Abstract
OncoTreat identified master regulators in gastroenteropancreatic neuroendocrine tumors (GEP-NET).
Major finding: OncoTreat identified master regulators in gastroenteropancreatic neuroendocrine tumors (GEP-NET).
Concept: A screen detected compounds that target master regulator activity and induce regression in GEP-NETs in vivo.
Impact: The OncoTreat methodology may enable precision oncology in tumors that lack actionable mutations.
Precision oncology has focused on the identification of pharmacologically actionable oncogenic mutations that may induce oncogene addictions, thereby leading to novel therapies. However, most adult malignancies lack actionable mutations, or harbor mutations in oncogenes that are not currently druggable. Further, where mutation-directed therapies are available, acquired drug resistance often leads to eventual relapse. Thus, new approaches are needed to identify novel therapies for precision oncology. Alvarez, Subramaniam, and colleagues sought to identify compounds that target master regulator proteins in cancer, developing a methodology termed OncoTreat to prioritize compounds based on their ability to invert the activity of patient-specific master regulator proteins. To identify master regulator proteins responsible for implementing and maintaining the cancer cell's transcriptional state, data from 212 gastroenteropancreatic neuroendocrine tumors (GEP-NET) with available RNA-sequencing profiles were analyzed. This analysis uncovered multiple GEP-NET master regulators linked to progression from primary to metastatic disease. Of the top 34 putative master regulators, 16 were successfully silenced using shRNA, and 15 of those suppressed tumor cell growth in vitro, indicating their potential as therapeutic targets. These validated GEP-NET master regulators included the early neuroendocrine lineage factors IKZF1, IKZF3, SPI1, GFI1, and POU2F2, the EMT drivers Notch2, EOMES, and GATA3, and the immunomodulatory factors CD45, IL2RB1, CD53, CD86, RUNX3, CIITA, and IL10. A screen of 107 small-molecule compounds identified several compounds predicted to invert the activity of identified GEP-NET master regulators in specific metastatic patients, thus inducing tumor-checkpoint collapse, including the HDAC1/3 inhibitor entinostat. In vivo, entinostat induced regression of tumor xenografts. In addition to identifying potential therapeutic targets in patients with GEP-NETs, the OncoTreat methodology may be more broadly applicable to identify potentially targetable master regulators for precision oncology.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
