Research

Glioblastoma radioresistance

Glioblastoma Image 1

Glioblastomas (GBM) are lethal brain tumors that are highly resistant to radio and chemotherapy. We are systematically examining the contributions of key GBM-specific genetic alterations to therapy resistance using state-of-the-art transgenic mouse models.

We are particularly interested in two key events driving gliomagenesis – amplification of EGFRvIII and loss of PTEN. Research from our (and other) labs has helped formulate an important concept in radiation oncology, i.e., key genetic changes occurring during carcinogenesis impact DNA repair pathways in specific ways.

Thus, GBMs (or other cancers) may be stratified for therapy with specific DNA repair inhibitors based upon the status of DNA repair pathways in these tumors and we are currently developing several such approaches to improve GBM therapy.

Top left, subcutaneous tumors generated in nude mice exhibit significant attrition when treated with a combination of ionizing radiation (IR) and a dual PI3K/mTOR inhibitor (BEZ). Above left, tumor growth profiles of mice treated with IR and/or BEZ. Top right, administration of BEZ to mice with intra-cranial tumors attenuates repair of IR-induced DNA double-strand breaks, visualized as 53BP1 foci (green). Above right, combination treatment with IR+BEZ attenuates growth of intra-cranial tumors, monitored by bioluminescence imaging.
(Top left) Subcutaneous tumors generated in nude mice exhibit significant attrition when treated with a combination of ionizing radiation (IR) and a dual PI3K/mTOR inhibitor (BEZ). (Above left) Tumor growth profiles of mice treated with IR and/or BEZ. (Top right) Administration of BEZ to mice with intra-cranial tumors attenuates repair of IR-induced DNA double-strand breaks, visualized as 53BP1 foci (green). (Above right) Combination treatment with IR+BEZ attenuates growth of intra-cranial tumors, monitored by bioluminescence imaging.