Evaluation of the Mechanism of Interaction between Temozolomide and TNFa in the Induction of Apoptosis
2005 Seed Grant
Bakhtiar Yamini, M.D.
The University of Chicago
Temozolomide is a standard chemotherapeutic agent used in conjunction with radiation therapy in the treatment of malignant brain tumors. Our work centers on a novel treatment of these tumors whereby Temozolomide is used to activate a known anticancer agent- tumor necrosis factor alpha (TNF)- that is injected directly into the tumor mass. In this combination strategy the Temozolomide and TNF work together to synergistically cause tumor cell killing. Although Temozolomide has been extensively studied for many years, our investigations demonstrate that this agent is working by a previously unreported mechanism to facilitate the killing of tumor cells by TNF. The experiments proposed in this project will specifically determine whether Temozolomide is blocking a known survival pathway in tumor cells thus allowing the TNF to kill them.
Malignant gliomas are the most common primary brain tumor in the United States and afflict patients in the prime of their lives. Standard treatment still centers on radiation and chemotherapy even though patient survival has not significantly changed in over 30 years. Newer treatment modalities such as gene therapy have had some success but have failed to uncover a ‘magic bullet’ . It is likely that a rationally devised, multimodal treatment approach will be necessary in this aggressive cancer. In this regard, we have been studying a radiation and chemotherapy activated gene therapy strategy in an animal model. This project will investigate the mechanisms underlying the success seen in our animal experiments and, if successful, may well open up an important area of combination anti-tumor therapy for use in patients suffering from this devastating disease.