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PHILADELPHIA—A drug that has fallen short of expectations in clinical trials of prostate cancer may be effective for treating multiple myeloma (MM), according to research presented at the AACR Annual Meeting 2015.
The drug, tasquinimod, inhibits the function of S100A9, a pro-inflammatory protein that is elevated in MM, prostate cancer, and other malignancies.
Researchers found that tasquinimod can reduce tumor growth and improve survival in mouse models of MM. And these effects are associated with reduced angiogenesis in the bone marrow.
Cindy Lin, PhD, of the Wistar Institute in Philadelphia, Pennsylvania, and her colleagues presented these findings as abstract 1364.* The research was supported by Active Biotech and Ipsen, the companies developing tasquinimod.
Dr Lin noted that tasquinimod has already been tested in clinical trials of prostate cancer and initially appeared to be very effective. However, recent results from a phase 3 trial suggested the drug does not confer a favorable risk-benefit ratio for this population.
So Active Biotech and Ipsen decided to discontinue all trials of tasquinimod in prostate cancer. But the preclinical results observed in MM suggest tasquinimod may hold promise for treating these patients.
Activity in MM
Dr Lin said previous preclinical experiments revealed that myeloid-derived suppressor cells are involved in regulating MM progression, and these cells produce S100A9.
Tasquinimod is a quinoline-3-carboxamide derivative that binds to S100A9 and inhibits interaction with its receptors. So Dr Lin and her colleagues decided to investigate the antitumor effect of the drug in mouse models of MM.
The researchers initially tested tasquinimod in a syngeneic MM model, randomizing mice to treatment or control. Mice in the treatment group received tasquinimod at 30 mg/kg/day in their drinking water for 28 days.
Tasquinimod significantly improved survival in this model (P<0.005). All control mice died within 30 days of tumor inoculation, but about 40% of tasquinimod-treated mice were still alive more than 80 days out.
The researchers then tested tasquinimod in xenograft models of human MM. The drug significantly reduced tumor size in both H929 (P=0.0042) and RPMI-8226 models (P=0.0003). Treatment significantly improved survival in the H929 (P=0.0008) and RPMI-8226 models as well (P=0.0243).
Dr Lin said she and her colleagues did not see any side effects of treatment in any of the mice.
Investigating the mechanism
To determine if the antitumor effect of tasquinimod is, in fact, mediated through inhibition of S100A9, the researchers administered the drug to S100A9-knockout mice with MM. Tasquinimod did not improve survival in these mice, which suggests its anti-MM effects are mediated through S100A9 inhibition.
“To try and investigate some of the mechanisms of how survival is improved in tasquinimod-treated, tumor-bearing mice, we looked at a variety of different things, including angiogenesis,” Dr Lin said.
“We used CD31 immunohistochemistry to look at angiogenesis, and, in the untreated mice, we didn’t see a lot of staining. But in the tumor-bearing mice, there was a lot more staining [P=0.0231]. And when we gave the mice tasquinimod, angiogenesis was significantly decreased [P<0.0001].”
The researchers also looked at different angiogenic factors. And they found that, compared to control-treated mice with MM, tumor-bearing mice that received tasquinimod had a significant decrease in serum levels of VEGF, FGF2, tissue factor, and endoglin.
The team is now assessing the effects of S100A9 and tasquinimod on megakaryocytes and platelets, 2 of the major cell populations that promote angiogenesis. 
*Information in the abstract differs from that presented at the meeting.
PHILADELPHIA—A drug that has fallen short of expectations in clinical trials of prostate cancer may be effective for treating multiple myeloma (MM), according to research presented at the AACR Annual Meeting 2015.
The drug, tasquinimod, inhibits the function of S100A9, a pro-inflammatory protein that is elevated in MM, prostate cancer, and other malignancies.
Researchers found that tasquinimod can reduce tumor growth and improve survival in mouse models of MM. And these effects are associated with reduced angiogenesis in the bone marrow.
Cindy Lin, PhD, of the Wistar Institute in Philadelphia, Pennsylvania, and her colleagues presented these findings as abstract 1364.* The research was supported by Active Biotech and Ipsen, the companies developing tasquinimod.
Dr Lin noted that tasquinimod has already been tested in clinical trials of prostate cancer and initially appeared to be very effective. However, recent results from a phase 3 trial suggested the drug does not confer a favorable risk-benefit ratio for this population.
So Active Biotech and Ipsen decided to discontinue all trials of tasquinimod in prostate cancer. But the preclinical results observed in MM suggest tasquinimod may hold promise for treating these patients.
Activity in MM
Dr Lin said previous preclinical experiments revealed that myeloid-derived suppressor cells are involved in regulating MM progression, and these cells produce S100A9.
Tasquinimod is a quinoline-3-carboxamide derivative that binds to S100A9 and inhibits interaction with its receptors. So Dr Lin and her colleagues decided to investigate the antitumor effect of the drug in mouse models of MM.
The researchers initially tested tasquinimod in a syngeneic MM model, randomizing mice to treatment or control. Mice in the treatment group received tasquinimod at 30 mg/kg/day in their drinking water for 28 days.
Tasquinimod significantly improved survival in this model (P<0.005). All control mice died within 30 days of tumor inoculation, but about 40% of tasquinimod-treated mice were still alive more than 80 days out.
The researchers then tested tasquinimod in xenograft models of human MM. The drug significantly reduced tumor size in both H929 (P=0.0042) and RPMI-8226 models (P=0.0003). Treatment significantly improved survival in the H929 (P=0.0008) and RPMI-8226 models as well (P=0.0243).
Dr Lin said she and her colleagues did not see any side effects of treatment in any of the mice.
Investigating the mechanism
To determine if the antitumor effect of tasquinimod is, in fact, mediated through inhibition of S100A9, the researchers administered the drug to S100A9-knockout mice with MM. Tasquinimod did not improve survival in these mice, which suggests its anti-MM effects are mediated through S100A9 inhibition.
“To try and investigate some of the mechanisms of how survival is improved in tasquinimod-treated, tumor-bearing mice, we looked at a variety of different things, including angiogenesis,” Dr Lin said.
“We used CD31 immunohistochemistry to look at angiogenesis, and, in the untreated mice, we didn’t see a lot of staining. But in the tumor-bearing mice, there was a lot more staining [P=0.0231]. And when we gave the mice tasquinimod, angiogenesis was significantly decreased [P<0.0001].”
The researchers also looked at different angiogenic factors. And they found that, compared to control-treated mice with MM, tumor-bearing mice that received tasquinimod had a significant decrease in serum levels of VEGF, FGF2, tissue factor, and endoglin.
The team is now assessing the effects of S100A9 and tasquinimod on megakaryocytes and platelets, 2 of the major cell populations that promote angiogenesis.
*Information in the abstract differs from that presented at the meeting.
PHILADELPHIA—A drug that has fallen short of expectations in clinical trials of prostate cancer may be effective for treating multiple myeloma (MM), according to research presented at the AACR Annual Meeting 2015.
The drug, tasquinimod, inhibits the function of S100A9, a pro-inflammatory protein that is elevated in MM, prostate cancer, and other malignancies.
Researchers found that tasquinimod can reduce tumor growth and improve survival in mouse models of MM. And these effects are associated with reduced angiogenesis in the bone marrow.
Cindy Lin, PhD, of the Wistar Institute in Philadelphia, Pennsylvania, and her colleagues presented these findings as abstract 1364.* The research was supported by Active Biotech and Ipsen, the companies developing tasquinimod.
Dr Lin noted that tasquinimod has already been tested in clinical trials of prostate cancer and initially appeared to be very effective. However, recent results from a phase 3 trial suggested the drug does not confer a favorable risk-benefit ratio for this population.
So Active Biotech and Ipsen decided to discontinue all trials of tasquinimod in prostate cancer. But the preclinical results observed in MM suggest tasquinimod may hold promise for treating these patients.
Activity in MM
Dr Lin said previous preclinical experiments revealed that myeloid-derived suppressor cells are involved in regulating MM progression, and these cells produce S100A9.
Tasquinimod is a quinoline-3-carboxamide derivative that binds to S100A9 and inhibits interaction with its receptors. So Dr Lin and her colleagues decided to investigate the antitumor effect of the drug in mouse models of MM.
The researchers initially tested tasquinimod in a syngeneic MM model, randomizing mice to treatment or control. Mice in the treatment group received tasquinimod at 30 mg/kg/day in their drinking water for 28 days.
Tasquinimod significantly improved survival in this model (P<0.005). All control mice died within 30 days of tumor inoculation, but about 40% of tasquinimod-treated mice were still alive more than 80 days out.
The researchers then tested tasquinimod in xenograft models of human MM. The drug significantly reduced tumor size in both H929 (P=0.0042) and RPMI-8226 models (P=0.0003). Treatment significantly improved survival in the H929 (P=0.0008) and RPMI-8226 models as well (P=0.0243).
Dr Lin said she and her colleagues did not see any side effects of treatment in any of the mice.
Investigating the mechanism
To determine if the antitumor effect of tasquinimod is, in fact, mediated through inhibition of S100A9, the researchers administered the drug to S100A9-knockout mice with MM. Tasquinimod did not improve survival in these mice, which suggests its anti-MM effects are mediated through S100A9 inhibition.
“To try and investigate some of the mechanisms of how survival is improved in tasquinimod-treated, tumor-bearing mice, we looked at a variety of different things, including angiogenesis,” Dr Lin said.
“We used CD31 immunohistochemistry to look at angiogenesis, and, in the untreated mice, we didn’t see a lot of staining. But in the tumor-bearing mice, there was a lot more staining [P=0.0231]. And when we gave the mice tasquinimod, angiogenesis was significantly decreased [P<0.0001].”
The researchers also looked at different angiogenic factors. And they found that, compared to control-treated mice with MM, tumor-bearing mice that received tasquinimod had a significant decrease in serum levels of VEGF, FGF2, tissue factor, and endoglin.
The team is now assessing the effects of S100A9 and tasquinimod on megakaryocytes and platelets, 2 of the major cell populations that promote angiogenesis.
*Information in the abstract differs from that presented at the meeting.