A5059492779- Pancreatic and Hepatic Oncology Research
- Advanced Breast Cancer Therapies
- Colorectal Cancer Treatments and Studies
- Protein Degradation and Inhibitors
- PI3K/AKT/mTOR signaling in cancer
- Cancer, Hypoxia, and Metabolism
- Growth Hormone and Insulin-like Growth Factors
- Melanoma and MAPK Pathways
- Neuroendocrine Tumor Research Advances
- Sarcoma Diagnosis and Treatment
- Ubiquitin and proteasome pathways
- Chromatin Remodeling and Cancer
- Protein Kinase Regulation and GTPase Signaling
- Cancer Genomics and Diagnostics
- Autophagy in Disease and Therapy
- Histone Deacetylase Inhibitors Research
- Caveolin-1 and cellular processes
- Cell death mechanisms and regulation
- Cancer-related Molecular Pathways
- Peptidase Inhibition and Analysis
- Pancreatic function and diabetes
- Cancer Mechanisms and Therapy
- interferon and immune responses
- Endoplasmic Reticulum Stress and Disease
- Cellular transport and secretion
University of North Carolina at Chapel Hill
2018-2024
Goodwin College
2021
Vanderbilt University
2015-2020
UNC Lineberger Comprehensive Cancer Center
2020
University of Alabama
2011
Erskine College
2008
The 3 human RAS genes, KRAS, NRAS, and HRAS, encode 4 different proteins which belong to the protein family of small GTPases that function as binary molecular switches involved in cell signaling. Activating mutations are among most common oncogenic drivers cancers, with KRAS being frequently mutated oncogene. Although is an excellent drug discovery target for many despite decades research, no therapeutic agent directly targeting has been clinically approved. Using structure-based design, we...
Abstract Allele-specific signaling by different KRAS alleles remains poorly understood. The KRASG12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of mutations: It is rare (∼1%) in lung and colorectal cancers, yet relatively common (∼20%) pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific properties. We evaluated whether functionally distinct from more KRASG12D- or KRASG12V-mutant proteins (KRASG12D/V). found KRASG12D/V but not drives...
Mutational loss of CDKN2A (encoding p16INK4A) tumor-suppressor function is a key genetic step that complements activation KRAS in promoting the development and malignant growth pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration p16INK4A with inhibitors CDK4 CDK6 (CDK4/6) has shown limited clinical efficacy PDAC. Here, we found concurrent treatment both CDK4/6 inhibitor (CDK4/6i) an ERK-MAPK (ERKi) synergistically suppresses PDAC cell lines organoids by cooperatively...
How the
Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family proteins responsible for regulation programmed death. Amplification Mcl-1 common genetic aberration in human cancer whose overexpression contributes to evasion apoptosis and one major resistance mechanisms many chemotherapies. mediates its effects primarily through interactions with pro-apoptotic BH3 containing that achieve high affinity target by utilizing four hydrophobic pockets binding groove. Here we describe discovery...
We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF ERK (ERKi), is highly synergistic at low doses cell line, organoid, rat models PDAC, whereas each alone only cytostatic. Comprehensive mechanistic signaling studies using reverse phase protein array (RPPA)...
Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family proteins that overexpressed and amplified in many cancers. Overexpression Mcl-1 allows cancer cells to evade apoptosis contributes resistance be effectively treated with various chemotherapies. From NMR-based screen a large fragment library, several distinct chemical scaffolds bind were discovered. Here, we describe discovery potent tricyclic 2-indole carboxylic acid inhibitors exhibit single digit nanomolar...
Abstract The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) mandates the development improved therapies. As KRAS mutations are found in 95% PDAC and critical for tumor maintenance, one promising strategy involves exploiting KRAS-dependent metabolic perturbations. macrometabolic process autophagy is upregulated KRAS-mutant PDAC, growth reliant on autophagy. However, inhibition as monotherapy using lysosomal inhibitor hydroxychloroquine (HCQ) has shown limited clinical efficacy....
Missense mutations at the three hotspots in guanosine triphosphatase (GTPase) RAS-Gly
Highlights•p130Cas and βIII-tubulin support PDAC growth by enhancing MYC expression•p130Cas transcriptionally regulates through SRC-p130Cas-DOCK1-RAC1-β-catenin•Microtubules post-translationally regulate stability calpains•Triple targeting of ERK/p130Cas/tubulin with ERKi KX2-391 inhibits growthSummaryTo identify therapeutic targets for KRAS mutant pancreatic cancer, we conduct a druggable genome small interfering RNA (siRNA) screen determine that suppression BCAR1 sensitizes cancer cells to...
Human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide with an unmet need for more effective, less toxic treatments. Currently, both the disease treatment of HNSCC cause significant mortality morbidity. Targeted therapies hold new promise patients HPV-negative status whose tumors harbor oncogenic HRAS mutations. Recent promising clinical results have renewed interest in development farnesyltransferase inhibitors (FTIs) as therapeutic...
Oncogenic RAS signaling is an attractive target for fusion-negative rhabdomyosarcoma (FN-RMS). Our study validates the role of ERK MAPK effector pathway in mediating dependency a panel H/NRASQ61X mutant RMS cells and correlates vivo efficacy MEK inhibitor trametinib with pharmacodynamics activity. A screen used to identify trametinib-sensitizing targets, combinations are evaluated tumor xenografts. We find that central cells; however, there poor response clinically relevant exposures...
DC high potential and insulation resistance testing have historically been used as the primary means for field installation verification medium voltage power cables. Since frequency AC is not a practical solution environment other techniques developed to effectively test integrity of cables terminations before placing MV in service. Among these methods are very low (VLF), partial discharge, tan delta testing.
We and others have recently shown that proteins involved in the DNA damage response (DDR) are critical for KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cell growth vitro.However, CRISPR-Cas9 library enabled us to identify these key had limited representation of DDR-related genes.To further investigate DDR this context, we performed a comprehensive, DDRfocused loss-of-function screen.This screen identified valosin-containing protein (VCP) as an essential gene PDAC lines.We observed...
Cellular phenotype plasticity between the epithelial and mesenchymal states has been linked to metastasis heterogeneous responses cancer therapy, remains a challenge for treatment of triple‐negative breast (TNBC). Here, we used isogenic human cell lines, D492 D492M, representing phenotypes, respectively. We employed CRISPR‐Cas9 loss‐of‐function screen targeting 2240‐gene ‘druggable genome’ identify phenotype‐specific vulnerabilities. Cells with were more vulnerable loss genes related...
<div>Abstract<p>Human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide with an unmet need for more effective, less toxic treatments. Currently, both the disease treatment of HNSCC cause significant mortality morbidity. Targeted therapies hold new promise patients HPV-negative status whose tumors harbor oncogenic <i>HRAS</i> mutations. Recent promising clinical results have renewed interest in development...
<div>Abstract<p>Human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide with an unmet need for more effective, less toxic treatments. Currently, both the disease treatment of HNSCC cause significant mortality morbidity. Targeted therapies hold new promise patients HPV-negative status whose tumors harbor oncogenic <i>HRAS</i> mutations. Recent promising clinical results have renewed interest in development...
Cancer-associated mutations in the guanosine triphosphatase (GTPase) RHOA are found at different locations from mutational hotspots structurally and biochemically related RAS. Tyr 42 -to-Cys (Y42C) Leu 57 -to-Val (L57V) substitutions two most prevalent diffuse gastric cancer (DGC). Y42C exhibits a gain-of-function phenotype is an oncogenic driver DGC. Here, we determined how L57V promotes DGC growth. In mouse organoids with deletion of Cdh1 , which encodes cell adhesion protein E-cadherin,...