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The Teachey Lab studies perturbations in leukemic cell signal transduction pathways to identify targeted cancer inhibitors and immunotherapies that can treat children with high-risk leukemias and autoimmune lymphoproliferative syndrome (ALPS). The lab’s long-term goal is to develop better therapies, improve cure rates, and minimize toxicities for these children.
The lab demonstrated that children with high-risk leukemias, such as Philadelphia chromosome-like lymphoblastic leukemia (Ph-like ALL) and early T-cell precursor acute lymphoblastic leukemia (T-ALL), have dysregulated cell signaling in the MAPK/JAK/STAT and PI3K/mTOR pathways. The targeted JAK kinase inhibitor ruxolitinib was found to be highly active in slowing disease progression in these leukemias in animal models.
Based on these findings, researchers in the Teachey Lab are participating in a clinical trial to evaluate the effectiveness of ruxolitinib to treat children with high-risk ALL with dysregulated JAK/STAT signaling mutations.
Other lab studies found that PI3K/AKT/mTOR protein kinase signaling is dysregulated in children with ALPS. The targeted mTOR kinase inhibitor sirolimus (rapamycin) was found to inhibit disease progression in mouse xenograft models of ALPS. Pilot clinical studies with pediatric ALPS patients revealed that sirolimus treatment resulted in a complete and durable response (with minimal toxicity) to over 90 percent of the trial participants.
The lab also studyies the molecular mechanisms contributing to cytokine release syndrome, which occurs in some children with ALL who are treated with chimeric antigen receptor T cells (CART) or bispecific T-cell engaging (BiTE) antibody immunotherapy. Clinical studies have revealed that tocilizumab — a humanized anti-IL6 receptor monoclonal antibody that interferes with secretion of the cytokine IL6 — can effectively treat pediatric patients who develop CRS after CART or BiTE immunotherapy. Studies are underway to gain a better understanding of the role of IL6 in CRS and to identify genetic markers to identify children who may be at high risk of developing CRS.
David T. Teachey, MD
Co-Leader, Immune Dysregulation Frontier Program
Dr. Teachey's research focuses on investigating novel therapeutics for children with white blood cell diseases, including ALL and a rare autoimmune disease called Autoimmune Lymphoproliferative Syndrome (ALPS). His research in ALL focuses on studying leukemic cells from children with high-risk disease.