A5065498389- Inflammatory Bowel Disease
- Cancer-related molecular mechanisms research
- Cancer-related Molecular Pathways
- RNA regulation and disease
- RNA Research and Splicing
- Ubiquitin and proteasome pathways
- Colorectal Cancer Treatments and Studies
- PI3K/AKT/mTOR signaling in cancer
- Melanoma and MAPK Pathways
- Microtubule and mitosis dynamics
- CRISPR and Genetic Engineering
- Cancer Mechanisms and Therapy
- Inflammatory mediators and NSAID effects
- Microscopic Colitis
- Autoimmune and Inflammatory Disorders
- Cancer, Hypoxia, and Metabolism
- Genetic factors in colorectal cancer
- Anorectal Disease Treatments and Outcomes
- 14-3-3 protein interactions
- Hormonal and reproductive studies
- Cell death mechanisms and regulation
- Advanced biosensing and bioanalysis techniques
- Protein Kinase Regulation and GTPase Signaling
- Peptidase Inhibition and Analysis
- Cancer Genomics and Diagnostics
Children's Healthcare of Atlanta
2024-2025
Emory University
2024-2025
UCSF Helen Diller Family Comprehensive Cancer Center
2019-2024
University of California, San Francisco
2019-2024
Quantitative BioSciences
2021-2023
City College of San Francisco
2020-2022
Inhibitors targeting KRASG12C, a mutant form of the guanosine triphosphatase (GTPase) KRAS, are promising new class oncogene-specific therapeutics for treatment tumors driven by protein. These inhibitors react with cysteine residue binding covalently to switch-II pocket (S-IIP) that is present only in inactive diphosphate (GDP)-bound sparing wild-type We used genome-scale CRISPR interference (CRISPRi) functional genomics platform systematically identify genetic interactions KRASG12C...
Genetic alterations that activate protein kinase A (PKA) are found in many tumor types. Yet, their downstream oncogenic signaling mechanisms poorly understood. We used global phosphoproteomics and activity profiling to map conserved outputs driven by a range of genetic changes PKA human cancer. Two networks were identified PKA: RAS/MAPK components an Aurora Kinase (AURKA)/glycogen synthase (GSK3) sub-network with toward MYC oncoproteins. Findings validated two PKA-dependent cancer models:...
Abstract BRAF V600E mutation confers a poor prognosis in metastatic colorectal cancer (CRC) despite combinatorial targeted therapies based on the latest understanding of signaling circuitry. To identify parallel resistance mechanisms induced by BRAF–MEK–EGFR co-targeting, we used high-throughput kinase activity mapping platform. Here show that SRC kinases are systematically activated CRC following inhibition ± EGFR and coordinated targeting with increases treatment efficacy vitro vivo....
The BCL-2 inhibitor venetoclax is effective in chronic lymphocytic leukemia (CLL); however, resistance may develop over time. Other lymphoid malignancies such as diffuse large B-cell lymphoma (DLBCL) are frequently intrinsically resistant to venetoclax. Although genomic mechanisms mutations have been described, this likely only explains a subset of cases. Using two complementary functional precision medicine techniques -- BH3-profiling and high throughput-kinase activity mapping we found...
Abstract Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified nuclear-enriched lncRNA ( AC004540.4 ) that is upregulated NRAS/MAPK-dependent melanoma, named T-RECS . Considering potential innovative treatment...
Crohn's disease (CD) involves a complex intestinal microenvironment driven by chronic inflammation. While single-cell RNA sequencing has provided valuable insights into this biology, the spatial context is lost during preparation of mucosal biopsies. To deepen our understanding distinct inflammatory signatures CD and overcome limitations sequencing, we combined transcriptomics frozen surgical tissue sections with ileal mucosa. Coexpressed genes cell-cell communication from analyses...
Abstract The androgen receptor (AR) is a central driver of aggressive prostate cancer. After initial treatment with signaling inhibitors (ARSi), reactivation AR leads to resistance. Alternative splicing mRNA yields the AR-V7 splice variant, which currently an undruggable mechanism ARSi resistance: lacks ligand binding domain, where hormones and anti-androgen antagonists act, but still activates signaling. We reveal PKCβ as druggable regulator transcription at genomic locus. identify clinical...
Abstract Purpose: Metastatic colorectal cancer (mCRC) is the second leading cause of death worldwide. Roughly 8% mCRC tumors harbor a BRAF(V600E) mutation, associated with worst prognosis and limited treatment options. Most CRC research most clinical trials targeted therapies have narrowly focused on targeting vertical mechanisms MAPK re-activation (i.e., EGFR-MAPK), incremental advances for patients. New approaches are needed to address how therapeutic resistance mediated by coordinated...
Crohn's disease (CD) is a chronic and relapsing inflammatory condition that affects segments of the gastrointestinal tract. CD activity determined by histological findings, particularly density neutrophils observed on Hematoxylin Eosin stains (H&E) imaging. However, understanding broader morphometry local cell arrangement beyond counting tissue morphology remains challenging. To address this, we characterize six distinct types from H&E images develop novel approach for spatial signature each...
Abstract Introduction: Pancreatic ductal adenocarcinoma (PDA) is the 3rd most common cause of cancer death in United States, with a 5-year survival rate only 13%, part due to late detection and metastatic dissemination at early stages progression. Most PDA tumors exhibit dense fibro-inflammatory stroma consisting fibroblasts, immune cells, collagen-rich extracellular matrix (ECM) that regulate disease How distinct collagens (COLs) influence progression remains unclear. COLs signal via...
The ability to identify and target oncogenic signals has transformed clinical oncology. Drug development for targeted therapies historically focused on the inhibition of kinases GTPases. However, many cancer patients do not benefit from approaches because their tumors lack targetable mutations. Therapeutic augmentation tumor suppressive signaling could be a viable alternative but poses challenges. Specifically, designing compounds capable stimulating kinase activity is more structurally...
Abstract Protein Kinase A (PKA) is a major effector of cyclic-AMP (cAMP) signaling and has recently been appreciated to play role in multiple malignancies. Mutations its catalytic subunit (PRKACA) have identified substantial proportion adrenocortical tumors, are also detected wide spectrum tumor types the TCGA dataset, although at low frequency. unique fusion protein PRKACA DNAJB1 seen majority fibrolamellar liver cancers (FLC), rare malignancy young adults, where it suspected be primary...
Abstract MAPK-pathway up-regulation is responsible for over 40% of human cancer cases. Finding effective therapeutic targets melanoma therapy continues to be a challenge due drug resistance. Using computational and experimental pipeline, we discovered the nuclear enriched long non-coding RNA (lncRNA) TRASH, which induced upon MAPK-pathway-activation in melanoma. LncRNA hold essential regulatory functions many types. TRASH-targeting Antisense Oligonucleotides (TRASH-ASOs) greatly reduced...
Abstract Genetic alterations that activate protein kinase A (PKA) signaling are found across many tumor types, but their downstream oncogenic mechanisms poorly understood. We used global phosphoproteomics and kinome activity profiling to map the conserved outputs driven by diverse genetic changes PKA in human cancer, including melanoma fibrolamellar carcinoma (FLC). define two consensus networks of effectors cancer models. One is centered on RAS/MAPK components, a second involves Aurora...
Crohn's disease (CD) is a chronic and relapsing inflammatory condition that affects segments of the gastrointestinal tract. CD activity determined by histological findings, particularly density neutrophils observed on Hematoxylin Eosin stains (H&E) imaging. However, understanding broader morphometry local cell arrangement beyond counting tissue morphology remains challenging. To address this, we characterize six distinct types from H&E images develop novel approach for spatial...
Abstract Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified nuclear-enriched lncRNA ( AC004540.4 ) that is upregulated NRAS/MAPK-dependent melanoma, named T-RECS . Considering potential innovative treatment...
Abstract Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified nuclear-enriched lncRNA ( AC004540.4 ) that is upregulated NRAS/MAPK-dependent melanoma, named T-RECS . Considering potential innovative treatment...
Abstract Drug resistance emerges in response to most targeted therapies and is a common mechanism of treatment failure patients with advanced cancer. We have studied intrahepatic cholangiocarcinoma (ICC) oncogenic FGFR2 fusions. fusions are seen 10-15% ICC patients, FGFR inhibition (FGFRi) associated relatively rapid emergence resistance. While some FGFRi results from mutations that block drug binding, previous analysis has revealed polyclonal mechanisms relying on multiple pathways. Given...
Abstract Cancer treatment has been considerably advanced by the relatively recent development of small molecules capable inhibiting oncogenic kinase signaling, but exogenous enhancement tumor suppressive signaling remains elusive. Here, we sought to design activating suppressor LKB1. Designing compounds increasing activity more structurally challenging than those aimed at them: apart from ATP-binding pocket, there is rarely a site that would be conducive binding molecule. Unlike most protein...