Rational pairing of tumors with off-patent targeted therapies (TT): Next 3 generation sequencing with global applications for the unprivileged patients!

Since the success of imatinib as the inaugural TT, attempts to identify rational targets for similar approaches have gained prime importance. Cancer is defined by genomic alterations producing constantly activated oncogenes (O). Classically, this was inferred by clonal DNA alterations in proto-oncogenes which became the basis for identifying actionable changes in Next Generation Sequencing (NGS) platforms (successful in <25% of cases). Mutations, translocations and amplifications generate ‘constant' pathologic state but this can also result from DNA amplification of transcription factors (TF) or ligands (for receptor Os). TTs are priced beyond the reach of uninsured or impoverished populations. Few TTs are off-patent, however, with affordable formulations enabling access to such agents even in underprivileged communities. We hypothesized that a substantial portion of cancers might be rationally paired to off-patent TTs if extended, but scientifically sound, criteria were used to identify therapeutic targets. Methods: We examined The Cancer Genome Atlas for cases that are wild type but over-expressed for an inclusive O list. We report on amplifications of the TF or ligand of receptor Os. We then examined the list for cases that could benefit from unpatented TTs. We also report on cases with increased transcriptional O activity. All histologies/stages were included when >5 cases were available. Results: Table reports the findings per type of tumor examined. Conclusions: Our method provides underprivileged patients with affordable TTs that wouldn't have otherwise been considered with classic NGS in 9-60% of genomically defined Os. Pairing Os with effective TT should extend beyond the classic NGS criteria. Relevant DNA events in TFs and ligands seem to play a variable role in O-wild type cancers depending on histology (0% in pancreas, kidney, thyroid and glioma). In others, the finding is noted in 13-100% of cases.