Fremont, CA (February 28, 2005) – Quark Biotech, Inc. announced today that the Company has discovered the role of Ero-1L alpha gene in protein secretion under hypoxic conditions. This suggests that inhibition of Ero-1L alpha may have therapeutic applications in cancer and other pathologies involving hypoxia, a condition of reduced oxygen supply to tissues. Ero-1L alpha was originally discovered as part of Quark’s pipeline development program to identify genes induced by hypoxia. The present discovery was published in a paper titled “Ero-1L alpha plays a key role in a HIF-1-mediated pathway to improve disulphide bond formation and VEGF secretion under hypoxia: implication for cancer” in Oncogene 2005 Feb 3; 24(6): 1011-20. The work was performed in research collaboration led by Professor Eli Keshet of the Hebrew University, Jerusalem, Israel.
Dr. Daniel Zurr, Chief Executive Officer of Quark Biotech, Inc. said, “Our program to discover hypoxia-responsive genes has yielded exciting results to date. Discoveries as part of this program include: the potential of Ero-1L alpha as an antiangiogenic/anticancer target, deciphering a unique enzymatic role of Hi95 (sestrin 2) in establishing cellular antioxidant firewall, and the role of another target, RTP801 in diseases associated with hypoxia-dependent apoptosis and blood vessel pathology. Our recent research on RTP801 has already led to the development of a product candidate for the potential treatment of diabetic retinopathy and other diseases of the eye, lung, heart and kidney. We look forward to our research on Ero-1L alpha yielding similar results.” A patent application of Quark is pending on the Ero-1L alpha gene, polypeptide and antibody.
Oxygen is an essential factor for viability and normal function of living organisms, and its level is closely monitored by intracellular mechanisms. As an adaptive response, under hypoxic conditions, oxygen-sensing machinery activates a transcription factor known as hypoxia-inducible factor 1 (HIF-1). This factor switches on a series of genes participating in compensatory mechanisms that support cell survival in a potentially lethal microenvironment. In this study, it was found that a HIF-1 target, Ero-1L alpha, is an oxidoreductase involved in formation of disulphide bonds and in proper folding and secretion of proteins such as VEGF, a growth factor involved in promoting blood vessel formation (angiogenesis) in tumors. Under hypoxic or hypoglycemic (low glucose) conditions in vitro, expression of Ero-1L alpha is induced in a HIF-1-dependent manner. Ero-1L alpha is also overexpressed in human malignant tumors in vivo. Most importantly, two- to three-fold reduction of Ero-1L alpha levels, using siRNA technology, resulted in significant inhibition of VEGF secretion, compromised proliferation capacity and enhanced programmed cell death (apoptosis) of tumor cells. Cancer cells are known to secrete a variety of proteins that are important for their growth and invasion, including growth and angiogenic (e.g. VEGF) factors, chemokines, extracellular matrix proteins, metalloproteinases etc. On the other hand, cancer cells are also generally known to exist in hypoxic conditions and have to adapt to them. Thus, hypoxic induction of Ero-1L alpha is the key adaptive response in a previously unrecognized HIF-1-mediated pathway that operates to improve protein secretion under hypoxia. These findings suggest that Ero-1L alpha has the potential to be a promising new target for cancer therapy. In addition to cancer, inhibition of Ero-1L alpha may be a useful therapeutic approach for reduction of pathological growth of blood vessels occurring in other, non-malignant, pathological conditions associated with the lack of oxygen supply.
About Quark Biotech, Inc.
Quark Biotech, Inc. is a privately held development-stage, biopharmaceutical company headquartered in Fremont, CA. Through innovative combination of gene silencing and DNA microarray technology, Quark has pioneered and patented its BiFARTM platform for high-throughput functional profiling, allowing significant advances in the identification of target genes and proteins. This technology allows the company to develop conceptually novel drugs that provide previously unavailable benefits to patients. Quark is currently harvesting novel targets identified using this enabling foundation technology. Quark has focused development efforts on treatment of fibrotic and ischemic diseases of the eye, kidney and lungs, in indications with clear unmet medical needs.
Quark corporate product development teams and research facilities are based in Fremont, CA with research facilities also in Ness-Ziona, Israel. Additional information is available at www.quarkbiotech.com.