A5029143392- Advanced Breast Cancer Therapies
- Melanoma and MAPK Pathways
- Protein Degradation and Inhibitors
- Cancer Immunotherapy and Biomarkers
- CAR-T cell therapy research
- Ocular Oncology and Treatments
- Cancer-related Molecular Pathways
- HER2/EGFR in Cancer Research
- Advanced Biosensing Techniques and Applications
- Cancer Genomics and Diagnostics
- Chromatin Remodeling and Cancer
- Histone Deacetylase Inhibitors Research
- Nanoplatforms for cancer theranostics
- Cancer, Stress, Anesthesia, and Immune Response
- Cancer Mechanisms and Therapy
- Neuroscience and Neuropharmacology Research
- Biochemical and Molecular Research
- Protein Kinase Regulation and GTPase Signaling
- PI3K/AKT/mTOR signaling in cancer
- Cancer Research and Treatments
- Receptor Mechanisms and Signaling
- Protein Tyrosine Phosphatases
- Cancer Cells and Metastasis
- Cancer Treatment and Pharmacology
- Computational Drug Discovery Methods
Thomas Jefferson University
2015-2024
Arvinas (United States)
2024
Sidney Kimmel Cancer Center
2016-2024
The University of Texas MD Anderson Cancer Center
2019-2020
Jefferson College
2016
Rutgers, The State University of New Jersey
2011-2015
Abstract Purpose: Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor 2 negative (HER2−) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become central strategy in the treatment ER+ advanced However, suboptimal ER inhibition and resistance resulting from ESR1 mutation dictates that new therapies are needed. Experimental Design: A medicinal chemistry campaign identified...
Abstract Targeting cyclin-dependent kinases 4/6 (CDK4/6) represents a therapeutic option in combination with BRAF inhibitor and/or MEK (MEKi) melanoma; however, continuous dosing elicits toxicities patients. Using quantitative and temporal vivo reporting, we show that MEKi intermittent CDK4/6 (CDK4/6i) led to more complete tumor responses versus other schedules. Nevertheless, some tumors acquired resistance was associated enhanced phosphorylation of ribosomal S6 protein. These data were...
Abstract Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS-mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi CDK4i therapy but subsequently developed resistance. Whole-exome sequencing functional validation identified an acquired PIK3CAE545K mutation as conferring drug We demonstrate that preexisted rare subpopulation was missed by both research testing, revealed upon...
Research Article4 January 2019Open Access Source DataTransparent process Stromal fibroblast growth factor 2 reduces the efficacy of bromodomain inhibitors in uveal melanoma Vivian Chua Corresponding Author [email protected] orcid.org/0000-0002-1873-6820 Department Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA Search for more papers by this author Marlana Orloff Medical Oncology, Jessica LF Teh Takahito Sugase Connie Liao Timothy J Purwin Bao Q Lam Mizue Terai Grazia...
Abstract KRAS is the most frequently mutated oncogene with high prevalence of alterations in pancreatic, colorectal, and non-small cell lung tumors. The alleviation negative feedback control activity upon downstream inhibition has limited clinical efficacy MAPK pathway drugs mutant context. guanine nucleotide exchange factor (GEF) SOS1 a mediator this control, protein key activator itself. BI 1701963 first SOS1::KRAS inhibitor to advance trials. Both as well previously reported probe...
Abstract G‐protein‐coupled receptors (GPCRs) represent a class of therapeutic targets that have been widely exploited for drug designs and development. Metabotropic glutamate (mGluRs) belong to Class C GPCRs are predominantly involved in maintaining cellular homeostasis the central nervous system (CNS). The surprising accumulating evidence suggesting other functional roles mGluRs human malignancies addition synaptic transmission has presented intriguing possibilities make putative novel...
Frequent GNAQ and GNA11 mutations in uveal melanoma hyperactivate the MEK-ERK signaling pathway, leading to aberrant regulation of cyclin-dependent kinases (CDK) cell-cycle progression. MEK inhibitors (MEKi) alone show poor efficacy melanoma, raising question whether downstream targets can be vertically inhibited provide long-term benefit. CDK4/6 selective are FDA-approved patients with estrogen receptor (ER)-positive breast cancer combination ER antagonists/aromatase inhibitors. We...
Aberrant cell-cycle progression is a hallmark feature of cancer cells. Cyclin-dependent kinases 4 and 6 (CDK4/6) drive through the G1 stage cell cycle, at least in part, by inactivating tumor suppressor, retinoblastoma. CDK4/6 are targetable selective inhibitor, palbociclib, was recently FDA approved for treatment estrogen receptor-positive, HER2-negative advanced breast cancer. In cutaneous melanoma, driver mutations NRAS BRAF promote activation, suggesting that inhibitors such as...
Several epidemiological studies have suggested a link between melanoma and breast cancer. Metabotropic glutamate receptor 1 (GRM1), which is involved in many cellular processes including proliferation differentiation, has been implicated melanomagenesis, with ectopic expression of GRM1 causing malignant transformation melanocytes. This study was undertaken to evaluate polymorphic variants for associations cancer phenotypes. Three single nucleotide polymorphisms (SNPs) were evaluated...
Summary Our laboratory previously described the oncogenic properties of metabotropic glutamate receptor 1 (m G lu R 1) in melanocytes. mGluR1 transformed immortalized mouse melanocytes vitro and induced vigorous tumor formation vivo. Subsequently, we observed activation PI3K/AKT m 1‐mediated melanocytic tumorigenesis In particular, identified AKT2 being predominant isoform contributing to AKT. Suppression Grm1 or using an inducible Tet‐R siRNA system resulted a 60 30% reduction,...
Abstract Concurrent MEK and CDK4/6 inhibition shows promise in clinical trials for patients with advanced-stage mutant BRAF/NRAS solid tumors. The effects of inhibitor (CDK4/6i) combination BRAF/MEK-targeting agents on the tumor immune microenvironment are unclear, especially melanoma, which checkpoint inhibitors effective approximately 50% patients. Here, we show that progressing CDK4/6i/MEK pathway combinations exhibit T-cell exclusion. We found targeting was more at delaying regrowth BRAF...
<div>AbstractPurpose:<p>Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER<sup>+</sup>)/human epidermal growth factor 2 negative (HER2<sup>−</sup>) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become central strategy in the treatment ER<sup>+</sup> advanced However, suboptimal ER inhibition and resistance resulting from <i>ESR1</i> mutation...
Abstract KRAS is the most frequently mutated oncogene with high prevalence in pancreatic, colorectal, and non-small cell lung tumors. signaling tightly regulated various factors, including negative feedback pathways have limited clinical efficacy of inhibitors downstream MAPK mutant context. Here we report discovery BI-3406 demonstrate it a highly potent selective, orally bioavailable SOS1::KRAS inhibitor which binds to catalytic domain guanine nucleotide exchange factor (GEF) SOS1 thereby...
<p>Supplementary Data, Table S1, S3, S6, S8, S10-S13</p>
Abstract Intrapatient heterogeneity among different metastatic sites contributes to targeted therapy resistance. Determining the proteomic profile of melanoma lesions that develop within same patient could help elucidate adaptive mechanisms drive tumor progression during therapy. Tumors persist through treatment and colonize distant organs adapt rely on organ-specific microenvironments. To assess how protein expression is altered in cutaneous derived from a single patient, we utilized...
The mechanisms driving late relapse in uveal melanoma (UM) patients remains a medical mystery and major challenge. Clinically it is inferred that UM disseminated cancer cells (DCCs) persist asymptomatic for years-to-decades mainly the liver before they manifest as symptomatic metastasis. Here we reveal using Gαq/11
Abstract Intrapatient heterogeneity among different metastatic sites contributes to immunotherapy (ICi) and targeted therapy resistance. Determining the evolution of melanoma lesions that develop within same patient could help elucidate adaptive mechanisms drive tumor progression during therapy. To assess how persists through inhibitor treatments, we utilized samples from a single who had received anti-CTLA4, BRAFi/MEKi, BRAFi/MEKi+CDK4/6i treatments LOGIC2 clinical trial. Eight short-term...
<p>Supplementary Tables S1-S4 and Figures S1-S16</p>
<p>Extended Methods</p>