Publications by authors named "Evan Flietner"
Drug resistance and disease progression are common in multiple myeloma (MM) patients, underscoring the need for new therapeutic combinations. A high-throughput drug screen in 47 MM cell lines and in silico Huber robust regression analysis of drug responses revealed 43 potentially synergistic combinations. We hypothesized that effective combinations would reduce MYC expression and enhance p16 activity.
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- * The VQ model shows different disease characteristics and survival rates, and the study utilized whole-exome sequencing and RNA-Seq to categorize the VQ lines into two groups based on their genetic profiles.
- * Group A cells were more sensitive to bortezomib treatment, while Group B cells exhibited features of high-risk MM and were resistant to the drug, indicating that Group B closely mirrors a dangerous subset of human MM.
Stimulatory type 1 conventional dendritic cells (cDC1s) engage in productive interactions with CD8 effectors along tumor-stroma boundaries. The paradoxical accumulation of "poised" cDC1s within stromal sheets is unlikely to simply reflect passive exclusion from tumor cores. Drawing parallels with embryonic morphogenesis, we hypothesized that invasive margin stromal remodeling generates developmentally conserved cell fate cues that regulate cDC1 behavior.
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- Multiple myeloma (MM) is a type of cancer that affects plasma cells, and it's often resistant to common treatments, especially in advanced stages with genetic mutations in the RAS pathway.
- Researchers developed a mouse model called VQ MM to study this advanced form and screened 147 FDA-approved anti-cancer drugs, finding that the combination of trametinib (Tra) and ponatinib (Pon) was particularly effective, prolonging survival in mice.
- However, ponatinib negatively impacted the function of CD8 T cells, which are important for immune response, suggesting that while it enhances treatment effects, it may also reduce immune response, highlighting the need for balanced therapy approaches.
Article Synopsis
- * Research shows that patients with both ASXL1 and NRAS mutations experience shorter leukemia-free survival compared to those with only ASXL1 mutations, and similar results were observed in mouse models which also exhibited aggressive disease progression.
- * NA-AML cells (from the mouse model) overexpress immune checkpoint ligands and show high MEK/ERK signaling activity, but combining treatments targeting MEK and BET can improve immune responses and extend survival
NRAS Q61 mutations are prevalent in advanced/relapsed multiple myeloma (MM) and correlate with poor patient outcomes. Thus, we generated a novel MM model by conditionally activating expression of endogenous NrasQ61R and an MYC transgene in germinal center (GC) B cells (VQ mice). VQ mice developed a highly malignant MM characterized by a high proliferation index, hyperactivation of extracellular signal-regulated kinase and AKT signaling, impaired hematopoiesis, widespread extramedullary disease, bone lesions, kidney abnormalities, preserved programmed cell death protein 1 and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain immune-checkpoint pathways, and expression of human high-risk MM gene signatures.
View Article and Find Full Text PDFRecent advances in our understanding of the dynamics of cellular cross-talk have highlighted the significance of host-versus-tumor effect that can be harnessed with immune therapies. Tumors exploit immune checkpoints to evade adaptive immune responses. Cancer immunotherapy has witnessed a revolution in the past decade with the development of immune checkpoint inhibitors (ICIs), monoclonal antibodies against cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or their ligands, such as PD1 ligand 1 (PD-L1).
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