acute lymphoblastic leukemia
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Preclinical research suggests that 2 investigational drugs synergize to kill T-cell acute lymphoblastic leukemia (T-ALL) cells while having a minimal impact on normal blood cells.
Both drugs—the CK2 inhibitor CX-4945 and the BET inhibitor JQ1—have already been tested as single agents in clinical trials of hematologic malignancies and solid tumors.
However, the effects of the drugs in combination were not known until now.
“Previous studies provided us a rationale to test the combination of CX-4945 and JQ1 on refractory/relapsed T-cell leukemia,” said Hui Feng, MD, PhD, of Boston University School of Medicine in Massachusetts.
“Our findings suggest that the combination treatment of CX-4945 and JQ1 could be an effective strategy to target refractory/relapsed T-cell leukemia.”
Dr Feng and her colleagues reported these findings in Haematologica.
The researchers noted that targeting MYC-mediated transcriptional programs using JQ1 produces anti-leukemic activity in vitro and in vivo. However, global repression of transcription is likely to cause toxicities.
Therefore, the team theorized that finding drugs that synergize with JQ1 might allow them to reduce the dose of JQ1 and therefore decrease the risk of toxicity while enhancing the efficacy of treatment.
For this, the researchers looked to CX-4945, which is currently being investigated in clinical trials of breast cancer and multiple myeloma.
The team said CX-4945 has been shown to significantly reduce the growth and survival of human T-ALL cells on its own.
In a series of experiments, Dr Feng and her colleagues were able to show that CX-4945 destabilizes NOTCH1 and synergizes with JQ1 to induce apoptosis in human T-ALL cells.
The researchers also assessed the effects of JQ1 and CX-4946, alone and in combination, on normal peripheral blood monocytes (PBMs).
PBMs proved less sensitive than ALL-SIL T-ALL cells to each drug alone and to the drugs in combination. In fact, the combination had an antagonistic effect in PBMs.
Dr Feng and her colleagues said this research suggests JQ1 and CX-4946 in combination may be a feasible treatment option for relapsed/refractory T-ALL and other cancers involving CK2 and NOTCH1/MYC.
