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Browsing by Author "Sciaky, Noah"
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Item FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036(Springer Nature, 2021-05-12) Angus, Steven P.; Stuhlmiller, Timothy J.; Mehta, Gaurav; Bevill, Samantha M.; Goulet, Daniel R.; Olivares-Quintero, J. Felix; East, Michael P.; Tanioka, Maki; Zawistowski, Jon S.; Singh, Darshan; Sciaky, Noah; Chen, Xin; He, Xiaping; Rashid, Naim U.; Chollet-Hinton, Lynn; Fan, Cheng; Soloway, Matthew G.; Spears, Patricia A.; Jefferys, Stuart; Parker, Joel S.; Gallagher, Kristalyn K.; Forero-Torres, Andres; Krop, Ian E.; Thompson, Alastair M.; Murthy, Rashmi; Gatza, Michael L.; Perou, Charles M.; Earp, H. Shelton; Carey, Lisa A.; Johnson, Gary L.; Pediatrics, School of MedicineInhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy.Item A molecular basis for neurofibroma-associated skeletal manifestations in NF1(Elsevier, 2020-11) Ma, Yun; Gross, Andrea; Dombi, Eva; Pemov, Alex; Choi, Kwangmin; Chaney, Katherine; Rhodes, Steven D.; Angus, Steven P.; Sciaky, Noah; Clapp, D. Wade; Ratner, Nancy; Widemann, Brigitte C.; Rios, Jonathan J.; Elefteriou, Florent; Pediatrics, School of MedicinePurpose: Plexiform neurofibromas (pNF) develop in children with neurofibromatosis type 1 (NF1) and can be associated with several skeletal comorbidities. Preclinical mouse studies revealed Nf1 deficiency in osteoprogenitor cells disrupts, in a MEK-dependent manner, pyrophosphate (PPi) homeostasis and skeletal mineralization. The etiology of NF-associated skeletal manifestations remains unknown. Methods: We used mouse models of NF1 neurofibromas to assess bone mineralization of skeletal structures adjacent to tumors. Expression of genes involved in pyrophosphate homeostasis was assessed in mouse and human NF tumors and Schwann cell cultures. We used dual-energy X-ray absorptiometry (DXA) to assess tumor-associated changes in bone mineral density (BMD) in an individual with NF1 following treatment with the MEK inhibitor selumetinib. Results: We detected increased nonmineralized bone surfaces adjacent to tumors in mouse models of NF1 neurofibromas. Expression of Enpp1, a PPi-generating ectophosphatase, and ANKH, a PPi transporter, was increased in mouse and human neurofibroma-derived tissues and Schwann cells, respectively. In one patient, tumor-associated reductions in BMD were partially rescued following therapy with selumetinib. Conclusion: Results indicate that NF-associated skeletal pathologies in NF1 are associated with dysregulated pyrophosphate homeostasis in adjacent NF tumors and suggest that treatment of NFs with MEK inhibitors may improve skeletal manifestations of the disease.