Glioblastoma (GBM) is the most common malignant brain tumor in adults. It is incurable, with average patient survival of about 13 months even with an aggressive therapeutic regimen consisting of maximal tumor resection, and concomitant chemotherapy and radiotherapy. One of the reasons for therapeutic failure is the complex functional heterogeneity in this brain tumor. In fact, not all cells are functionally identical in GBM, but a small population has properties reminiscent of normal stem cells, whereby they are uniquely responsible for tumor growth and recurrence. We call these specialized cells “cancer stem cells,” or tumor-initiating cells.  

Whereas current treatments are relatively successful at targeting the other cells in this tumor, cancer stem cells have ways of evading current therapeutic intervention. We have recently shown that one feature that distinguishes cancer stem cells from the other cells in GBM is the way DNA is packaged. Cancer stem cells have regions of highly compacted DNA, which is caused by low levels of a protein that binds the DNA and relaxes its architecture.  

We have designed a protein that can change DNA architecture and can be directed by us to any site in the human genome. We will use this engineered protein to unravel the DNA structure that is specifically found in the cancer stem cells of GBM patients.  

We will provide proof-of-principle that altering DNA architecture is an effective way of targeting cancer stem cells. We will do so by testing the efficacy of our approach in a collection of patient-derived cancer stem cell cultures. We will then test the pre-clinical implication of our findings by transplanting GBM cancer stem cells in mice and treat their resultant “human” tumors with our engineered protein. We will then assess the effects of our treatment on tumor growth and recurrence. Essentially, our technology will enable us to perform a new kind of gene therapy by directly targeting DNA structure which is the ultimate determinant of cancer stem cell behavior.

Cancers are heterogeneous diseases that, in many cases, are not effectively managed with existing treatments. Oncolytic viruses are promising biotherapeutic tools for cancer, whose clinical and commercial development is progressing rapidly. Currently, a major preclinical initiative in the field is to engineer next generation viruses or virus/drug combinations that break through the barriers to successful treatment. 

Our goal is to harness the innate cytokine response of the immune system — normally a major impediment to oncolytic virus therapy — to attack and kill tumours. Our preliminary experiments demonstrate one strategy to accomplish this: antagonizing the Inhibitor of APoptosis (IAP) gene family. In this case, a drug that antagonized the “Inhibitor of APoptosis” (IAP) gene family rewired tumour cells to initiate a self-destruct sequence upon exposure to cytokines, which were strongly induced in tumours infected with an oncolytic virus.  

To build upon these data, and to broaden the underlying concept, we propose a research plan to (1) elucidate the mechanisms responsible for synergy between oncolytic virus therapy and IAP antagonism, and (2) identify new opportunities to reprogram tumour cells to die in response to the cytokine cloud generated by oncolytic virus therapy.