A5090143432- FOXO transcription factor regulation
- PI3K/AKT/mTOR signaling in cancer
- CAR-T cell therapy research
- Melanoma and MAPK Pathways
- Cancer-related molecular mechanisms research
- RNA modifications and cancer
- Single-cell and spatial transcriptomics
- Hormonal Regulation and Hypertension
- Immune cells in cancer
- Ubiquitin and proteasome pathways
- CRISPR and Genetic Engineering
- Mast cells and histamine
- Cancer Cells and Metastasis
- Estrogen and related hormone effects
- Cancer Immunotherapy and Biomarkers
- Immune Response and Inflammation
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- vaccines and immunoinformatics approaches
- Epigenetics and DNA Methylation
- Cancer, Lipids, and Metabolism
- Telomeres, Telomerase, and Senescence
- Caveolin-1 and cellular processes
- interferon and immune responses
- Bioinformatics and Genomic Networks
- Cancer Mechanisms and Therapy
Princeton University
2023-2025
Memorial Sloan Kettering Cancer Center
2020-2024
Ludwig Cancer Research
2023-2024
Kettering University
2020-2023
Pennsylvania State University
2015-2017
Medulloblastoma is the most common malignant paediatric brain tumour, with ~30% mediated by Sonic hedgehog signalling. Vismodegib-mediated inhibition of effector Smoothened inhibits tumour growth but causes plate fusion at effective doses. Here, we report a nanotherapeutic approach targeting endothelial vasculature to enhance blood-brain barrier crossing. We use fucoidan-based nanocarriers P-selectin induce caveolin-1-dependent transcytosis and thus nanocarrier transport into...
Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T targeting the senescence-associated protein...
Abstract Current KRAS G12C (OFF) inhibitors that target inactive GDP-bound cause responses in less than half of patients and these are not durable. A class RAS (ON) targets active GTP-bound blocks ERK signaling more potently the inactive-state inhibitors. Sensitivity to either agents is strongly correlated with inhibition mTORC1 activity. We have previously shown PI3K/mTOR ERK-signaling pathways converge on key cellular processes both required for significant antitumor find here combination...
Abstract PAX3-FOXO1, an oncogenic transcription factor, drives a particularly aggressive subtype of rhabdomyosarcoma (RMS) by enforcing gene expression programs that support malignant cell states. Here we show PAX3-FOXO1 + RMS cells exhibit altered pyrimidine metabolism and increased dependence on enzymes involved in de novo synthesis, including dihydrofolate reductase (DHFR). Consequently, display sensitivity to inhibition DHFR the chemotherapeutic drug methotrexate, this is rescued...
Abstract BRAFV600E mutations occur in 46% of melanomas and drive high levels ERK activity ERK-dependent proliferation. However, is insufficient to melanoma genetically engineered mouse models, 82% human benign nevi harbor mutations. We found that inhibited mesenchymal migration by causing feedback inhibition RAC1 activity. pathway induced activation restored invasion. In cells with BRAFV600E, mutant or PTEN inactivation cell motility. Together, these lesions occurred 26% Thus, although...
Abstract Background: A ketogenic diet, with high fat (90% kCal) and low carbohydrate (5% intake, induces ketosis [2], altering cancer cell carbon utilization toward the tricarboxylic acid cycle (TCA) [3]. While overall impact on growth is unclear, most literature suggests an anti-cancer effect. Our hypothesis aims to uncover pancreatic adaptations revealing metabolic vulnerabilities for informed therapeutic strategies. Methods: Mice a or normal diet (control) underwent xenograft observation....
The Ah receptor (AHR) is directly involved in the regulation of both innate and adaptive immunity. However, these activities are poorly understood at level gene regulation. chemokine (c–c motif) ligand 20 (CCL20) plays a nonredundant role chemoattraction C–C motif 6 expressing cells (eg, T others). A survey promoter regions genes revealed that there several putative dioxin responsive elements mouse Ccl20 promoter. addition an AHR agonist along with lipopolysaccharide (LPS) to cultured...
Chemokines are components of the skin microenvironment, which enable immune cell chemotaxis. Traditionally, transcription factors involved in inflammatory signaling (eg, NFκB) important mediators chemokine expression. To what extent xenobiotics and their associated receptors control expression is poorly understood. The aryl hydrocarbon receptor (AHR) a ligand-activated factor known to mediate physiological responses through regulation genes xenobiotic metabolism, epidermal differentiation,...
Abstract The majority of human breast cancers are dependent on hormone-stimulated estrogen receptor alpha (ER) and sensitive to its inhibition. Treatment resistance arises in most advanced due genetic alterations that promote ligand independent activation ER itself or target genes. Whereas re-targeting the binding domain (LBD) with newer antagonists can work some cases, these drugs largely ineffective many backgrounds including fusions lose LBD hyperactivate targets. By identifying mechanism...
SUMMARY Intestinal stem cells (ISCs) drive the rapid regeneration of gut epithelium to maintain organismal homeostasis. Aging, however, significantly reduces intestinal regenerative capacity. While cellular senescence is a key feature aging process, little known about in vivo effects senescent on fitness. Here, we identify accumulation and, by harnessing senolytic CAR T eliminate them, uncover their detrimental impact epithelial integrity and overall homeostasis natural aging, injury...
Abstract Senescent cells accumulate in organisms over time because of tissue damage and impaired immune surveillance contribute to age-related decline 1,2 . In agreement, genetic ablation studies reveal that elimination senescent from aged tissues can ameliorate various pathologies, including metabolic dysfunction decreased physical fitness 3-7 While small-molecule drugs capable eliminating (known as ‘senolytics’) partially replicate these phenotypes, many have undefined mechanisms action...
Pancreatic cancer is the third leading cause of death in United States, and while conventional chemotherapy remains standard treatment, responses are poor. Safe alternative therapeutic strategies urgently needed
The FOXA1 pioneer factor is an essential mediator of steroid receptor function in multiple hormone-dependent cancers, including breast and prostate enabling nuclear receptors such as estrogen (ER) androgen (AR) to activate lineage-specific growth programs. also highly expressed non-small cell lung cancer (NSCLC), but whether how it regulates tumor this context not known. Analyzing data from loss-of-function screens, we identified a subset NSCLC lines where proliferation dependent. Using...
Though somatic mutations play a critical role in driving cancer initiation and progression, the systems-level functional impacts of these mutations-particularly, how they alter expression across genome give rise to hallmarks-are not yet well-understood, even for well-studied driver genes. To address this, we designed an integrative machine learning model, Dyscovr, that leverages mutation, gene expression, copy number alteration (CNA), methylation, clinical data uncover putative relationships...
<div><p>The FOXA1 pioneer factor is an essential mediator of steroid receptor function in multiple hormone-dependent cancers, including breast and prostate enabling nuclear receptors such as estrogen (ER) androgen (AR) to activate lineage-specific growth programs. also highly expressed non–small cell lung cancer (NSCLC), but whether how it regulates tumor this context not known. Analyzing data from loss-of-function screens, we identified a subset NSCLC lines where proliferation...
<p>Identification of a FOXA1–GR interaction through endogenous purification FOXA1-associated proteins using RIME. <b>A,</b> Schematic overview the RIME assay. <b>B,</b> Graphic representation GR protein sequence coverage unique peptides identified by LC/MS-MS in H441, HCC-44, and H3255 FOXA1 samples. Yellow regions string represent alignment peptide sequences to Mascot database for protein. Full list found <a href="#SMT2" target="_blank">Supplementary...
<p>FOXA1 gene effect scores in NSCLC cell lines from DepMap</p>
<p>Supplemental figure S1 data panels and legend accompanying main body 2. Supplementary Figure shows GR is the top-ranked interacting protein of FOXA1 in FOXA1-dependent NSCLC cell lines models. Additionally, FOXA1-dependent, but not FOXA1-independent cells depend on for sustained proliferation.</p>
<p>Growth promoting functions of GR in FOXA1/GR-dependent NSCLC can be inhibited by ORIC-101. <b>A,</b> Chemical structures steroidal antagonist, ORIC-101 and non-steroidal OP-4954. Proliferation H441 H3255 cells cultured normal media treated with indicated concentrations (<b>B</b>) or OP-4954 (<b>C</b>). Datapoints are Resazurin fluorescence normalized to DMSO cells, means ± SD, <i>n</i> = 6. <b>D,</b> Measurement luciferase...