Thema: Presse: Preclinical results at AACR for panzem and ENMD-1198
Presse: Preclinical results at AACR for panzem and ENMD-1198
Katja[a]
07.04.2006 14:31:50
Press Release Source: EntreMed, Inc.
EntreMed Presents Preclinical Results at AACR for Panzem(R) and ENMD-1198
Monday April 3, 2006
Results Support Combination Therapy with 2ME2 in Brain and Colon Cancer
EntreMed, Inc. today announced the presentation of preclinical results for its lead clinical-stage compound, Panzem® (2-methoxyestradiol or 2ME2), and tubulin binding agent, ENMD-1198. The results from these studies were presented at the 97th Annual Meeting of the American Association for Cancer Research being held this week in Washington, DC.
Preclinical studies demonstrate that 2ME2 can be combined with maximally tolerated doses (MTD) of standard chemotherapeutic agents without additive toxicity, resulting in greater antitumor activity than either agent alone. In one preclinical study, daily oral administration of 2ME2 in combination with a maximally tolerated course of temozolomide resulted in 87% growth inhibition of advanced glioblastoma (brain cancer). Treatment with either 2ME2 or TMZ alone was only marginally effective in slowing tumor growth.
In a separate preclinical study, 2ME2 was used in combination with a maximally tolerated course of 5-fluorouracil (5FU) in colon carcinoma. Daily oral administration of 2ME2 with 5FU resulted in 84% growth inhibition of established tumors, while treatment with either agent alone was only minimally effective in arresting tumor growth.
Taken together, these preclinical results suggest that incorporating 2ME2 into maximally tolerated courses of temozolomide or 5FU for cancer treatment may provide the ability to maximize the therapeutic potential of each agent. In addition, reduced doses of temozolomide or 5FU are not required when combined with 2ME2. These results support further evaluation of 2ME2 in combination therapy with approved standard-of-care cytotoxic agents.
In an additional AACR presentation, preclinical results were also presented for ENMD-1198, a novel tubulin binding agent. Oral administration of ENMD-1198 showed pronounced in vivo antitumor activity in three preclinical models of human cancer. Daily oral treatment with ENMD-1198 in an orthotopic MDA MB 231 breast cancer model led to the disruption of microtubules within tumor cells and a substantial decrease in HIF-1alpha, a tumor cell survival protein over-expressed in more than 70% of human tumors. HIF-1alpha over- expression correlates with tumor aggressiveness, metastases and poor prognosis. Activation of two additional transcription factors, NFkappaB and Stat3, known to modulate HIF-1alpha protein levels in vitro and promote tumorigenesis, were also reduced following daily oral ENMD-1198 treatment. All three transcription factors are known to regulate multiple genes and their proteins that contribute to tumor growth, angiogenesis and progression.
In a separate preclinical orthotopic breast cancer model, serum proteins regulated by HIF-1alpha, NFkappaB and Stat3, were also reduced substantially following oral administration of ENMD-1198. Results from several studies demonstrate that treatment with ENMD-1198 decreased plasma or serum levels of the human proangiogenic growth factor VEGF (secreted by tumor cells) substantially (40-100%). Serum levels of human IL-6, which is modulated by NFkappaB, were also decreased significantly (62-96%) following ENMD-1198 treatment. Over-expression of IL-6 is associated with higher morbidity in breast cancers, bone metastases, and increased cancer drug resistance.
Carolyn F. Sidor, M.D., EntreMed Vice President and Chief Medical Officer, commented on the presentations, "These studies continue to support the potential for 2ME2 in combination cancer therapy. We believe 2ME2´s safety profile provides multiple opportunities for combining it with conventional chemotherapies to increase the effectiveness of both anticancer drugs. EntreMed is currently evaluating Panzem® NCD in Phase 1 and 2 clinical oncology studies, as well as preclinical studies of 2ME2 in rheumatoid arthritis."
Dr. Sidor continued, "Preclinical results for ENMD-1198 continue to be impressive. ENMD-1198 is a novel molecule with potent antitumor and antiangiogenic properties. These data provide valuable information regarding the potential importance of HIF-1alpha inhibition in the treatment of human cancers. We have an active IND for this compound and anticipate commencing Phase 1 oncology studies during the second quarter of 2006."
EntreMed Presents Preclinical Results at AACR for Panzem(R) and ENMD-1198
Monday April 3, 2006
Results Support Combination Therapy with 2ME2 in Brain and Colon Cancer
EntreMed, Inc. today announced the presentation of preclinical results for its lead clinical-stage compound, Panzem® (2-methoxyestradiol or 2ME2), and tubulin binding agent, ENMD-1198. The results from these studies were presented at the 97th Annual Meeting of the American Association for Cancer Research being held this week in Washington, DC.
Preclinical studies demonstrate that 2ME2 can be combined with maximally tolerated doses (MTD) of standard chemotherapeutic agents without additive toxicity, resulting in greater antitumor activity than either agent alone. In one preclinical study, daily oral administration of 2ME2 in combination with a maximally tolerated course of temozolomide resulted in 87% growth inhibition of advanced glioblastoma (brain cancer). Treatment with either 2ME2 or TMZ alone was only marginally effective in slowing tumor growth.
In a separate preclinical study, 2ME2 was used in combination with a maximally tolerated course of 5-fluorouracil (5FU) in colon carcinoma. Daily oral administration of 2ME2 with 5FU resulted in 84% growth inhibition of established tumors, while treatment with either agent alone was only minimally effective in arresting tumor growth.
Taken together, these preclinical results suggest that incorporating 2ME2 into maximally tolerated courses of temozolomide or 5FU for cancer treatment may provide the ability to maximize the therapeutic potential of each agent. In addition, reduced doses of temozolomide or 5FU are not required when combined with 2ME2. These results support further evaluation of 2ME2 in combination therapy with approved standard-of-care cytotoxic agents.
In an additional AACR presentation, preclinical results were also presented for ENMD-1198, a novel tubulin binding agent. Oral administration of ENMD-1198 showed pronounced in vivo antitumor activity in three preclinical models of human cancer. Daily oral treatment with ENMD-1198 in an orthotopic MDA MB 231 breast cancer model led to the disruption of microtubules within tumor cells and a substantial decrease in HIF-1alpha, a tumor cell survival protein over-expressed in more than 70% of human tumors. HIF-1alpha over- expression correlates with tumor aggressiveness, metastases and poor prognosis. Activation of two additional transcription factors, NFkappaB and Stat3, known to modulate HIF-1alpha protein levels in vitro and promote tumorigenesis, were also reduced following daily oral ENMD-1198 treatment. All three transcription factors are known to regulate multiple genes and their proteins that contribute to tumor growth, angiogenesis and progression.
In a separate preclinical orthotopic breast cancer model, serum proteins regulated by HIF-1alpha, NFkappaB and Stat3, were also reduced substantially following oral administration of ENMD-1198. Results from several studies demonstrate that treatment with ENMD-1198 decreased plasma or serum levels of the human proangiogenic growth factor VEGF (secreted by tumor cells) substantially (40-100%). Serum levels of human IL-6, which is modulated by NFkappaB, were also decreased significantly (62-96%) following ENMD-1198 treatment. Over-expression of IL-6 is associated with higher morbidity in breast cancers, bone metastases, and increased cancer drug resistance.
Carolyn F. Sidor, M.D., EntreMed Vice President and Chief Medical Officer, commented on the presentations, "These studies continue to support the potential for 2ME2 in combination cancer therapy. We believe 2ME2´s safety profile provides multiple opportunities for combining it with conventional chemotherapies to increase the effectiveness of both anticancer drugs. EntreMed is currently evaluating Panzem® NCD in Phase 1 and 2 clinical oncology studies, as well as preclinical studies of 2ME2 in rheumatoid arthritis."
Dr. Sidor continued, "Preclinical results for ENMD-1198 continue to be impressive. ENMD-1198 is a novel molecule with potent antitumor and antiangiogenic properties. These data provide valuable information regarding the potential importance of HIF-1alpha inhibition in the treatment of human cancers. We have an active IND for this compound and anticipate commencing Phase 1 oncology studies during the second quarter of 2006."
Katja[a]
