Thread by @DHymanMD

New at @nature - Efficacy of MEK inhibition in patients with histiocytosis. The culmination of an amazing 7-year collaboration @sloan_kettering with Eli Diamond @AbdelWahablab @ECDGA @Histiocytosis @Roche and many others! rdcu.be/bqSIq [1/x]

We stumbled into histiocytosis after Barret Rollins' lab discovered BRAF V600 mutations in ~50% of LCH, followed later by Julian Haroche making similar observations in ECD.
bloodjournal.org/content/116/11…
bloodjournal.org/content/120/13… [2/x]

At the time I had just opened the vemurafenib basket (VE-BASKET) study and the first patient we treated was a woman who had been neurologically devastated by ECD - 7 years later she remains healthy on drug! [3/x]

Through Eli Diamond's leadership & help of @ECDGA @Roche we eventually treated 26 histiocytosis patients - ORR 61.5%, 2-year PFS 86%. Based on these data, vemurafenib was approved by @FDAOncology for BRAF V600 ECD! ja.ma/2F4ZATs [4/x]

The @AbdelWahablab led an international collaboration to define oncogenic drivers in non-V600 histiocytosis patients, ultimately discovering a diversity of MAPK pathway events. cancerdiscovery.aacrjournals.org/content/6/2/154 [5/x]

We opened cobimetinib (MEKi) investigator-initiated study based on the hypothesis that histiocytic neoplasms are defined by obligate MAPK pathway dependence. Results exceeded all expectations and may one day extend the benefits of targeted Rx to all histiocytosis patients! [6/x]

Most of our prior #PrecisionMedicine work has focused on defining phenotype of rare genotypes. This is the opposite - defining the genotypes underlying the observed phenotype. Through this approach were were able to define several novel activating MAPK alterations [7/x]

So much foundational prior work by others not cited here due to format - tried to include all in paper. HUGE thanks to this amazing patient community that made this work possible led by @KathyGBrewer ! [fin]