Treatment of high-risk pediatric brain tumors with a CD133-targeted adenovirus in combination with temozolomide

Background
Brain tumors are the most frequent solid tumor in pediatric patients and are the leading cause of cancer-death in children under 15 years. Moreover, most of the patients that are cured suffer from long-term side effects of the aggressive treatment, in some instances impairing them to live a normal live. Thus, it is clear that new therapeutic strategies are required that allow not only for more effective treatments of these tumors but also that defer the severe side effects derived from the current therapeutic choices that make them unacceptable options especially in the very young ones.

One of the main problems of brain tumors is that they invariably recur after treatment. For that reason identification and elimination of the causes of the recurrence is one of the main objectives of cancer research.

Recently, a new population of cells, term cancer stem cells, has been found responsible for the initiation of adult and pediatric brain tumors and may constitute the cause of resistance of these tumors to chemotherapy and radiotherapy and therefore responsible for the lethal recurrence after surgery. This population of cells is characterized by the expression in the cell surface of a protein called CD133.

Project Goal
In this proposal we aim to build a "smart" adenovirus (Delta-24-CSI) that is able to recognize the CD133 marker, infect these cells and subsequently kill them. In addition this adenovirus is built in such a way that even if infect normal cells is not capable to kill them. In addition, because the percentage of cancer stem cells would vary along the different pediatric brain tumors ranging from 90% in medulloblastomas to less than 50% in malignant gliomas we propose to combine Delta-24-CSI with temozolomide, which is the golden standard for malignant gliomas. This combination treatment will help to achieve a higher effect against these tumors and to minimize opportunities for resistant cancer cells to emerge. Importantly, Delta-24-CSI in combination with chemotherapy would avoid the use of radiotherapy and thus improving the overall quality of life for these children. We propose a new biological therapeutic tool that has the potential to drastically improve the prognosis of the children with brain tumors without resulting in unacceptable toxicity.

Additional PI Dr. Juan Feuyo