Browsing by Author "Davis, Christopher"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Efficacy of the Allosteric MEK Inhibitor Trametinib in Relapsed and Refractory Juvenile Myelomonocytic Leukemia
    (American Association for Cancer Research, 2024) Stieglitz, Elliot; Lee, Alex G.; Angus, Steven P.; Davis, Christopher; Barkauskas, Donald A.; Hall, David; Kogan, Scott C.; Meyer, Julia; Rhodes, Steven D.; Tasian, Sarah K.; Xuei, Xiaoling; Shannon, Kevin; Loh, Mignon L.; Fox, Elizabeth; Weigel, Brenda J.; Pediatrics, School of Medicine
    Juvenile myelomonocytic leukemia (JMML) is a hematologic malignancy of young children caused by mutations that increase Ras signaling output. Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment, but patients with relapsed or refractory (advanced) disease have dismal outcomes. This phase II trial evaluated the safety and efficacy of trametinib, an oral MEK1/2 inhibitor, in patients with advanced JMML. Ten infants and children were enrolled, and the objective response rate was 50%. Four patients with refractory disease proceeded to HSCT after receiving trametinib. Three additional patients completed all 12 cycles permitted on study and continue to receive off-protocol trametinib without HSCT. The remaining three patients had progressive disease with two demonstrating molecular evolution by the end of cycle 2. Transcriptomic and proteomic analyses provided novel insights into the mechanisms of response and resistance to trametinib in JMML. ClinicalTrials.gov Identifier: NCT03190915. Significance: Trametinib was safe and effective in young children with relapsed or refractory JMML, a lethal disease with poor survival rates. Seven of 10 patients completed the maximum 12 cycles of therapy or used trametinib as a bridge to HSCT and are alive with a median follow-up of 24 months.
  • Thumbnail Image
    Item
    Oxygen tension-dependent variability in the cancer cell kinome impacts signaling pathways and response to targeted therapies
    (Elsevier, 2024-05-21) Adebayo, Adedeji K.; Bhat-Nakshatri, Poornima; Davis, Christopher; Angus, Steven P.; Erdogan, Cihat; Gao, Hongyu; Green, Nick; Kumar, Brijesh; Liu, Yunlong; Nakshatri, Harikrishna; Surgery, School of Medicine
    Most cells in solid tumors are exposed to oxygen levels between 0.5% and 5%. We developed an approach that allows collection, processing, and evaluation of cancer and non-cancer cells under physioxia, while preventing exposure to ambient air. This aided comparison of baseline and drug-induced changes in signaling pathways under physioxia and ambient oxygen. Using tumor cells from transgenic models of breast cancer and cells from breast tissues of clinically breast cancer-free women, we demonstrate oxygen-dependent differences in cell preference for epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor beta (PDGFRβ) signaling. Physioxia caused PDGFRβ-mediated activation of AKT and extracellular regulated kinase (ERK) that reduced sensitivity to EGFR and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) inhibition and maintained PDGFRβ+ epithelial-mesenchymal hybrid cells with potential cancer stem cell (CSC) properties. Cells in ambient air displayed differential EGFR activation and were more sensitive to targeted therapies. Our data emphasize the importance of oxygen considerations in preclinical cancer research to identify effective drug targets and develop combination therapy regimens.
  • Thumbnail Image
    Item
    PLK1 Inhibition Induces Synthetic Lethality in Fanconi Anemia Pathway-Deficient Acute Myeloid Leukemia
    (American Association for Cancer Research, 2025) Sheth, Aditya S.; Chan, Ka-Kui; Liu, Sheng; Wan, Jun; Angus, Steve P.; Rhodes, Steven D.; Mitchell, Dana K.; Davis, Christopher; Ridinger, Maya; Croucher, Peter J.; Zeidan, Amer M.; Wijeratne, Aruna; Qian, Shaomin; Tran, Ngoc Tung; Sierra Potchanant, Elizabeth A.; Pediatrics, School of Medicine
    This work demonstrates that FA pathway mutations, which are frequently observed in sporadic AML, induce hypersensitivity to PLK1 inhibition, providing rationale for a novel synthetic lethal therapeutic strategy for this patient population.