Study helps explain how drug fights DLBCL

PHILADELPHIA—The tumor microenvironment may play a key role in treatment with CUDC-427, according to researchers.

Their experiments showed that certain diffuse large B-cell lymphoma (DLBCL) cell lines were sensitive to CUDC-427, and others were not.

However, co-culturing with stromal cells or TNF family ligands made resistant cell lines sensitive to CUDC-427.

And mice bearing cells that resisted CUDC-427 in vitro responded very well to treatment, experiencing complete tumor regression.

Ze Tian, PhD, and her colleagues from Curis, Inc. (the company developing CUDC-427) presented these findings at the AACR Annual Meeting 2015 (abstract 5502).

CUDC-427 is an inhibitor of apoptosis (IAP) antagonist that is in early stage clinical testing in patients with solid tumors and lymphomas.

For the current research, Dr Tian and her colleagues first evaluated the effects of CUDC-427 against a range of hematologic malignancies in vitro. They tested the drug in activated B-cell-like (ABC) DLBCL, germinal center B-cell-like (GCB) DLBCL, other non-Hodgkin lymphomas, Hodgkin lymphoma, multiple myeloma, and various leukemia cell lines.

DLBCL cells (both ABC and GCB) proved the most sensitive to treatment, and CUDC-427 induced apoptosis in these cells. However, certain DLBCL cell lines, such as Karpas 422, were not sensitive to treatment.

The researchers found they could remedy that in two ways. The presence of stromal cells in culture sensitized resistant DLBCL cells to treatment, as did TNF family ligands (TNFα or TRAIL). In previous research, TNF family ligands were shown to synergize with IAP antagonists.

The investigators then analyzed CUDC-427’s mechanism of action. In the sensitive WSU-DLCL2 cell line, the drug worked by activating caspases 3, 8, and 9 by inhibiting cIAP1 and XIAP, as well as activating the non-canonical NF-ĸB pathway and inducing TNFα.

In the resistant Karpas 422 cell line, there was no caspase activity following CUDC-427 treatment. However, when the researchers co-cultured the cell line with stromal cells, they saw caspase activity.

“Because of this finding, we think that the microenvironment may play a role in CUDC-427 treatment,” Dr Tian said.

So the investigators went on to test CUDC-427 in mouse models. The drug inhibited tumor growth by 94% in the WSU-DLCL2 xenograft model. But CUDC-427 induced complete tumor regression in the Karpas 422 xenograft model.

To further investigate the interaction between the tumor microenvironment and CUDC-427, the researchers tested the drug in the A20 B-cell lymphoma mouse syngeneic model.

They found that CUDC-427 induced tumor stasis in this fast-growing lymphoma. They believe this may be due, in part, to the high levels of TRAIL in this model.

Dr Tian and her colleagues said the interaction between CUDC-427 and TNF family ligands or stromal cells warrants further analysis. And this research supports additional investigation to improve outcomes in patients with DLBCL.

PHILADELPHIA—The tumor microenvironment may play a key role in treatment with CUDC-427, according to researchers.

Their experiments showed that certain diffuse large B-cell lymphoma (DLBCL) cell lines were sensitive to CUDC-427, and others were not.

However, co-culturing with stromal cells or TNF family ligands made resistant cell lines sensitive to CUDC-427.

And mice bearing cells that resisted CUDC-427 in vitro responded very well to treatment, experiencing complete tumor regression.

Ze Tian, PhD, and her colleagues from Curis, Inc. (the company developing CUDC-427) presented these findings at the AACR Annual Meeting 2015 (abstract 5502).

CUDC-427 is an inhibitor of apoptosis (IAP) antagonist that is in early stage clinical testing in patients with solid tumors and lymphomas.

For the current research, Dr Tian and her colleagues first evaluated the effects of CUDC-427 against a range of hematologic malignancies in vitro. They tested the drug in activated B-cell-like (ABC) DLBCL, germinal center B-cell-like (GCB) DLBCL, other non-Hodgkin lymphomas, Hodgkin lymphoma, multiple myeloma, and various leukemia cell lines.

DLBCL cells (both ABC and GCB) proved the most sensitive to treatment, and CUDC-427 induced apoptosis in these cells. However, certain DLBCL cell lines, such as Karpas 422, were not sensitive to treatment.

The researchers found they could remedy that in two ways. The presence of stromal cells in culture sensitized resistant DLBCL cells to treatment, as did TNF family ligands (TNFα or TRAIL). In previous research, TNF family ligands were shown to synergize with IAP antagonists.

The investigators then analyzed CUDC-427’s mechanism of action. In the sensitive WSU-DLCL2 cell line, the drug worked by activating caspases 3, 8, and 9 by inhibiting cIAP1 and XIAP, as well as activating the non-canonical NF-ĸB pathway and inducing TNFα.

In the resistant Karpas 422 cell line, there was no caspase activity following CUDC-427 treatment. However, when the researchers co-cultured the cell line with stromal cells, they saw caspase activity.

“Because of this finding, we think that the microenvironment may play a role in CUDC-427 treatment,” Dr Tian said.

So the investigators went on to test CUDC-427 in mouse models. The drug inhibited tumor growth by 94% in the WSU-DLCL2 xenograft model. But CUDC-427 induced complete tumor regression in the Karpas 422 xenograft model.

To further investigate the interaction between the tumor microenvironment and CUDC-427, the researchers tested the drug in the A20 B-cell lymphoma mouse syngeneic model.

They found that CUDC-427 induced tumor stasis in this fast-growing lymphoma. They believe this may be due, in part, to the high levels of TRAIL in this model.

Dr Tian and her colleagues said the interaction between CUDC-427 and TNF family ligands or stromal cells warrants further analysis. And this research supports additional investigation to improve outcomes in patients with DLBCL.

PHILADELPHIA—The tumor microenvironment may play a key role in treatment with CUDC-427, according to researchers.

Their experiments showed that certain diffuse large B-cell lymphoma (DLBCL) cell lines were sensitive to CUDC-427, and others were not.

However, co-culturing with stromal cells or TNF family ligands made resistant cell lines sensitive to CUDC-427.

And mice bearing cells that resisted CUDC-427 in vitro responded very well to treatment, experiencing complete tumor regression.

Ze Tian, PhD, and her colleagues from Curis, Inc. (the company developing CUDC-427) presented these findings at the AACR Annual Meeting 2015 (abstract 5502).

CUDC-427 is an inhibitor of apoptosis (IAP) antagonist that is in early stage clinical testing in patients with solid tumors and lymphomas.

For the current research, Dr Tian and her colleagues first evaluated the effects of CUDC-427 against a range of hematologic malignancies in vitro. They tested the drug in activated B-cell-like (ABC) DLBCL, germinal center B-cell-like (GCB) DLBCL, other non-Hodgkin lymphomas, Hodgkin lymphoma, multiple myeloma, and various leukemia cell lines.

DLBCL cells (both ABC and GCB) proved the most sensitive to treatment, and CUDC-427 induced apoptosis in these cells. However, certain DLBCL cell lines, such as Karpas 422, were not sensitive to treatment.

The researchers found they could remedy that in two ways. The presence of stromal cells in culture sensitized resistant DLBCL cells to treatment, as did TNF family ligands (TNFα or TRAIL). In previous research, TNF family ligands were shown to synergize with IAP antagonists.

The investigators then analyzed CUDC-427’s mechanism of action. In the sensitive WSU-DLCL2 cell line, the drug worked by activating caspases 3, 8, and 9 by inhibiting cIAP1 and XIAP, as well as activating the non-canonical NF-ĸB pathway and inducing TNFα.

In the resistant Karpas 422 cell line, there was no caspase activity following CUDC-427 treatment. However, when the researchers co-cultured the cell line with stromal cells, they saw caspase activity.

“Because of this finding, we think that the microenvironment may play a role in CUDC-427 treatment,” Dr Tian said.

So the investigators went on to test CUDC-427 in mouse models. The drug inhibited tumor growth by 94% in the WSU-DLCL2 xenograft model. But CUDC-427 induced complete tumor regression in the Karpas 422 xenograft model.

To further investigate the interaction between the tumor microenvironment and CUDC-427, the researchers tested the drug in the A20 B-cell lymphoma mouse syngeneic model.

They found that CUDC-427 induced tumor stasis in this fast-growing lymphoma. They believe this may be due, in part, to the high levels of TRAIL in this model.

Dr Tian and her colleagues said the interaction between CUDC-427 and TNF family ligands or stromal cells warrants further analysis. And this research supports additional investigation to improve outcomes in patients with DLBCL.