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HOUSTON—Preclinical data suggest the second-generation cyclin-dependent kinase (CDK) inhibitor CYC065 is active against lymphomas as well as leukemias.
Previous research showed that CYC065 can fight acute myeloid leukemia (AML) in vitro and in vivo.
New research shows that CYC065 can decrease cell viability in a range of B-cell lymphoma cell lines, and the drug synergizes with both venetoclax and cytarabine.
Sheelagh Frame, PhD, and her colleagues presented these results at the SOHO 2015 Annual Meeting (poster 213). All of the investigators involved in the research are employees of Cyclacel Ltd., the company developing CYC065.
The investigators analyzed the anticancer activity of CYC065 in a range of cell lines and found that CYC065 induced apoptosis by inhibiting the expression of CDK9-dependent oncogenic transcripts, including Mcl-1, c-Myc, Hoxa9, and Meis1.
Results in AML
Experiments in the AML-MLL cell line MOLM-13 showed that short pulses of CYC065 (6 hours), rather than continuous treatment, were sufficient to achieve maximal cytotoxicity.
CYC065 induced apoptosis, in a dose-dependent manner, in other AML cell lines as well, including EOL-1 (MLL-PTD), MV4-11 (MLL-AF4, FLT3-ITD, and trisomy chr 8), HL60 (Myc amplified), and Kasumi-1.
The investigators noted that AML cell lines with MLL rearrangements were especially sensitive to CYC065, and the reliance of AML on Mcl-1 confers sensitivity to CYC065.
They also found evidence to suggest that Bak and Bcl-xL levels may be predictive of CYC065 response in AML. Cell lines that were less sensitive to treatment had high levels of Bcl-xL and negligible levels of Bak.
B-cell lymphomas
In B-cell lymphoma cell lines, the investigators observed a dose-dependent reduction in cell viability after CYC065 treatment (8-hour pulses).
CYC065 proved most effective in cell lines without genomic alterations associated with poor prognosis (HT and U-698-M) and in cell lines with Myc rearrangements (SU-DHL-8 and WILL-1).
The drug also decreased cell viability—but to a lesser degree—in cell lines with Bcl-2 rearrangements (SU-DHL-4 and U2932) and in double-hit lymphoma cell lines (MAVER-1, RI-1, SC-1, and SU-DHL-10).
The investigators therefore theorized that combining CYC065 with a Bcl-2 inhibitor might prove more effective in these cell lines.
CYC065 in combination
CYC065 synergized with the Bcl-2 inhibitor venetoclax in all B-cell lymphoma cell lines tested. The drugs were “strongly synergistic” in U2932 and RI-1 cell lines but simply “synergistic” in SU-CHL-4 and MAVER-1 cell lines.
CYC065 also synergized with cytarabine to fight AML. The combination proved synergistic at a range of doses in the HL60 and MV4-11 cell lines.
Considering these results together, the investigators concluded that CYC065 has shown potential for treating a range of leukemias and lymphomas with unmet clinical need, including MLL-rearranged leukemia and Myc-driven lymphoma.
And the drug might prove effective in combination with standard cytotoxic agents or agents targeting apoptotic regulators. 
HOUSTON—Preclinical data suggest the second-generation cyclin-dependent kinase (CDK) inhibitor CYC065 is active against lymphomas as well as leukemias.
Previous research showed that CYC065 can fight acute myeloid leukemia (AML) in vitro and in vivo.
New research shows that CYC065 can decrease cell viability in a range of B-cell lymphoma cell lines, and the drug synergizes with both venetoclax and cytarabine.
Sheelagh Frame, PhD, and her colleagues presented these results at the SOHO 2015 Annual Meeting (poster 213). All of the investigators involved in the research are employees of Cyclacel Ltd., the company developing CYC065.
The investigators analyzed the anticancer activity of CYC065 in a range of cell lines and found that CYC065 induced apoptosis by inhibiting the expression of CDK9-dependent oncogenic transcripts, including Mcl-1, c-Myc, Hoxa9, and Meis1.
Results in AML
Experiments in the AML-MLL cell line MOLM-13 showed that short pulses of CYC065 (6 hours), rather than continuous treatment, were sufficient to achieve maximal cytotoxicity.
CYC065 induced apoptosis, in a dose-dependent manner, in other AML cell lines as well, including EOL-1 (MLL-PTD), MV4-11 (MLL-AF4, FLT3-ITD, and trisomy chr 8), HL60 (Myc amplified), and Kasumi-1.
The investigators noted that AML cell lines with MLL rearrangements were especially sensitive to CYC065, and the reliance of AML on Mcl-1 confers sensitivity to CYC065.
They also found evidence to suggest that Bak and Bcl-xL levels may be predictive of CYC065 response in AML. Cell lines that were less sensitive to treatment had high levels of Bcl-xL and negligible levels of Bak.
B-cell lymphomas
In B-cell lymphoma cell lines, the investigators observed a dose-dependent reduction in cell viability after CYC065 treatment (8-hour pulses).
CYC065 proved most effective in cell lines without genomic alterations associated with poor prognosis (HT and U-698-M) and in cell lines with Myc rearrangements (SU-DHL-8 and WILL-1).
The drug also decreased cell viability—but to a lesser degree—in cell lines with Bcl-2 rearrangements (SU-DHL-4 and U2932) and in double-hit lymphoma cell lines (MAVER-1, RI-1, SC-1, and SU-DHL-10).
The investigators therefore theorized that combining CYC065 with a Bcl-2 inhibitor might prove more effective in these cell lines.
CYC065 in combination
CYC065 synergized with the Bcl-2 inhibitor venetoclax in all B-cell lymphoma cell lines tested. The drugs were “strongly synergistic” in U2932 and RI-1 cell lines but simply “synergistic” in SU-CHL-4 and MAVER-1 cell lines.
CYC065 also synergized with cytarabine to fight AML. The combination proved synergistic at a range of doses in the HL60 and MV4-11 cell lines.
Considering these results together, the investigators concluded that CYC065 has shown potential for treating a range of leukemias and lymphomas with unmet clinical need, including MLL-rearranged leukemia and Myc-driven lymphoma.
And the drug might prove effective in combination with standard cytotoxic agents or agents targeting apoptotic regulators.
HOUSTON—Preclinical data suggest the second-generation cyclin-dependent kinase (CDK) inhibitor CYC065 is active against lymphomas as well as leukemias.
Previous research showed that CYC065 can fight acute myeloid leukemia (AML) in vitro and in vivo.
New research shows that CYC065 can decrease cell viability in a range of B-cell lymphoma cell lines, and the drug synergizes with both venetoclax and cytarabine.
Sheelagh Frame, PhD, and her colleagues presented these results at the SOHO 2015 Annual Meeting (poster 213). All of the investigators involved in the research are employees of Cyclacel Ltd., the company developing CYC065.
The investigators analyzed the anticancer activity of CYC065 in a range of cell lines and found that CYC065 induced apoptosis by inhibiting the expression of CDK9-dependent oncogenic transcripts, including Mcl-1, c-Myc, Hoxa9, and Meis1.
Results in AML
Experiments in the AML-MLL cell line MOLM-13 showed that short pulses of CYC065 (6 hours), rather than continuous treatment, were sufficient to achieve maximal cytotoxicity.
CYC065 induced apoptosis, in a dose-dependent manner, in other AML cell lines as well, including EOL-1 (MLL-PTD), MV4-11 (MLL-AF4, FLT3-ITD, and trisomy chr 8), HL60 (Myc amplified), and Kasumi-1.
The investigators noted that AML cell lines with MLL rearrangements were especially sensitive to CYC065, and the reliance of AML on Mcl-1 confers sensitivity to CYC065.
They also found evidence to suggest that Bak and Bcl-xL levels may be predictive of CYC065 response in AML. Cell lines that were less sensitive to treatment had high levels of Bcl-xL and negligible levels of Bak.
B-cell lymphomas
In B-cell lymphoma cell lines, the investigators observed a dose-dependent reduction in cell viability after CYC065 treatment (8-hour pulses).
CYC065 proved most effective in cell lines without genomic alterations associated with poor prognosis (HT and U-698-M) and in cell lines with Myc rearrangements (SU-DHL-8 and WILL-1).
The drug also decreased cell viability—but to a lesser degree—in cell lines with Bcl-2 rearrangements (SU-DHL-4 and U2932) and in double-hit lymphoma cell lines (MAVER-1, RI-1, SC-1, and SU-DHL-10).
The investigators therefore theorized that combining CYC065 with a Bcl-2 inhibitor might prove more effective in these cell lines.
CYC065 in combination
CYC065 synergized with the Bcl-2 inhibitor venetoclax in all B-cell lymphoma cell lines tested. The drugs were “strongly synergistic” in U2932 and RI-1 cell lines but simply “synergistic” in SU-CHL-4 and MAVER-1 cell lines.
CYC065 also synergized with cytarabine to fight AML. The combination proved synergistic at a range of doses in the HL60 and MV4-11 cell lines.
Considering these results together, the investigators concluded that CYC065 has shown potential for treating a range of leukemias and lymphomas with unmet clinical need, including MLL-rearranged leukemia and Myc-driven lymphoma.
And the drug might prove effective in combination with standard cytotoxic agents or agents targeting apoptotic regulators.