A5076790826- Lung Cancer Treatments and Mutations
- Fibroblast Growth Factor Research
- RNA modifications and cancer
- Cancer Immunotherapy and Biomarkers
- Cell Adhesion Molecules Research
- Ferroptosis and cancer prognosis
- Caveolin-1 and cellular processes
- Eosinophilic Disorders and Syndromes
- Metastasis and carcinoma case studies
- Click Chemistry and Applications
- CAR-T cell therapy research
- Medical Imaging and Pathology Studies
- Chemical Synthesis and Analysis
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Tryptophan and brain disorders
- Cancer, Stress, Anesthesia, and Immune Response
- Protein Degradation and Inhibitors
- Immune Cell Function and Interaction
- HER2/EGFR in Cancer Research
- Lung Cancer Research Studies
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Monoclonal and Polyclonal Antibodies Research
- Immunotherapy and Immune Responses
- Epigenetics and DNA Methylation
- Immune cells in cancer
Weatherford College
2022
Akebia Therapeutics (United States)
2018-2020
Kura Oncology (United States)
2020
The University of Texas at Austin
2019
Infinity Pharmaceuticals (United States)
2015-2018
The University of Texas MD Anderson Cancer Center
2008-2017
Dana-Farber Cancer Institute
2013-2016
Ludwig Cancer Research
2013-2016
Harvard University
2013-2016
Dana-Farber/Harvard Cancer Center
2013-2014
The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and signature of immunosuppression manifested by upregulation PD-1, PD-L1, CTL antigen-4 (CTLA-4), multiple tumor-promoting inflammatory cytokines. observed decreased CTLs increased markers T-cell exhaustion mouse models EGFR-driven cancer. PD-1 antibody improved the...
Abstract Tryptophan catabolism by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2 (IDO/TDO) promotes immunosuppression across different cancer types. The metabolite L-Kynurenine (Kyn) interacts with ligand-activated transcription factor aryl hydrocarbon receptor (AHR) to drive generation of Tregs tolerogenic myeloid cells PD-1 up-regulation in CD8 + T cells. Here, we show that AHR pathway is selectively active IDO/TDO-overexpressing tumors associated resistance immune checkpoint...
A hallmark of prostate cancer progression is dysregulation lipid metabolism via overexpression fatty acid synthase (FASN), a key enzyme in de novo synthesis. Metastatic castration-resistant (mCRPC) develops resistance to inhibitors androgen receptor (AR) signaling through variety mechanisms, including the emergence constitutively active AR variant V7 (AR-V7). Here, we developed an FASN inhibitor (IPI-9119) and demonstrated that selective inhibition antagonizes CRPC growth metabolic...
Amplification of MYC is one the most common genetic alterations in lung cancer, contributing to a myriad phenotypes associated with growth, invasion, and drug resistance. Murine genetics has established both centrality somatic Kras as well dependency mutant tumors on function. Unfortunately, drug-like small-molecule inhibitors KRAS have yet be realized. The recent discovery, hematologic malignancies, that bromodomain extra-terminal (BET) inhibition impairs expression transcriptional function...
A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SCC) has recently been reported, enabling the identification events that contribute to oncogenesis this disease. In SCC, one most frequently altered receptor tyrosine kinase families is fibroblast growth factor (FGFR) family, with amplification or mutation observed all four family members. Here, we describe oncogenic nature mutations FGFR2 and FGFR3, each which are 3% samples, for a rate 6% across both...
The LKB1/STK11 tumor suppressor encodes a serine/threonine kinase, which coordinates cell growth, polarity, motility, and metabolism. In non-small lung carcinoma, LKB1 is somatically inactivated in 25% to 30% of cases, often concurrently with activating KRAS mutations. Here, we used an integrative approach define novel therapeutic targets KRAS-driven LKB1-mutant cancers. High-throughput RNA interference screens cancer lines from genetically engineered mouse models driven by activated or...
Abstract Glioblastoma multiforme (GBM) is a highly invasive brain tumor that develops florid microvascular proliferation and hemorrhage. However, mechanisms favor invasion versus angiogenesis in this setting remain largely uncharacterized. Here, we show integrin β8 an essential regulator of both GBM-induced cell invasiveness. Highly angiogenic poorly tumors expressed low levels integrin, whereas with limited neovascularization high integrin. Manipulating protein altered the growth properties...
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered several cancer types cause the neurometabolic syndrome D2-hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting production of acid (D-2HG). To study pathophysiological consequences accumulation D-2HG, we generated transgenic mice with conditionally activated IDH2 R140Q R172K alleles. Global induction expression adults resulted dilated cardiomyopathy, white matter abnormalities...
Abstract Aryl hydrocarbon receptor (AHR) is a transcription factor that regulates the activity of multiple innate and adaptive immune cells subsequent to binding numerous endogenous exogenous ligands. For example, AHR activated by metabolite kynurenine, which secreted into tumor microenvironment cancer leading broad immunosuppression. Therefore, inhibition provides novel ideal approach stimulate immune-mediated recognition eradication cells. We report here discovery characterization IK-175,...
Central nervous system (CNS) neurovascular units are multicellular complexes consisting of neural cells, blood vessels and a milieu extracellular matrix (ECM) proteins. ECM-mediated adhesion signaling events within probably contribute to proper CNS development physiology; however, the molecular mechanisms that control these remain largely undetermined. Previous studies from our group others showed ablation ECM receptor, αvβ8 integrin, in progenitor cells (NPCs) embryonic mouse brain results...
Non-small cell lung cancers (NSCLC) that express EGF receptor with activating mutations frequently develop resistance to EGFR kinase inhibitors. The mucin 1 (MUC1) heterodimeric protein is aberrantly overexpressed in NSCLC cells and confers a poor prognosis; however, the functional involvement of MUC1 mutant signaling not known.Targeting oncogenic C-terminal subunit (MUC1-C) harboring was studied for effects on signaling, growth, clonogenic survival, tumorigenicity.Stable silencing MUC1-C...
The malignant brain cancer glioblastoma multiforme (GBM) displays invasive growth behaviors that are regulated by extracellular cues within the neural microenvironment. adhesion and signaling pathways drive GBM cell invasion remain largely uncharacterized. Here we use human lines, primary patient samples, preclinical mouse models to demonstrate integrin αvβ8 is a major driver of invasion. β8 overexpressed in many cells, with higher expression correlating increased diminished survival....
Adoptive cell therapies (ACT) have shown reduced efficacy against solid tumor malignancies compared to hematologic malignancies, partly due the immunosuppressive nature of microenvironment (TME). ACT may be enhanced with pleiotropic cytokines that remodel TME; however, their expression needs tightly controlled avoid systemic toxicities. Here we show T cells can armored membrane-bound surface regulated using drug-responsive domains (DRDs) developed from 260-amino acid protein human carbonic...
Somatic mutations in FGFR2 are present 4% to 5% of patients diagnosed with non-small cell lung cancer (NSCLC). Amplification and FGFR genes have been identified NSCLCs, clinical trials testing the efficacy anti-FGFR therapies. other kinase family gene alterations found both squamous carcinoma adenocarcinoma, although mouse models FGFR-driven cancers not reported. Here, we generated a genetically engineered model (GEMM) NSCLC driven by domain mutation FGFR2. Combined p53 ablation, primary...
Abstract The recent clinical success of therapeutic blockade the immune checkpoint Programmed Death (PD)-1 in advanced lung cancer patients suggests that mechanisms escape may contribute to tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and gene signature indicative immunosuppression manifested by upregulation PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4) multiple tumor-promoting inflammatory cytokines. Accordingly,...
Recurrent fusion of the v-myb avian myelobastosis viral oncogene homolog (MYB) and nuclear factor I/B (NFIB) generates MYB-NFIB transcription factor, which has been detected in a high percentage individuals with adenoid cystic carcinoma (ACC). To understand functional role this protein carcinogenesis, we generated conditional mutant transgenic mouse that expresses along p53 mutation tissues give rise to ACC: mammary tissue, salivary glands, or systemically whole body. Expression tissue...
Abstract Introduction: Adoptive cellular therapies (ACT) have encountered challenges in solid tumors due part to the immunosuppressive tumor microenvironment (TME). We developed OBX-115, TIL engineered express mbIL15 regulatable using cytoDRiVE® platform, which allows for expansion, persistence, and anti-tumor efficacy under control of FDA-approved small-molecule ligand, acetazolamide (ACZ), eliminating need co-administration IL2 (NCT05470283). LIGHT, a necrosis factor family member,...
Abstract Tumor infiltrating lymphocyte (TIL) therapy has shown promising results in the treatment of metastatic melanoma. However, TIL conventionally required co-administration IL2, which is associated with toxicity patients. We previously showed that melanoma TILs engineered to express membrane-bound IL15 (mbIL15) under control ligand acetazolamide (ACZ) can achieve IL2-independent expansion during manufacturing, antigen-independent persistence vitro and anti-tumor efficacy vivo. In current...
Abstract The phosphoinositide-3-kinase (PI3K) lipid kinases transduce signals in response to various stimuli different cell types. PI3K-γ is predominantly expressed leukocytes and not most epithelial tumors or sarcomas. Genetic studies highlight an important role for myeloid-derived cells that constitute a key component of the immune suppressive tumor microenvironment (Schmid et al. Canc Cell 2011). Targeting could therefore alter microenvironment, enabling system attack more effectively. We...
There were errors published in J. Cell Sci. 122, 1842-1851.In Fig. 3, panels A and C (rather than B) mistakenly labeled as wild type B D D) β8–/–. The correct figure is shown below:In 5, the units on y axis for panel should be micrometers (μm), not millimeters (mm). below:The authors apologise these mistakes.