PHILADELPHIA—Preclinical research suggests a cyclin-dependent kinase (CDK) inhibitor is active against acute leukemias, particularly those with mixed-lineage leukemia rearrangements (MLL-r).
CYC065 selectively inhibits CDK2, which drives cell-cycle transition and activates major DNA double-strand break repair pathways; CDK5, which drives metastatic spread; and CDK9, which regulates the transcription of genes important for the proliferation and survival of malignant cells.
Experiments have shown that CYC065 exhibits activity against acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), with and without MLL-r.
Daniella Zheleva, PhD, and her colleagues described these experiments in a poster at the AACR Annual Meeting 2015 (abstract 1650). All of the researchers are employees of Cyclacel Ltd., the company developing CYC065.
The researchers tested CYC065 in a panel of AML cell lines with wild-type MLL (HEL, HL60, Kasumi-1, KG-1, OCI-AML5, and PL21) and MLL-r (EOL-1, ML-2, MOLM-13, MV4-11, Nomo-1, OCI-AML2, and THP-1).
They found that MLL-r cell lines were “highly sensitive” to CYC065, but the sensitivity of cell lines with wild-type MLL correlated with the level of Bcl-2 family proteins. In the wild-type cell lines, IC50/70/90 values were correlated with BclXL and inversely correlated with Bak.
Six-hour pulse treatment of CYC065 at 0.5 µM to 1 µM was sufficient to cause 90% or greater cell death in sensitive cell lines. And cell lines with reduced sensitivity to the drug could be targeted by exposure to 10-hour pulse treatments of CYC065, or to CYC065 in combination with short pulses of Bcl-2 inhibitors.
The researchers observed “potent antitumor activity” when they administered CYC065 in AML xenograft models.
In an EOL-1 model, the median tumor growth inhibition on day 19 was 97% for mice that received CYC065 at 40 mg/kg (every day on days 1-5 and 8-12), 95% for mice that received CYC065 at 20 mg/kg every day on days 1-5 and 8-12), and 41% for mice that received cytarabine at 100 mg/kg (every day on days 1-5).
In the HL60 model, the median tumor growth inhibition on day 11 was 90% for mice that received CYC065 at 70 mg/kg (every day on days 1-5 and 8-12). And 2 mice achieved a complete response to treatment.
The researchers also found that CYC065 synergizes with cytarabine, particularly when CYC065 is given first. In fact, the combination could overcome the cytarabine resistance observed in the MV4-11 cell line.
CYC065 was “strongly synergistic” with Bcl2/BclXL inhibitors as well, the researchers said. CYC065 synergized with ABT-199, ABT-263, and ABT-737 in both AML cell lines (THP-1 and HEL) and ALL cell lines (Jurkat and SEM).
The researchers said the potent in vitro and in vivo activity of CYC065 and the ability to combine the drug with other antileukemic agents suggest that it may have therapeutic potential in AML and ALL.
