Dina Ben-Yehuda, MD, Department of Hematology, Hadassah University Hospital.
The death mechanism by which mammalian cells maintain homeostasis is apoptosis. Defects in the apoptotic pathway lead to expansion of cancer and affect the ability to respond to therapy. The Inhibitor of Apoptosis Proteins (IAPs) family has become increasingly prominent in the field of cancer and aberrant expression or function of IAPs have been implied to be involved in the pathogenesis and progression of human cancer. Livin is an IAP family member, which is expressed at high levels preferentially in melanoma. Livinspecific antisense oligonucleotides were developed for modulation of Livin expression and for treatment of diseases associated with aberrant expression of Livin.
Medical Need: The lack of a cancer cure results in the increasing number of drugs in development to treat cancer. Progress toward highly targeted drugs will increase significantly in the next years, as there are more drugs that apply new science and target difficult-to-treat forms of cancer.
There is a strong need that the new cancer treatments continue to improve, to become more targeted and less toxic medicines.
The drug industry for cancer is growing rapidly. No single cure has been found, but many new treatments have come to market. The potentially broad and lucrative market for these treatments has prompted large and small drug companies to target oncology. Worldwide cancer drug sales are expected to more than double over five years, from $24 billion in 2004 to $55 billion in 2009, according to IMS Health. The financial costs of cancer treatment are likely to increase at the individual level as new, more advanced, and more expensive treatments are adopted as standards of care. In the United States, cancer treatment accounted for an estimated $72.1 billion in 2004. Between 1995 and 2004, the overall costs of treating cancer increased by 75 percent.
In their studies, the inventors established IAPs as regulators of apoptosis. It was demonstrated that following apoptotic stimuli Livin is cleaved by the effector caspases to produce a truncated form with a paradoxical proapoptotic activity. The cleaved Livin does not only lose its anti-apoptotic effect, but even gains a pro-apoptotic effect thereby enabling apoptoticenhancing chemotherapy to effectively combat the tumor. The pro-apoptotic effect correlates with a decline in the full-length protein and the presence of the cleavage product. Using mutation-analysis domains crucial for the proapoptotic activity were identified. Surprisingly we found that cleaved Livin, contrary to Livin, has a pro-apoptotic activity.
The major effort is searching for drugs that will specifically trigger the apoptotic process in cancer cells. Research will explore the mechanism of Livin conversion from anti to a powerful pro-apoptotic protein and the genetic variations that stand behind the differences in Livin expression will be investigated.
- Creation of plasmids expressing the short Livin-derived peptides definition of regions essential for its pro-apoptotic activity.
- Gene therapy experiments for finding anti cancer activity in an animal model developed to elucidate the in vivo function of Livin and cleaved Livin in the regulation of apoptosis in malignancy, tumor development (initiation, growth, and metastasis) and response to anti-cancer therapy.
- Screening of low MW compounds that enhanced the cleavage of Livin.
- Understanding and model for mechanism of action.
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