Biology subjects

Olshen, A. B.

Publications and source records attributed to Olshen, A. B..

2 recordsLinked to original sources

bioRxiv2020

Exploiting KRAS-driven Ferroaddiction in Cancer Through Ferrous Iron-Activatable Drug Conjugates (FeADC)

KRAS mutations cause a quarter of cancer mortality and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at dosages required to adequately extinguish RAS/RAF/MAPK signaling. We found that oncogenic KRAS signaling induces ferrous iron (Fe2+) accumulation early in and throughout KRAS-mediated transformation. We used an FDA-approved MEK inhibitor to produce a prototypical Ferrous Iron-Activatable Drug Conjugate (FeADC) which achieved potent MAPK blockade in tumor cells while sparing normal tissues. This innovation allowed sustainable, effective treatment of tumor bearing animals, with tumor-selective drug activation producing superior systemic tolerability. Ferrous iron accumulation is an exploitable feature of KRAS transformation and FeADCs hold promise for improving treatment of KRAS-driven solid tumors.

cancer biology↗

bioRxiv2020

Pan-cancer identification of clinically relevant genomic subtypes using outcome-weighted integrative clustering

Molecular phenotypes of cancer are complex and influenced by a multitude of factors. Conventional unsupervised clustering of heterogeneous cancer patient populations is inevitably driven by the dominant variation from major factors such as cell-of-origin or histology. Drawing from ideas in supervised text classification, we developed survClust, an outcome-weighted clustering algorithm for integrative patient stratification. We show survClust outperforms unsupervised clustering in identifying cancer patient subpopulations characterized by specific genomic phenotypes with more aggressive clinical behavior. The algorithm and tools we developed have direct utility toward clinically relevant patient stratification based on tumor genomics to inform clinical decision-making.

genomics↗