Proapoptotic therapy of breast cancer and malignant melanoma.

All cells are equipped with a mechanism for suicide (apoptosis) that is activated if the cells acquire severe injuries. Cancer therapy strategies often try to stimulate the apoptotic pathway provoking a suicidal death of the cancer cells. One popular protein that triggers the apoptotic pathway is TRAIL (Tumor necrosis factor related apoptosis inducing ligand), a transmembrane protein that induces apoptosis in tumor cells of diverse origin, but does not affect most normal cells. The protein promotes apoptosis by binding to either of the two cell death receptors DR4 and DR5. In our studies, we initially delivered TRAIL using an adenovirus encoding the TRAIL gene, but we have recently chosen to use monoclonal agonistic antibodies to initiate the TRAIL-effect. The Abs are obtained through collaboration with Human Genome Sciences (Rockville, MD).

Many cancer cells do show resistance or reduced susceptibility to TRAIL-induced apoptosis. Although the mechanism involved in TRAIL resistance are not fully understood, various studies have shown that expression of decoy receptors, mutations in the death receptors, loss of caspase activity, increased levels of anti-apoptotic molecules such as FLIP, Bcl-2, Bcl-XL, Mcl-1 and IAPs (inhibitors of apoptosis proteins) all may be involved in resistance to TRAIL-mediated apoptosis. Many groups have shown that exposing tumor cells to other therapeutic modalities often improve their susceptibility to TRAIL. Thus, the therapeutical potential of TRAIL is primarily in combination with other treatment regiments. We aim to evaluate the effect of TRAIL therapy in combination with chemotherapy, HDACIs (histone deacetylase inhibitiors) and siRNAs targeting anti-apoptotic molecules. We study the potential of TRAIL as therapeutic agent in two types of solid tumors - breast cancer and malignant melanoma. Our initial studies are performed in cell lines and "close-to-patient" cell cultures. Subsequently, we plan to use in vivo animal models for investigating and optimizing the treatment efficacy. For more information contact Birgit Engesæter.

The overall aim of this project is to evaluate if cell lines, "close-to-patient" cell cultures and xenografts exposed to TRAIL show an enhanced apoptotic induction after co-treatment with chemotherapy, HDACI or siRNAs targeting anti-apoptotic molecules.