A5014027011- Lung Cancer Research Studies
- RNA modifications and cancer
- Peptidase Inhibition and Analysis
- Fungal Infections and Studies
- Advanced biosensing and bioanalysis techniques
- Neuroendocrine Tumor Research Advances
- Multiple Myeloma Research and Treatments
- Lung Cancer Treatments and Mutations
- RNA and protein synthesis mechanisms
- Cancer-related Molecular Pathways
- Cancer therapeutics and mechanisms
- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- Microtubule and mitosis dynamics
- Chromatin Remodeling and Cancer
- RNA Research and Splicing
- interferon and immune responses
- Advanced Breast Cancer Therapies
Dana-Farber Cancer Institute
2021-2024
Harvard University
2021-2024
Dana-Farber Brigham Cancer Center
2021-2023
Brigham and Women's Hospital
2021-2023
Washington and Lee University
2022
Some small cell lung cancers (SCLCs) are highly sensitive to inhibitors of the histone demethylase LSD1. LSD1 thought induce their anti-proliferative effects by blocking neuroendocrine differentiation, but mechanisms which controls SCLC phenotype not well understood. To identify genes required for inhibitor sensitivity in SCLC, we performed a positive selection genome-wide CRISPR/Cas9 loss function screen and found that ZFP36L1, an mRNA-binding protein destabilizes mRNAs, is sensitivity....
Abstract Neuroendocrine to nonneuroendocrine plasticity supports small cell lung cancer (SCLC) tumorigenesis and promotes immunogenicity. Approximately 20% 25% of SCLCs harbor loss-of-function (LOF) NOTCH mutations. Previous studies demonstrated that functions as a SCLC tumor suppressor, but can also drive support growth. Given the dual functionality NOTCH, it is not understood why select for LOF mutations how these affect tumorigenesis. In CRISPR-based genetically engineered mouse model...
Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype) have durable responses to PD-L1. Some are highly sensitive Aurora kinase inhibitors, but early-phase trials show short-lived responses, suggesting effective therapeutic combinations needed increase...
Cancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small lung cancer (SCLC) cells with inherent high by blocking RxL-mediated interactions cyclin A B select substrates. Genome-wide CRISPR/Cas9 knockout random mutagenesis screens found A/B RxL macrocyclic inhibitors (cyclin A/Bi) induced apoptosis paradoxically B- Cdk2-dependent spindle assembly checkpoint...
Messenger RNA (mRNA) translation can lead to higher rates of mRNA decay, suggesting the ribosome plays a role in destruction. Furthermore, features, such as codon identities, which are directly probed by ribosome, correlate with decay rates. Many amino acids encoded synonymous codons, some decoded more abundant tRNAs leading optimal and increased stability. Variable for codons ribosomal collisions ribosomes transit regions suboptimal promote decay. In addition different rates, presence...
Abstract Some small cell lung cancers (SCLCs) are highly sensitive to inhibitors of the histone demethylase LSD1. LSD1 thought induce their anti-proliferative effects by blocking neuroendocrine differentiation, but mechanisms which controls SCLC phenotype not well understood. To identify genes required for inhibitor sensitivity in SCLC, we performed a positive selection genome-wide CRISPR/Cas9 loss function screen and found that ZFP36L1 , an mRNA-binding protein destabilizes mRNAs, is...
<div>Abstract<p>Neuroendocrine to nonneuroendocrine plasticity supports small cell lung cancer (SCLC) tumorigenesis and promotes immunogenicity. Approximately 20% 25% of SCLCs harbor loss-of-function (LOF) <i>NOTCH</i> mutations. Previous studies demonstrated that NOTCH functions as a SCLC tumor suppressor, but can also drive support growth. Given the dual functionality NOTCH, it is not understood why select for LOF mutations how these affect tumorigenesis. In...
<p>Supplementary Data including supplementary methods, figures, and figure legends.</p>
<p>Supplementary Data including supplementary methods, figures, and figure legends.</p>
Abstract Most cancer-directed targeted therapies are developed using small molecule inhibitors that require a druggable binding pocket on the target of interest. Macrocyclic peptides can selectively block protein-protein interactions required for function and hence be used to previously undruggable proteins. Using structure-guided approach, Circle Pharma cell-permeable macrocyclic ability Cyclin A and/or B, bind RxL motifs their substrates thereby inhibiting activity. separate study (Gleason...
<div>Abstract<p>Neuroendocrine to nonneuroendocrine plasticity supports small cell lung cancer (SCLC) tumorigenesis and promotes immunogenicity. Approximately 20% 25% of SCLCs harbor loss-of-function (LOF) <i>NOTCH</i> mutations. Previous studies demonstrated that NOTCH functions as a SCLC tumor suppressor, but can also drive support growth. Given the dual functionality NOTCH, it is not understood why select for LOF mutations how these affect tumorigenesis. In...