CEST Reporter Genes

The highly invasive nature of many cancers and the toxicity of most systemic chemotherapies represent significant challenges for cancer therapies and limit their effectiveness. A very promising therapeutic approach for overcoming these challenges is the use of oncolytic viruses that selectively kill only cancer cells, while sparing the surrounding normal cells. Oncolytic viruses can generate progeny on-site that spread throughout the tumor and reach distal malignant cells, thus representing an ideal strategy for treating invasive cancers such as glioblastoma multiforme (GBM). In addition, oncolytic viruses can be engineered to express chemotherapeutics and thereby provide multimodal, targeted drug delivery. Finally, oncolytic viruses can elicit a strong immune response against viral infected tumor cells. However, the lack of means to non-invasively monitor such therapeutic agents in a clinical setting constitutes an important limitation in evaluating and optimizing the outcome of these therapeutic strategies.

Chemical Exchange Saturation Transfer (CEST) MRI opens up new avenues for imaging biological therapeutics, such as oncolytic viruses, by direct detection of protein reporters. CEST uses selective radio-frequency (RF) pulses to detect exchangeable protons on proteins. We have recently demonstrated that an oncolytic Herpes Simplex Virus (oHSV) engineered with an artificial gene encoding for a Lysine-Rich Protein (LRP) generated significantly higher CEST MRI tumor contrast, due to lysine amide exchangeable protons, than tumors infected with control, non-LRP expressing virus. We also demonstrated that the introduction of the LRP gene did not interfere with the viral replication or therapeutic efficacy. We are currently working on developing CEST-MRI methods and viral reporters with increased CEST specificity and sensitivity that will enable the longitudinal monitoring of both oncolytic viral infection and replication in tumors.