Combo may overcome bortezomib resistance in MCL

SAN DIEGO—Preclinical research suggests that combining a BET inhibitor with lenalidomide may overcome resistance to bortezomib in mantle cell lymphoma (MCL).

Experiments in MCL cell lines and mouse models of the disease showed that lenalidomide alone is active in bortezomib-resistant cells and tumors.

But the anticancer effects are more pronounced with the addition of the BET inhibitor CPI203.

“So we think that this new combination based on BET inhibition and lenalidomide may be helpful for the design of new therapies in the subset of MCL patients resistant to bortezomib,” said study investigator Gael Roue, PhD, of IDIBAPS in Barcelona, Spain.

Dr Roue and his colleagues presented this research in a poster at the AACR Annual Meeting 2014 (abstract 1691*). The team included researchers from Constellation Pharmaceuticals, the company developing CPI203.

With this research, the investigators wanted to assess the possibility of targeting IRF4 and MYC signaling and overcoming bortezomib resistance with lenalidomide-based therapies.

To that end, they tested lenalidomide in 9 MCL cell lines. They found the drug’s antitumor activity is mediated by inhibition of the plasmacytic differentiation program in bortezomib-resistant MCL.

The team then evaluated the effects of lenalidomide on REC-1 cells injected into SCID mice. And they found that lenalidomide significantly reduced tumor growth compared to vehicle control (P=0.04).

The researchers next injected mice with REC-1 cells and treated them with 50 mg/kg of lenalidomide, 0.15 mg/kg of bortezomib, both agents, or vehicle control. The mice received lenalidomide 5 days a week and bortezomib twice a week for up to 18 days.

Lenalidomide alone significantly reduced tumor volume when compared to control (P=0.04). The same was true of the combination treatment compared to control (P=0.02).

The investigators also noted a 25% increase in MYC expression in cells and tumors that were resistant to bortezomib. So they speculated that inhibiting MYC could increase lenalidomide activity.

“This was the rationale for combining lenalidomide with a BET inhibitor,” Dr Roue said. “BET inhibitors are known to inhibit MYC transcription, to inhibit MYC signaling, in multiple myeloma and lymphoma cells.”

The researchers first evaluated the effects of CPI203 alone. They cultured 9 MCL cell lines and peripheral blood mononuclear cells from 2 healthy donors with increasing concentrations of CPI203 and assessed cytotoxicity, MYC levels, and cell viability.

They found that CPI203 was active in all the cell lines tested, but it didn’t affect the proliferation or viability of the healthy cells. And CPI203 activity was linked to the downregulation of MYC.

The team then tested CPI203 in combination with lenalidomide. They treated REC-1 cells for 72 hours with 0.1 μM to 0.5 μM of CPI203 and/or 1 μM to 5 μM of lenalidomide.

“[W]e observed synergistic activity in vitro, linked to a complete disappearance of MYC and also of IRF4,” Dr Roue said.

Finally, the investigators tested the 2 agents in mice with bortezomib-resistant MCL. The mice were injected with REC-1 cells and randomized to treatment with lenalidomide at 50 mg/kg/day, CPI203 at 2.5 mg/kg BID, both agents, or vehicle control.

“We found that by treating mice with [both agents] for 3 weeks, we reached 80% tumor remission, which was linked to inhibition of mitosis, complete disappearance of MYC and IRF4 protein levels, and induction of apoptosis in about 30% to 40% of the tumors.”

The researchers said these results suggest the lenalidomide-BET inhibitor combination warrants investigation in MCL patients who are refractory to bortezomib.

*Information in the abstract differs from that presented at the meeting.

SAN DIEGO—Preclinical research suggests that combining a BET inhibitor with lenalidomide may overcome resistance to bortezomib in mantle cell lymphoma (MCL).

Experiments in MCL cell lines and mouse models of the disease showed that lenalidomide alone is active in bortezomib-resistant cells and tumors.

But the anticancer effects are more pronounced with the addition of the BET inhibitor CPI203.

“So we think that this new combination based on BET inhibition and lenalidomide may be helpful for the design of new therapies in the subset of MCL patients resistant to bortezomib,” said study investigator Gael Roue, PhD, of IDIBAPS in Barcelona, Spain.

Dr Roue and his colleagues presented this research in a poster at the AACR Annual Meeting 2014 (abstract 1691*). The team included researchers from Constellation Pharmaceuticals, the company developing CPI203.

With this research, the investigators wanted to assess the possibility of targeting IRF4 and MYC signaling and overcoming bortezomib resistance with lenalidomide-based therapies.

To that end, they tested lenalidomide in 9 MCL cell lines. They found the drug’s antitumor activity is mediated by inhibition of the plasmacytic differentiation program in bortezomib-resistant MCL.

The team then evaluated the effects of lenalidomide on REC-1 cells injected into SCID mice. And they found that lenalidomide significantly reduced tumor growth compared to vehicle control (P=0.04).

The researchers next injected mice with REC-1 cells and treated them with 50 mg/kg of lenalidomide, 0.15 mg/kg of bortezomib, both agents, or vehicle control. The mice received lenalidomide 5 days a week and bortezomib twice a week for up to 18 days.

Lenalidomide alone significantly reduced tumor volume when compared to control (P=0.04). The same was true of the combination treatment compared to control (P=0.02).

The investigators also noted a 25% increase in MYC expression in cells and tumors that were resistant to bortezomib. So they speculated that inhibiting MYC could increase lenalidomide activity.

“This was the rationale for combining lenalidomide with a BET inhibitor,” Dr Roue said. “BET inhibitors are known to inhibit MYC transcription, to inhibit MYC signaling, in multiple myeloma and lymphoma cells.”

The researchers first evaluated the effects of CPI203 alone. They cultured 9 MCL cell lines and peripheral blood mononuclear cells from 2 healthy donors with increasing concentrations of CPI203 and assessed cytotoxicity, MYC levels, and cell viability.

They found that CPI203 was active in all the cell lines tested, but it didn’t affect the proliferation or viability of the healthy cells. And CPI203 activity was linked to the downregulation of MYC.

The team then tested CPI203 in combination with lenalidomide. They treated REC-1 cells for 72 hours with 0.1 μM to 0.5 μM of CPI203 and/or 1 μM to 5 μM of lenalidomide.

“[W]e observed synergistic activity in vitro, linked to a complete disappearance of MYC and also of IRF4,” Dr Roue said.

Finally, the investigators tested the 2 agents in mice with bortezomib-resistant MCL. The mice were injected with REC-1 cells and randomized to treatment with lenalidomide at 50 mg/kg/day, CPI203 at 2.5 mg/kg BID, both agents, or vehicle control.

“We found that by treating mice with [both agents] for 3 weeks, we reached 80% tumor remission, which was linked to inhibition of mitosis, complete disappearance of MYC and IRF4 protein levels, and induction of apoptosis in about 30% to 40% of the tumors.”

The researchers said these results suggest the lenalidomide-BET inhibitor combination warrants investigation in MCL patients who are refractory to bortezomib.

*Information in the abstract differs from that presented at the meeting.

SAN DIEGO—Preclinical research suggests that combining a BET inhibitor with lenalidomide may overcome resistance to bortezomib in mantle cell lymphoma (MCL).

Experiments in MCL cell lines and mouse models of the disease showed that lenalidomide alone is active in bortezomib-resistant cells and tumors.

But the anticancer effects are more pronounced with the addition of the BET inhibitor CPI203.

“So we think that this new combination based on BET inhibition and lenalidomide may be helpful for the design of new therapies in the subset of MCL patients resistant to bortezomib,” said study investigator Gael Roue, PhD, of IDIBAPS in Barcelona, Spain.

Dr Roue and his colleagues presented this research in a poster at the AACR Annual Meeting 2014 (abstract 1691*). The team included researchers from Constellation Pharmaceuticals, the company developing CPI203.

With this research, the investigators wanted to assess the possibility of targeting IRF4 and MYC signaling and overcoming bortezomib resistance with lenalidomide-based therapies.

To that end, they tested lenalidomide in 9 MCL cell lines. They found the drug’s antitumor activity is mediated by inhibition of the plasmacytic differentiation program in bortezomib-resistant MCL.

The team then evaluated the effects of lenalidomide on REC-1 cells injected into SCID mice. And they found that lenalidomide significantly reduced tumor growth compared to vehicle control (P=0.04).

The researchers next injected mice with REC-1 cells and treated them with 50 mg/kg of lenalidomide, 0.15 mg/kg of bortezomib, both agents, or vehicle control. The mice received lenalidomide 5 days a week and bortezomib twice a week for up to 18 days.

Lenalidomide alone significantly reduced tumor volume when compared to control (P=0.04). The same was true of the combination treatment compared to control (P=0.02).

The investigators also noted a 25% increase in MYC expression in cells and tumors that were resistant to bortezomib. So they speculated that inhibiting MYC could increase lenalidomide activity.

“This was the rationale for combining lenalidomide with a BET inhibitor,” Dr Roue said. “BET inhibitors are known to inhibit MYC transcription, to inhibit MYC signaling, in multiple myeloma and lymphoma cells.”

The researchers first evaluated the effects of CPI203 alone. They cultured 9 MCL cell lines and peripheral blood mononuclear cells from 2 healthy donors with increasing concentrations of CPI203 and assessed cytotoxicity, MYC levels, and cell viability.

They found that CPI203 was active in all the cell lines tested, but it didn’t affect the proliferation or viability of the healthy cells. And CPI203 activity was linked to the downregulation of MYC.

The team then tested CPI203 in combination with lenalidomide. They treated REC-1 cells for 72 hours with 0.1 μM to 0.5 μM of CPI203 and/or 1 μM to 5 μM of lenalidomide.

“[W]e observed synergistic activity in vitro, linked to a complete disappearance of MYC and also of IRF4,” Dr Roue said.

Finally, the investigators tested the 2 agents in mice with bortezomib-resistant MCL. The mice were injected with REC-1 cells and randomized to treatment with lenalidomide at 50 mg/kg/day, CPI203 at 2.5 mg/kg BID, both agents, or vehicle control.

“We found that by treating mice with [both agents] for 3 weeks, we reached 80% tumor remission, which was linked to inhibition of mitosis, complete disappearance of MYC and IRF4 protein levels, and induction of apoptosis in about 30% to 40% of the tumors.”

The researchers said these results suggest the lenalidomide-BET inhibitor combination warrants investigation in MCL patients who are refractory to bortezomib.

*Information in the abstract differs from that presented at the meeting.