Targeting anti-apoptotic Bcl-2 family members in lung cancer
Initial Award Abstract
According to the National Cancer Institute, lung cancer is the leading cancer-related cause of death in both men and women in the United States, accounting for approximately one third of all cancer-related deaths. Despite efforts in prevention and research, it is estimated that $9.6 billion is spent country-wise each year on treatment, and the survival rate is of only 15% after 5 years. Part of the problem is related to the absence of well-established methods for diagnostics, and thus most cases of lung cancer are diagnosed in advanced stages. Additionally, most lung cancers exhibit minimal sensitivity to or rapidly acquire resistance to radio- and chemotherapy. Therefore, the development of more efficient therapies is necessary.
In this proposal, we aim to study two anti-death proteins, Bcl-B and Bfl-1, which are frequently over-produced in lung cancers, as well as some other types of cancers frequently associated with tobacco abuse. The Bcl-B and Bfl-1 proteins are involved in the body’s natural mechanism for controlling cell death, also known as apoptosis. Under normal conditions, these proteins protect the cells against stress but lung cancer cells subverted this function by producing large amounts of these proteins in order to survive as their behavior becomes progressively deranged from accumulation of genetic mutations caused by carcinogens in tobacco. Several lines of investigation have shown that these anti-death proteins are also causatively involved in radio- and chemoresistance and that new drugs capable of targeting Bcl-B and Bfl-1 have the potential to sensitize tumors to death in combination with lower doses of current drugs, thus promising of improved anti-tumor efficacy with fewer side effects.
To develop new chemical inhibitors that neutralize Bcl-B and Bfl-1, we propose to solve the three-dimensional structures of these proteins by either X-ray crystallography or Nuclear Magnetic Resonance methods. These methods have the potential to uncover details about these protein molecules, allowing for the design of new drugs to inactivate them and promote killing of cancer cells. The project I propose involves a multi-disciplinary collaboration, with involvement of experts in structural biology, tumor cell biology, protein biochemistry, and chemistry, towards a collective goal of generating more effective therapies that restore tumor sensitivity to natural mechanisms for cell eradication and that therefore provide new ways to combat lung cancer and other cancers associated with tobacco use. |