An innovative paper by Dr. Jean-Simon Diallo (TFRI-funded Canadian Oncolytic Virus Consortium (COVCo) and collaborators Drs. Jeffrey Smith and Christopher Boddy was published in Scientific Reports (May 2016). They discovered and developed a class of new small molecule compounds that selectively enhance oncolytic viruses (OV) in cancer tissue, making them more likely to destroy tumour cells and eradicate the disease.
The use of engineered viral strains such as gene therapy vectors and oncolytic viruses to selectively destroy cancer cells is poised to make a major impact in the clinic and to revolutionize cancer therapies. Yet in clinical studies, OV therapy has shown highly variable rates of patient response. The heterogeneous nature of tumours is widely accepted to be a major obstacle for OV therapeutics and highlights a need for strategies to improve the efficacy of viral replication.
The present study looked at the development of a new class of small molecules for selectively enhancing OV replication in cancer tissue. Medicinal chemistry studies led to the identification of compounds that enhance multiple OVs and gene therapy vectors. The lead compounds increase OV growth by up to 2,000-fold in vitro and demonstrate remarkable selectivity for cancer cells over normal tissue ex vivo and in vivo. These small molecules also demonstrate enhanced stability with reduced electrophilicity and are well-tolerated in animals. This pharmacoviral approach expands the scope of OVs to include resistant tumours, further potentiating this transformative therapy.
The process of selecting promising molecule compounds may be like looking for a needle in a haystack, but the present study’s results were very promising. Nearly 30,000 molecules were screened initially to find just over a dozen highly active ones. From there, the team selected a lead candidate that they used as a model to create nearly 100 more molecules closely related to that initial lead compound, from which a handful of compounds that hold promise for human applications were identified -- including one they are very excited about based on promising animal studies.
In summary, the current study has developed new molecular tools in the search for a cure for cancer, as well as identified credible drug candidates for evaluation in OV clinical trials. In addition, these new molecular tools provide an opportunity to better understand how cells protect themselves from viral infection. The applications of this span beyond cancer but are also relevant for treating hereditary diseases using gene therapy, and also to the development and manufacturing of vaccines.
Study: First-in-class small molecule potentiators of cancer virotherapy.
Authors: Mark H. Dornan, Ramya Krishnan, Andrew M. Macklin, Mohammed Selman,Nader El Sayes, Hwan Hee Son, Colin Davis, Andrew Chen, Kerkeslin Keillor, Penny J. Le, Christina Moi, Paula Ou, Christophe Pardin, Carlos R. Canez, Fabrice Le Boeuf, John C. Bell, Jeffrey C. Smith, Jean-Simon Diallo & Christopher N. Boddy.
Funding: JSD and JCB receive funding from the Terry Fox Research Institute program project grant (grant # TFF 122868) and a The Lotte & John Hecht Memorial Foundation Innovation Grant of the Canadian Cancer Society (grant #2012-701460). CNB, JSD and JCS are supported from the Canadian Institutes of Health Research (CIHR) and the National Science and Engineering Research Council (NSERC) through a Collaborative Research Project Grant. Additional NSERC funding supports CB, JCS and MHD.
TFRI Links, Fall 2016