Browsing by Author "Stieglitz, Elliot"

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    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.
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    In vivo validation of the palmitoylation cycle as a therapeutic target in NRAS-mutant cancer
    (bioRxiv, 2025-03-21) Decker, Matthew; Huang, Benjamin J.; Ware, Timothy; Boone, Christopher; Tang, Michelle; Ybarra, Julia; Ballapuram, Aishwarya C.; Taran, Katrine A.; Chen, Pan-Yu; Amendáriz, Marcos; Leung, Camille J.; Harris, Max; Tjoa, Karensa; Hongo, Henry; Abelson, Sydney; Rivera, Jose; Ngo, Nhi; Herbst, Dylan M.; Suciu, Radu M.; Guijas, Carlos; Sedighi, Kimia; Andalis, Taylor; Roche, Elysia; Xie, Boer; Liu, Yunlong; Smith, Catherine C.; Stieglitz, Elliot; Niphakis, Micah J.; Cravatt, Benjamin F.; Shannon, Kevin; Medical and Molecular Genetics, School of Medicine
    Normal and oncogenic Ras proteins are functionally dependent on one or more lipid modifications 1,2. Whereas K-Ras4b farnesylation is sufficient for stable association with the plasma membrane, farnesylated H-Ras, K-Ras4a, and N-Ras traffic to the Golgi where they must undergo palmitoylation before regulated translocation to cell membranes. N-Ras palmitoylation by the DHHC family of palmitoyl acyl transferases (PATs) and depalmitoylation by ABHD17 serine hydrolases is a dynamic process that is essential for the growth of acute myeloid leukemias (AMLs) harboring oncogenic NRAS mutations3-6. Here, we have tested whether co-targeting ABHD17 enzymes and Ras signal output would cooperatively inhibit the proliferation and survival of NRAS-mutant AMLs while sparing normal tissues that retain K-Ras4b function. We show that ABD778, a potent and selective ABHD17 inhibitor with in vivo activity, selectively reduces the growth of NRAS-mutant AML cells in vitro and is synergistic with the allosteric MEK inhibitor PD0325901 (PD901)7,8. Similarly, ABD778 and PD901 significantly extended the survival of recipient mice transplanted with three independent primary mouse AMLs harboring an oncogenic Nras G12D driver mutation. Resistant leukemias that emerged during continuous drug treatment acquired by-pass mutations that confer adaptive drug resistance and increase mitogen activated protein kinase (MAPK) signal output. ABD778 augmented the anti-leukemia activity of the pan-PI3 kinase inhibitor pictilisib9, the K/N-RasG12C inhibitor sotorasib10, and the FLT3 inhibitor gilteritinib11. Co-treatment with ABD778 and gilteritinib restored drug sensitivity in a patient-derived xenograft model of adaptive resistance to FLT3 inhibition. These data validate the palmitoylation cycle as a promising therapeutic target in AML and support exploring it in other NRAS-mutant cancers.
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    Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells
    (Elsevier, 2022) Ramdas, Baskar; Yuen, Lisa Deng; Palam, Lakshmi Reddy; Patel, Roshini; Pasupuleti, Santhosh Kumar; Jideonwo, Victoria; Zhang, Ji; Maguire, Callista; Wong, Eric; Kanumuri, Rahul; Zhang, Chujing; Sandusky, George; Chan, Rebecca J.; Zhang, Chi; Stieglitz, Elliot; Haneline, Laura; Kapur, Reuben; Pediatrics, School of Medicine
    Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasia that lacks effective targeted chemotherapies. Clinically, JMML manifests as monocytic leukocytosis, splenomegaly with consequential thrombocytopenia. Most commonly, patients have gain-of-function (GOF) oncogenic mutations in PTPN11 (SHP2), leading to Erk and Akt hyperactivation. Mechanism(s) involved in co-regulation of Erk and Akt in the context of GOF SHP2 are poorly understood. Here, we show that Bruton’s tyrosine kinase (BTK) is hyperphosphorylated in GOF Shp2-bearing cells and utilizes B cell adaptor for PI3K to cooperate with p110δ, the catalytic subunit of PI3K. Dual inhibition of BTK and p110δ reduces the activation of both Erk and Akt. In vivo, individual targeting of BTK or p110δ in a mouse model of human JMML equally reduces monocytosis and splenomegaly; however, the combined treatment results in a more robust inhibition and uniquely rescues anemia and thrombocytopenia. RNA-seq analysis of drug-treated mice showed a profound reduction in the expression of genes associated with leukemic cell migration and inflammation, leading to correction in the infiltration of leukemic cells in the lung, liver, and spleen. Remarkably, in a patient derived xenograft model of JMML, leukemia-initiating stem and progenitor cells were potently inhibited in response to the dual drug treatment.
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    Potential clinical use of azacitidine and MEK inhibitor combination therapy in PTPN11-mutated juvenile myelomonocytic leukemia
    (Elsevier, 2023) Pasupuleti, Santhosh Kumar; Chao, Karen; Ramdas, Baskar; Kanumuri, Rahul; Palam, Lakshmi Reddy; Liu, Sheng; Wan, Jun; Annesley, Colleen; Loh, Mignon L.; Stieglitz, Elliot; Burke, Michael J.; Kapur, Reuben; Pediatrics, School of Medicine
    Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative neoplasm of childhood. The molecular hallmark of JMML is hyperactivation of the Ras/MAPK pathway with the most common cause being mutations in the gene PTPN11, encoding the protein tyrosine phosphatase SHP2. Current strategies for treating JMML include using the hypomethylating agent, 5-azacitidine (5-Aza) or MEK inhibitors trametinib and PD0325901 (PD-901), but none of these are curative as monotherapy. Utilizing an Shp2E76K/+ murine model of JMML, we show that the combination of 5-Aza and PD-901 modulates several hematologic abnormalities often seen in JMML patients, in part by reducing the burden of leukemic hematopoietic stem and progenitor cells (HSC/Ps). The reduced JMML features in drug-treated mice were associated with a decrease in p-MEK and p-ERK levels in Shp2E76K/+ mice treated with the combination of 5-Aza and PD-901. RNA-sequencing analysis revealed a reduction in several RAS and MAPK signaling-related genes. Additionally, a decrease in the expression of genes associated with inflammation and myeloid leukemia was also observed in Shp2E76K/+ mice treated with the combination of the two drugs. Finally, we report two patients with JMML and PTPN11 mutations treated with 5-Aza, trametinib, and chemotherapy who experienced a clinical response because of the combination treatment.