Oncogene-Directed Virotherapy for Brain Cancer

Despite advancements in cancer treatment, the prognosis for brain cancer patients remains poor. Glioblastoma multiforme, the most aggressive type of brain tumor, is driven by genetic mutations and overexpression of growth-promoting receptors. While recent innovations in targeted therapies and immunotherapies aim to inhibit these growth signals or stimulate the immune system's attack on the tumor, their effectiveness against glioblastoma has been limited. This is likely due to restricted access of lymphocytes into the brain and potential toxicity to healthy tissues from overlapping biological pathways. These challenges underscore the urgent need for a self-regulating therapy that can operate effectively and safely within the brain’s unique environment. 

In this proposal, I present a novel approach that leverages the abnormal cancer-promoting signaling in glioblastoma—not by inhibiting it, but by harnessing it to our advantage. I propose to use a recently developed harmless derivative of vesicular stomatitis virus engineered to express the Rewiring Aberrant Signaling to Effector Release (RASER) system. This technology employs two synthetic proteins to detect and rewire cancer promoting activity to produce a programmed, therapeutic response. The engineered virus replicates exclusively within tumor cells, leading to their selective destruction. The brain’s immune-privileged nature allows the virus to spread throughout the tumor without being cleared by host antibodies. 

Prior work indicates that this virus is 10,000 times safer than the parental vector and significantly reduces tumor size while improving survival in animal models. Over the next two years, I will validate this approach by (1) investigating its specificity and efficacy in glioblastoma cell lines, as well as its safety in normal brain cells in vitro; (2) validating its distribution in relation to tumor and the highest safety dose in immunocompetent glioblastoma mouse models using real-time imaging and AI-enhanced histopathology in vivo; and (3) evaluating its potential synergy with current glioblastoma treatments. Our findings will determine the translational potential of this system as a viable treatment option for glioblastoma patients.