Pharmacotherapy
Role of 2-methoxyestradiol in Treating Various Types of Cancer
By EntreMed, Inc.
Apr 21, 2005, 14:09

EntreMed, Inc. today announced the results of multiple in vitro and in vivo preclinical studies confirming the mechanisms-of-action for 2-methoxyestradiol (2ME2 or Panzem(R)) in treating various types of cancer. The results from these studies, conducted by EntreMed researchers and their collaborators, were presented at the 96th Annual Meeting of the American Association for Cancer Research being held this week in Anaheim, California.

The antiproliferative and antiangiogenic activity of 2ME2 has been demonstrated previously in multiple preclinical models and in early clinical studies. Data from these studies have shown that 2ME2 disrupts interphase microtubules, down-regulates HIF-1alpha, inhibits de novo synthesis of HIF- 1alpha, and induces apoptosis.

New data presented at the AACR Annual Meeting further demonstrated that 2ME2 inhibits HIF-1alpha translation by preventing localization of HIF-1alpha mRNA complexes with depolymerized microtubules.

Results from a second study showed that 2ME2-treated cancer cells depolymerized microtubules in a dose- dependent manner, while 2ME2 resistant cells with acquired tubulin mutations were unaffected.

Taken together, these studies show a close correlation between the antitubulin properties of 2ME2 and its antiproliferative effects. Furthermore, 2ME2 resistance is the result of tubulin mutations, rather than multi-drug-resistance (MDR) mechanisms.

Paraskevi Giannakakou, Ph.D., Assistant Professor of Hematology, Oncology and Pharmacology, Winship Cancer Center, Emory University School of Medicine and author on both studies commented, "Recent mechanistic studies from our laboratory have shown that 2ME2 depolymerizes microtubules resulting in potent inhibition of the transcription factor HIF-1alpha. We have also developed a 2ME2-resistant ovarian carcinoma model with an acquired tubulin mutation, which blocks 2ME2's ability to bind to tubulin and down-regulate HIF-1alpha. Since acquired drug resistance poses a major obstacle for the successful treatment of cancer patients, the 2ME2 resistance model will help facilitate future 2ME2 clinical trials and guide the discovery of new 2ME2 analogs with activity against drug-resistant cancer cells."

Results from a separate preclinical study demonstrated that 2ME2 induced apoptosis in human pancreatic and gastric cancer cells that were either chemosensitive or resistant (MDR) to conventional chemotherapeutics. MDR- negative cells were up to 10-fold more resistant than chemosensitive pancreatic and gastric cells, while MDR-positive cells were up to 1000-fold more resistant to cytotoxic drugs such as paclitaxel and cisplatin. In all cases, pancreatic and gastric cells were highly sensitive to 2ME2 and showed strong growth inhibition.

In addition, the number of apoptotic chemoresistant cells increased by 3-8 fold over chemosensitive pancreatic and gastric cancer cells. These findings support the potential use of 2ME2 even when chemoresistance occurs or as rescue therapy following resistance to chemotherapeutic agents.

In a separate preclinical colon cancer study, EntreMed collaborators demonstrated that the combination of 2ME2 and capecitabine (Xeloda) plus radiation therapy was highly effective in delaying colon tumor growth compared to capecitabine alone or in combination with radiation.

EntreMed scientists also reported on results of preclinical studies to determine the effect of schedule, route of administration and dose on the antitumor activity of Panzem(R) NCD in an orthotopic lung cancer model. Inhibition of pulmonary metastases was equivalent for several routes of administration; enhanced inhibition of tumor growth was observed with continuous vs. daily dosing; therapeutic response was similar with a fixed daily dose vs. a dose-intensification regimen; and antitumor activity improved with an increase in frequency from daily to four times daily administration.

The results of these studies indicate that the schedule of Panzem(R) NCD administration is a key determinant of antitumor activity.

Carolyn F. Sidor, M.D., EntreMed Vice President and Chief Medical Officer, commented on the presentations, "These studies provide further evidence of 2ME2's antiproliferative and antiangiogenic mechanisms of action. 2ME2 is a potent inhibitor of HIF-1alpha, and its down-regulation is closely associated with 2ME2's tubulin inhibitor properties.HIF-1alpha is over-expressed in more than 70% of human tumors and HIF-1alpha over-expression correlates with tumor aggressiveness, metastases and poor prognosis. In addition, HIF-1alpha is an upstream regulator of VEGF, and may affect a different or broader range of tumors than current VEGF inhibitors."

Dr. Sidor further commented, "We believe that 2ME2 has the potential to be a unique cancer therapy and may be particularly well-suited to attack tumors that are dependent on the proangiogenic activity of HIF-1alpha and VEGF for survival. Furthermore, 2ME2's safety profile and lack of MDR chemoresistance provide opportunities for combining it with conventional chemotherapies to increase their effectiveness while decreasing toxicity. EntreMed is currently evaluating 2ME2 formulations (Panzem(R) Capsules and Panzem(R) NCD) in Phase I and II clinical oncology studies, as well as preclinical studies of 2ME2 in inflammatory diseases such as RA."

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