia (AML) and multiple myeloma refractory to standard therapy. In addition, the drug’s effectiveness was independent of p53 status. The study by Hein et al was presented at the American Association for Cancer Research (AACR) special conference Hematologic Malignancies: Translating Discoveries to Novel Therapies, held September 20 to 23 in Philadelphia.

Study Methodology

According to the study abstract, previous investigations by the researchers were instrumental in the development of CX-5461, which led to the discovery that ribosomal gene transcription by Pol 1 is not simply a “housekeeping” process in cancer cells but is highly regulated to maintain their viability. Pol 1 is a protein involved in a cellular process central to cell proliferation and survival and is referred to as a housekeeping protein. To explore the therapeutic potential of Pol I transcription inhibition via CX-5461 in hematologic malignancies refractory to standard chemotherapy, the researchers used mouse models of highly aggressive AML the MLL/ENL + Nras model, and mouse models of V-kappa-MYC–driven multiple myeloma.

Study Findings

The researchers found that in the AML-bearing mice, median survival was 17 days for mice treated with vehicle with no drug, compared with 21 days for mice treated with the standard chemotherapy combination of cytarabine and doxorubicin, and 36 days for mice treated with CX-5461.

Similarly, in the multiple myeloma–bearing mice, CX-5461 significantly prolonged overall survival: median survival was 103.5 days for mice receiving vehicle with no drug and 175 days for mice receiving CX-5461.

Based on these and earlier published test results, the researchers have launched a phase I clinical trial of CX-5461 in patients with advanced hematologic malignancies, including AML and multiple myeloma.

“We were excited to find that therapeutic doses of CX-5461 had little effect on normal cells in our experiments,” said study coauthor Ross D. Hannan, PhD, Head of the Oncogenic Signaling and Growth Control Program, Professor at the Peter MacCallum Cancer Centre, Melbourne, Australia, in a statement. “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.”

“This [study] is very exciting particularly the ability of this novel agent [and] mechanism to work even in p53-deleted cancers, which in solid tumors and hematologic malignancies alike are largely untreatable,” said Kenneth C. Anderson, MD, Chair of the AACR conference, and Program Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute in Boston, at a press briefing announcing the study results.

The study was funded by the National Health and Medical Research Council, Australia; the Leukaemia Foundation of Australia; and Cancer Council Victoria, Melbourne, Australia. Senhwa Biosciences provided CX-5461.

Dr. Hannon declared no conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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