• 10/29/2007
  • Edmonton, Alberta, Canada
  • press release
  • CNNMoney.com

Biomira Inc. announced today that preclinical data for its targeted anti-cancer drug candidates PX-478 and PX-866 were presented in a poster session yesterday at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, which is being held October 22-26 in San Francisco. The data may help to guide future clinical studies of these innovative small molecule compounds. A Phase 1 trial of PX-478 in patients with advanced metastatic cancers is in progress. Biomira expects to file an Investigational New Drug application for PX-866 early in 2008.

The PX-478 data (Abstract #284) provide insight into how and under what conditions the compound inhibits the activity of its target, the transcription factor hypoxia-inducible factor-1alpha (HIF-1 alpha). PX-478 works by a unique mechanism, decreasing both HIF-1 alpha gene expression and protein synthesis. This leads to a significant reduction in the amount and activity of HIF-1 alpha in the tumor. The results show that PX-478 is highly specific for HIF-1 alpha and does not inhibit the levels of any of the other proteins tested. Additionally, this inhibitory effect is independent of the tumor suppressor genes VHL and p53, genes that may significantly impact how cancer cells respond to a variety of therapeutic interventions.

“Hypoxia is a feature of many solid tumors and HIF-1 alpha is the tumor’s primary survival response to this stress,” said Dr. Garth Powis, Director, Center for Targeted Therapy, MD Anderson Cancer Center, Houston, Texas, and senior author of the abstract. “Inhibiting both transcription and translation is a double hit that dramatically decreases the activity of HIF-1 alpha, which regulates numerous pro-cancer pathways. That this reduction in HIF-1a activity occurs in cells regardless of oxygenation, p53 and VHL status suggests that PX-478 may have clinical activity in diverse cancers. The elucidation of the mechanisms by which PX-478 inhibits HIF-1 alpha confirms the compound’s specificity and may aid the direction of the clinical program with respect to identifying specific cancer indications and potential combination regimens for this promising agent.”

A second poster reported data from preclinical studies of PX-866, a small molecule inhibitor of phosphatidylinositol-3-kinase (PI-3 kinase) (Abstract #257). These studies evaluated mutations in several cancer-related genes that could be predictive of response to PX-866 in animal tumor models. In a range of different tumor types, response to PX-866 correlated with wildtype Ras, while mutations in Ras were associated with PX-866 resistance. These results suggest that selecting for patient Ras status could improve the clinical benefit of PX-866.

Dr. Powis noted, “Biomarkers that are predictive of response to particular therapies are playing an increasingly significant role in optimizing cancer treatment for individual patients. The PX-866 biomarker data suggest that it may be possible to identify those patients most likely to respond to the agent. These data also provide insight into how we could combine PX-866 with other agents based on the molecular profiles of specific cancers. Together, this knowledge may help to speed the clinical development of this promising new PI-3 kinase inhibitor”

Both posters will be available later today on the Biomira website, www.biomira.com.

About PX-478

PX-478 is a potent inhibitor of HIF-1 alpha, a protein target whose levels are elevated in a wide range of tumors. The protein is a key factor in the response of a cancer cell to hypoxia (lack of oxygen), including the angiogenic cascade that allows tumors to establish new blood vessels essential to their survival and growth. Inhibition of angiogenesis is a validated approach to treating cancer.

In preclinical studies, PX-478 demonstrated marked antitumor activity when delivered orally, showing tumor regression and long growth delay, both of which correlated to the HIF-1 alpha levels of the tumor models. The wide variety of models that showed sensitivity to PX-478 presents a large potential market for this product candidate. The ability to combine PX-478 with radiation therapy may further expand the opportunities for this novel compound.

About PX-866

PX-866 is an irreversible inhibitor of the phosphatidylinositol-3-kinase (PI3 kinase)/PTEN/AKT pathway, an important survival signaling pathway that is activated in many types of human cancer especially ovarian, colon, head and neck, urinary tract, and cervical cancers, where it leads to increased proliferation, inhibition of apoptosis (programmed cell death) and resistance to antitumor therapy. In preclinical studies, PX-866 has been shown to induce prolonged inhibition of tumor PI3 kinase signaling following both oral and intravenous administration. The compound also has been shown to have good in vivo anti-tumor activity in tumor models of human colon, pancreatic, breast, ovarian, prostate and lung cancer, as well as intracranial glioblastoma.