The immune checkpoint blocker pembrolizumab (Keytruda, Merck) has proven most successful to treat solid tumors harboring a DNA mismatch repair (MMR) deficiency. This striking result recently reported by Luis Diaz Jr., Bert Vogelstein and their collaborators was anticipated a couple of years before by Dr. Vogelstein, a towering figure in oncological research. Ariel Fernandez has now shown that it is possible to generate a drug-promoted phenotype mimicking the MMR deficiency in solid tumors and thereby engineer a generic hypersusceptibility to Keytruda. This sensitivity is achieved through drug-induced metabolic stress on DNA synthesis.
The striking results by Diaz, Vogelstein and coworkers prompted Ariel Fernandez to address the following question: Is it possible to induce the MMR deficiency in any solid tumor, for example through targeted drug-based therapy, and thereby enhance the cancer antigenic activity and diversity to turn the Keytruda-drug combination into a universal cure for cancer?
As work at Ariel Fernandez Consultancy reveals, the answer to this question is a resounding yes. The key to the problem resides in identifying a signaling pathway that gets recruited to promote MMR and then identifying a kinase inhibitor that would block that pathway. The MMR deficiency-inducing kinase inhibitor has been found at Ariel Fernandez Consultancy. The potential of such drug-Keytruda combinations as universal treatments for solid tumors deserves clinical evaluation. Collaborative work is underway at Ariel Fernandez Consultancy to validate this paradigm. This may well be a decisive step in cancer cure.
Ariel Fernandez: “Engineering Tumor Hypersusceptibility to Checkpoint Immunotherapy”, Trends in Cancer (2017) Published online September 4.