Oncology
CV6-168 is a potential first-in-class, oral, selective inhibitor of dUTPase, designed to exploit a vulnerability created by thymidylate synthase (TS) inhibitors such as 5-fluorouracil (5-FU), capecitabine and pemetrexed.
It is currently in a Phase 1a clinical trial in Northern Ireland and Great Britain, where eighteen patients have been treated across seven completed dose cohorts, with dose escalation ongoing and no dose-limiting toxicities observed. Pharmacodynamic assessment in patients evaluated to date is consistent with the intended mechanism.
TS inhibitors work by depleting thymine, one of DNA’s four building blocks (A, T, C and G). Without thymine, cancer cells cannot copy their DNA properly. But many cancers find ways around the blockade or evolve resistance over time, limiting what these cornerstone therapies can do.
CV6-168
CV6-168 takes a different approach. It blocks dUTPase, the enzyme that keeps uracil out of DNA. When TS inhibitors deplete thymine, uracil enters DNA in its place and the cancer cell comes under Genomic Uracil Stress.
Our shorthand for what follows is uracilate, destroy, signal. CV6-168 increases uracil pressure on tumor DNA, drives lethal genomic stress and, in preclinical studies, triggers innate immune signaling. This cellular response, the Genomic Uracil Stress Response (GUSR), is what CV6-168 is designed to exploit.
Genomic Uracil Stress may inflame the tumor microenvironment and increase sensitivity to immune checkpoint blockade, an area CV6 is exploring as the program advances.
Highly proliferative cancer cells, which may have impaired genomic maintenance, are expected to be most exposed to this stress, supporting investigation of differentiated anti-tumor activity.
Learn more about the Phase 1a trial here: ISRCTN registry.
