Wednesday March 15, 2010, 10:45 am IST

Research reveals direct connection between H19 and p53 - the main protein involved in tumor suppression

New scientific research reveals a direct connection between H19 gene that accelerates human tumor development and p53 - the main protein involved in the suppression of cancerous tumors. The research findings clarify the mechanism of action of the H19 gene and its results may have a major impact on the potential use in cancer therapy of BC-819, a drug candidate being developed by the scientists of the biomed company BioCancell. The results of this research were recently published in the prestigious scientific journal Molecular Cell Research.

The breakthrough research, headed by Professor Abraham Hochberg from the Hebrew University, Jerusalem, Israel, clarifies for the first time the mechanism of activation of the H19 gene in cancer tissue, supporting the scientific assumptions on which the technology of BioCancell are based. According to Professor Hochberg, “this is an additional proof that the H19 gene plays a primary role in the development of cancer”.

The H19 gene that was discovered in human cancers by Professor Hochberg, the founder of BioCancell, is one of the most important genes for the development of cancer in humans. Whereas H19 is expressed at substantial levels in the fetus during pregnancy, it is repressed after birth and expressed again when cancerous cells begin to develop. The gene accelerates the development of cancerous cells in the body, and according to Professor Hochberg’s research, is expressed in significant amounts in the cells of more than 40 cancer types, while remaining nearly undetectable in healthy tissues. The H19 gene enables cancerous cells to survive in the typical cancer environment of low serum and oxygen (hypoxia) conditions, thus enabling tumors to acquire new blood vessels and form metastases.

p53 is a protein known as the "genome guardian", playing a central role in determining cell fate, and is one of the most researched cancer-related proteins. p53 is a tumor-suppressing protein that either dictates cell death by apoptosis or prevents cell proliferation, in response to DNA damage and other stimuli, including hypoxia. The protein is a transcription factor that acts by controlling the activity of other genes involved in the cell cycle. In a normal cell, p53 is found in cytoplasm in an inactive state, but is activated under stress (a characteristic state for cancerous cells) and enters the cell nucleus, where it performs its anti-cancer activity. Although the protein is often present in large amounts, it is in a mutant form.

The research reveals that a stress condition characterized by hypoxia, a condition characteristic of nearly all types of solid tumors, triggers a significant enhancement of H19 gene expression. A team led by Dr. Imad Matouk from Professor Hochberg’s laboratory, demonstrated a direct connection between H19 and p53, proving that functional p53 has a repressing effect on H19 activation under hypoxic conditions, while in cancerous cells harboring different p53 mutations H19 RNA is greatly enhanced to support stressed cancer cell survival and possibly enabling tumors to acquire new blood vessels. The researchers demonstrated that in animals, cells with normal p53 activity showed no increase in the level of H19, while in cells with no p53 activity, the enhancement of the expression of H19 was very significant.

BC-819 acts by penetration into cells in the cancerous tumor and drives the expression of Diphtheria Toxin in cancerous cells that express the H19 gene. The use of the triggering mechanism of H19 ensures the selective destruction of the tumor cells without affecting normal cells.

Due to the central role of the p53 protein in cancer, many pharmaceutical companies are attempting to develop drugs that target p53 and restore it to its normal function.

The latest findings clarify the mechanism of action of H19 RNA activation and support the assumptions regarding the efficiency of the BC-819 drug against cancerous cells. The research results show that BC-819 is also efficient in targeting the cancerous cells in which p53 activities are either lost or harbor mutant forms that trigger tumorigenesis.

In addition, during clinical trials, the selective destruction of the cancerous cells caused no significant adverse events related to the use of BC-819. Thus, the drug selectively affects cancerous cells containing the mutant p53 protein that triggers the cancerous process, with no adverse effects.

Since the H19 gene is expressed in most of the cancer types, BC-819 is likely to be used on a wide scale, and may offer a unique drug for the therapy of all the cancer types that express the H19 gene.

BioCancell is a biopharmaceuticals company that specializes in the development of Patient-Oriented therapies for the treatment of numerous types of cancer. The company’s technology offers a safe and long-term treatment of cancer, with no adverse effects. The company was founded in 2004 by Professor Abraham Hochberg, Professor of Molecular Biology at the Hebrew University of Jerusalem, based on a technology developed by him during the last 15 years.

The drug candidates developed by the company are Patient-Oriented and their goal is to selectively destroy the cancer cells without affecting healthy cells (Personalized Targeted Therapy). The approach is based on the identification of target genes, such as H19, that are expressed only in cancerous tumors, and not in healthy cells, and on the use of those genes for the activation of a toxin inside the cancerous cells only, thus destroying them without harming healthy cells. This is how the H19 gene synthesizes Diphtheria Toxin for the targeted destruction of cancerous cells. BioCancell’s leading drug candidate, BC-819, is now in a Phase IIb clinical trial for the treatment of bladder carcinoma, and in Phase I/IIa trials for the treatment of pancreatic and ovarian cancer.

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About BioCancell Therapeutics

BioCancell Therapeutics Inc. is a biotechnology company specializing in the development of Patient-Oriented, Targeted Therapy for the treatment of a wide range of cancers. It is a plasmid-based therapy using the promoter of a cancer-specific expressed gene coupled with a toxin. As an efficacious, highly selective treatment that has shown no side effects - it has the potential to be the magic bullet for which the medical industry is searching.

This press release contains "forward-looking" statements, including statements with respect to the further development and potential safety and efficacy of BC-819, in the treatment of superficial bladder cancer and BioCancell's development strategy. Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. There are a number of important factors that could cause the results of BioCancell to differ materially from those indicated by these forward-looking statements, including, among others, the risk that the U.S. Food and Drug Administration may require changes to the protocols and informed consents for clinical trials of BC-819, which changes may have a material adverse effect on the timing of, and BioCancell's ability to conduct, those clinical trials, risks related to the clinical advancement of its BC-819 plasmid, including, but not limited, to the risk that clinical trials for this product candidate may not demonstrate safety and efficacy sufficient to obtain the requisite regulatory approvals or to result in a marketable product and risks related to the potential for others to develop products containing or based on BC-819. BioCancell does not undertake any obligation to update forward-looking statements.