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Pak, Ekaterina

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Pak

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Ekaterina

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Pak, Ekaterina

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    Resistance to Targeted Therapy in Sonic Hedgehog Subgroup Medulloblastoma: Mechanisms and Treatment Strategies
    (2016-05-17) Pak, Ekaterina; Hahn, William; Goodrich, Lisa; Hinds, Philip
    Aberrant activation of the Sonic Hedgehog (Shh) signaling network is implicated in many human cancers, including the most common cancer, basal cell carcinoma (BCC) and the brain tumor medulloblastoma. Suppressing Shh signaling is thus a promising strategy in oncology. The largest and most clinically advanced group of Shh signaling inhibitors comprises selective antagonists of the pathway component Smoothened (Smo). In 2012, the Food and Drug Administration approved the first Smo antagonist, and others are now approved or in clinical trials. However, there is already evidence that some patients can have primary or develop secondary resistance to therapy. Accordingly, a more comprehensive understanding of resistance mechanisms and alternative treatment approaches are needed. Here, we describe a genome-wide transposon mutagenesis screen to identify candidate resistance genes for Smo antagonists using an in vitro model of Shh-dependent medulloblastoma. Top hits from the screen include Suppressor of fused (Sufu), a known resistance gene and negative regulator in Shh signaling, and Oral-facial-digital syndrome 1 (Ofd1), a gene associated with an X-linked developmental syndrome. Independent gain- and loss-of-function experiments confirm Ofd1 as a bona fide resistance gene. Ofd1 mutant cells have reduced numbers of primary cilia, which are necessary for transducing canonical Shh signaling. Reduction of Kif3a and Ift88, two other cilia genes, also causes resistance. Strikingly, resistant cilia mutants are still dependent on active Shh signaling downstream of Smo. These mutants lack the truncated repressor form of the Shh transcription factor Gli2, but maintain full-length Gli2 levels and therefore shift the overall balance of transcriptional activators and repressors toward pathway reactivation. Importantly, we present evidence that resistance by loss of primary cilia may have clinical relevance. Subcutaneous medulloblastoma tumors in mice that acquire de novo resistance to Smo inhibition exhibit decreased numbers of primary cilia compared to tumors that remain sensitive. Additionally, resistant BCCs from patients treated with Smo antagonists have significantly more cilia gene mutations compared to untreated BCCs. Recognizing the need for more options to treat resistant tumors, we carried out a high-throughput small molecule screen in Shh-dependent medulloblastoma cells. From a set of over 900 small molecules, we identify histone deacetylase (HDAC) inhibitors as a class of promising therapeutics. While not all HDAC inhibitors are effective, we present some with similar chemical structures that work consistently within the nanomolar range across cell lines that are both sensitive and resistant to Smo inhibitors. Preliminary results indicate that inhibition of HDACs works within the Shh signaling axis and that specific HDACs may play a role in resistant human tumors. Together, these studies reveal new resistance mechanisms and explore the development of next-generation treatments in Shh-dependent tumors.