11 results on '"Tchaicha J"'
Search Results
2. 1008P cytoTIL15: A novel TIL therapy for melanoma with superior potency and enhanced persistence without IL2 to improve safety & efficacy and expand patient eligibility
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Khattar, M., primary, Burga, R., additional, Pedro, K., additional, Foley, C., additional, Lajoie, S., additional, Ocando, A.V., additional, Tremblay, J., additional, Thornton, D., additional, Tam, S., additional, Nabulsi, F., additional, Vallaster, C., additional, Saha, S., additional, Wilmes, G., additional, Helmlinger, G., additional, Tchaicha, J., additional, Sethi, D., additional, Ols, M., additional, Vanasse, G., additional, Subramanian, S., additional, and ter Meulen, J., additional
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- 2021
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3. A mosaic mouse model of astrocytoma identifies αvβ8 integrin as a negative regulator of tumor angiogenesis
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Tchaicha, J H, Mobley, A K, Hossain, M G, Aldape, K D, and McCarty, J H
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- 2010
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4. Kinase Domain Activation of FGFR2 Yields High-Grade Lung Adenocarcinoma Sensitive to a Pan-FGFR Inhibitor in a Mouse Model of NSCLC
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Tchaicha, J. H., Akbay, E, Altabef, A., Mikse, O. R., Kikuchi, E., Rhee, K., Liao, R, Bronson, Roderick Terry, Sholl, Lynette Marie, Meyerson, Matthew Langer, Hammerman, Peter Seth, and Wong, Kwok-Kin
- Subjects
Fibroblast growth factor receptor 2 ,genetically engineered mouse models ,non-small cell lung cancer ,adenocarcinoma ,BGJ-398 - Abstract
Somatic mutations in Fibroblast Growth Factor Receptor 2 (FGFR2) are present in 4-5% of patients diagnosed with non-small cell lung cancer (NSCLC). Amplification and mutations in FGFR genes have been identified in patients with NSCLC and clinical trials are testing the efficacy of anti-FGFR therapies. FGFR2 and other FGFR kinase family gene alterations have been found in both lung squamous cell carcinoma and lung adenocarcinoma though mouse models of FGFR driven lung cancers have not been reported. Here, we generated a genetically engineered mouse model (GEMM) of NSCLC driven by a kinase domain mutation in FGFR2. Combined with p53 ablation, primary grade III/IV adenocarcinoma was induced in the lung epithelial compartment exhibiting locally invasive and pleiotropic tendencies largely made up of multinucleated cells. Tumors were acutely sensitive to pan-FGFR inhibition. This is the first FGFR2-driven lung cancer GEMM, which can be applied across different cancer indications in a preclinical setting.
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- 2014
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5. Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors
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Akbay, E, Koyama, S., Carretero, J., Altabef, A., Tchaicha, J. H., Christensen, Camilla Laulund, Mikse, O. R., Cherniack, Andrew David, Beauchamp, Ellen Monica, Pugh, T, Wilkerson, M. D., Fecci, P, Butaney, M., Reibel, J. B., Soucheray, M., Cohoon, T. J., Janne, Pasi Antero, Meyerson, Matthew Langer, Hayes, D. N., Shapiro, Geoffrey Ira, Shimamura, T, Sholl, Lynette Marie, Rodig, Scott J., Freeman, Gordon James, Hammerman, Peter Seth, Dranoff, G, and Wong, Kwok-Kin
- Abstract
The success in lung cancer therapy with Programmed Death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased cytotoxic T cells and increased markers of T cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, and mechanistically link treatment response to PD-1 inhibition.
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- 2013
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6. Discovery and Characterization of a Novel Aryl Hydrocarbon Receptor Inhibitor, IK-175, and Its Inhibitory Activity on Tumor Immune Suppression.
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McGovern K, Castro AC, Cavanaugh J, Coma S, Walsh M, Tchaicha J, Syed S, Natarajan P, Manfredi M, Zhang XM, and Ecsedy J
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- Animals, Cytochrome P-450 CYP1A1 genetics, Cytochrome P-450 CYP1A1 metabolism, Cytokines metabolism, Humans, Immunosuppression Therapy, Kynurenine, Mice, Rats, Tumor Microenvironment, Neoplasms drug therapy, Receptors, Aryl Hydrocarbon genetics, Receptors, Aryl Hydrocarbon metabolism
- Abstract
Aryl hydrocarbon receptor (AHR) is a transcription factor that regulates the activity of multiple innate and adaptive immune cells subsequent to binding to numerous endogenous and exogenous ligands. For example, AHR is activated by the metabolite kynurenine, which is secreted into the tumor microenvironment by cancer cells leading to broad immunosuppression. Therefore, AHR inhibition provides a novel and ideal approach to stimulate immune-mediated recognition and subsequent eradication of tumor cells. We report here the discovery and characterization of IK-175, a novel, potent and selective AHR antagonist with favorable ADME and pharmacokinetic profiles in preclinical species. IK-175 inhibits AHR activity in experimental systems derived from multiple species including mouse, rat, monkey, and humans. In human primary immune cells, IK-175 decreased AHR target gene expression and anti-inflammatory cytokine release and increased proinflammatory cytokine release. Moreover, IK-175 led to a decrease in suppressive IL17A-, IL-22+ expressing T cells in a Th17 differentiation assay. IK-175 dose dependently blocks ligand-stimulated AHR activation of Cyp1a1 transcription in mouse liver and spleen, demonstrating on-target in vivo activity. IK-175 increases proinflammatory phenotype of the tumor microenvironment in mouse syngeneic tumors and in adjacent tumor-draining lymph nodes. As a monotherapy and combined with an anti-PD-1 antibody, IK-175 demonstrates antitumor activity in syngeneic mouse models of colorectal cancer and melanoma. IK-175 also demonstrates antitumor activity combined with liposomal doxorubicin in syngeneic mouse tumors. These studies provide rationale for targeting AHR in patients with cancer. IK-175 is being evaluated in a phase I clinical trial in patients with advanced solid tumors., (©2022 American Association for Cancer Research.)
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- 2022
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7. Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine.
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Campesato LF, Budhu S, Tchaicha J, Weng CH, Gigoux M, Cohen IJ, Redmond D, Mangarin L, Pourpe S, Liu C, Zappasodi R, Zamarin D, Cavanaugh J, Castro AC, Manfredi MG, McGovern K, Merghoub T, and Wolchok JD
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- Animals, Drug Resistance, Neoplasm, Humans, Immune Tolerance, Immunotherapy, Indoleamine-Pyrrole 2,3,-Dioxygenase genetics, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Mice, Neoplasms immunology, Neoplasms therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Receptors, Aryl Hydrocarbon genetics, Receptors, Aryl Hydrocarbon metabolism, Signal Transduction, Tryptophan Oxygenase genetics, Tryptophan Oxygenase metabolism, Tumor Cells, Cultured, Tumor Microenvironment, Kynurenine immunology, Macrophages immunology, Receptors, Aryl Hydrocarbon antagonists & inhibitors, T-Lymphocytes, Regulatory immunology
- Abstract
Tryptophan catabolism by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2 (IDO/TDO) promotes immunosuppression across different cancer types. The tryptophan metabolite L-Kynurenine (Kyn) interacts with the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) to drive the generation of Tregs and tolerogenic myeloid cells and PD-1 up-regulation in CD8
+ T cells. Here, we show that the AHR pathway is selectively active in IDO/TDO-overexpressing tumors and is associated with resistance to immune checkpoint inhibitors. We demonstrate that IDO-Kyn-AHR-mediated immunosuppression depends on an interplay between Tregs and tumor-associated macrophages, which can be reversed by AHR inhibition. Selective AHR blockade delays progression in IDO/TDO-overexpressing tumors, and its efficacy is improved in combination with PD-1 blockade. Our findings suggest that blocking the AHR pathway in IDO/TDO expressing tumors would overcome the limitation of single IDO or TDO targeting agents and constitutes a personalized approach to immunotherapy, particularly in combination with immune checkpoint inhibitors.- Published
- 2020
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8. Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer.
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Zadra G, Ribeiro CF, Chetta P, Ho Y, Cacciatore S, Gao X, Syamala S, Bango C, Photopoulos C, Huang Y, Tyekucheva S, Bastos DC, Tchaicha J, Lawney B, Uo T, D'Anello L, Csibi A, Kalekar R, Larimer B, Ellis L, Butler LM, Morrissey C, McGovern K, Palombella VJ, Kutok JL, Mahmood U, Bosari S, Adams J, Peluso S, Dehm SM, Plymate SR, and Loda M
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- Animals, Cell Line, Tumor, Enzyme Inhibitors pharmacology, Fatty Acid Synthase, Type I antagonists & inhibitors, Fatty Acid Synthase, Type I genetics, Fatty Acid Synthase, Type I metabolism, Humans, Male, Mice, Neoplasm Metastasis, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant pathology, Receptors, Androgen genetics, Xenograft Model Antitumor Assays, Lipogenesis, Neoplasm Proteins metabolism, Prostatic Neoplasms, Castration-Resistant metabolism, Receptors, Androgen metabolism, Signal Transduction
- Abstract
A hallmark of prostate cancer progression is dysregulation of lipid metabolism via overexpression of fatty acid synthase (FASN), a key enzyme in de novo fatty acid synthesis. Metastatic castration-resistant prostate cancer (mCRPC) develops resistance to inhibitors of androgen receptor (AR) signaling through a variety of mechanisms, including the emergence of the constitutively active AR variant V7 (AR-V7). Here, we developed an FASN inhibitor (IPI-9119) and demonstrated that selective FASN inhibition antagonizes CRPC growth through metabolic reprogramming and results in reduced protein expression and transcriptional activity of both full-length AR (AR-FL) and AR-V7. Activation of the reticulum endoplasmic stress response resulting in reduced protein synthesis was involved in IPI-9119-mediated inhibition of the AR pathway. In vivo, IPI-9119 reduced growth of AR-V7-driven CRPC xenografts and human mCRPC-derived organoids and enhanced the efficacy of enzalutamide in CRPC cells. In human mCRPC, both FASN and AR-FL were detected in 87% of metastases. AR-V7 was found in 39% of bone metastases and consistently coexpressed with FASN. In patients treated with enzalutamide and/or abiraterone FASN/AR-V7 double-positive metastases were found in 77% of cases. These findings provide a compelling rationale for the use of FASN inhibitors in mCRPCs, including those overexpressing AR-V7., Competing Interests: Conflict of interest statement: A patent relative to the findings described in this study has been filed from the Dana-Farber Cancer Institute (52095-584P01US). J.T., A.C., K.M., V.J.P., J.A. and S.P. were former employees of Infinity Pharmaceuticals. J.L.K. is a current employee of Infinity Pharmaceuticals., (Copyright © 2019 the Author(s). Published by PNAS.)
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- 2019
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9. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells.
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De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Cymerman DH, Budhu S, Ghosh A, Pink M, Tchaicha J, Douglas M, Tibbitts T, Sharma S, Proctor J, Kosmider N, White K, Stern H, Soglia J, Adams J, Palombella VJ, McGovern K, Kutok JL, Wolchok JD, and Merghoub T
- Subjects
- Animals, Cell Proliferation drug effects, Disease Models, Animal, Drug Resistance, Neoplasm immunology, Female, Humans, Immune Tolerance drug effects, Male, Melanoma pathology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Myeloid Cells enzymology, Neoplasm Metastasis drug therapy, Phenotype, Phosphatidylinositol 3-Kinases metabolism, Protein Kinase Inhibitors therapeutic use, T-Lymphocytes, Cytotoxic drug effects, T-Lymphocytes, Cytotoxic immunology, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Cell Cycle Checkpoints drug effects, Drug Resistance, Neoplasm drug effects, Melanoma drug therapy, Melanoma immunology, Myeloid Cells drug effects, Myeloid Cells immunology, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors pharmacology
- Abstract
Recent clinical trials using immunotherapy have demonstrated its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies against cytotoxic-T-lymphocyte-associated protein 4 or programmed cell death protein 1/programmed death-ligand 1 have displayed durable clinical responses in various cancers. Although these new immunotherapies have had a notable effect on cancer treatment, multiple mechanisms of immune resistance exist in tumours. Among the key mechanisms, myeloid cells have a major role in limiting effective tumour immunity. Growing evidence suggests that high infiltration of immune-suppressive myeloid cells correlates with poor prognosis and ICB resistance. These observations suggest a need for a precision medicine approach in which the design of the immunotherapeutic combination is modified on the basis of the tumour immune landscape to overcome such resistance mechanisms. Here we employ a pre-clinical mouse model system and show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumours. Furthermore, selective pharmacologic targeting of the gamma isoform of phosphoinositide 3-kinase (PI3Kγ), highly expressed in myeloid cells, restores sensitivity to ICB. We demonstrate that targeting PI3Kγ with a selective inhibitor, currently being evaluated in a phase 1 clinical trial (NCT02637531), can reshape the tumour immune microenvironment and promote cytotoxic-T-cell-mediated tumour regression without targeting cancer cells directly. Our results introduce opportunities for new combination strategies using a selective small molecule PI3Kγ inhibitor, such as IPI-549, to overcome resistance to ICB in patients with high levels of suppressive myeloid cell infiltration in tumours.
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- 2016
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10. Targeting the oncogenic MUC1-C protein inhibits mutant EGFR-mediated signaling and survival in non-small cell lung cancer cells.
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Kharbanda A, Rajabi H, Jin C, Tchaicha J, Kikuchi E, Wong KK, and Kufe D
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- Carcinoma, Non-Small-Cell Lung genetics, Cell Line, Tumor, Down-Regulation drug effects, Down-Regulation genetics, Humans, Lung Neoplasms genetics, Oncogenes drug effects, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt genetics, Antineoplastic Agents pharmacology, Carcinoma, Non-Small-Cell Lung drug therapy, Cell Survival drug effects, ErbB Receptors metabolism, Lung Neoplasms drug therapy, Mucin-1 metabolism, Signal Transduction drug effects
- Abstract
Purpose: 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 in mutant EGFR signaling is not known., Experimental Design: Targeting the oncogenic MUC1 C-terminal subunit (MUC1-C) in NSCLC cells harboring mutant EGFR was studied for effects on signaling, growth, clonogenic survival, and tumorigenicity., Results: Stable silencing of MUC1-C in H1975/EGFR(L858R/T790M) cells resulted in downregulation of AKT signaling and inhibition of growth, colony formation, and tumorigenicity. Similar findings were obtained when MUC1-C was silenced in gefitinib-resistant PC9GR cells expressing EGFR(delE746_A750/T790M). The results further show that expression of a MUC1-C(CQC → AQA) mutant, which blocks MUC1-C homodimerization, suppresses EGFR(T790M), AKT and MEK → ERK activation, colony formation, and tumorigenicity. In concert with these results, treatment of H1975 and PC9GR cells with GO-203, a cell-penetrating peptide that blocks MUC1-C homodimerization, resulted in inhibition of EGFR, AKT, and MEK → ERK signaling and in loss of survival. Combination studies of GO-203 and afatinib, an irreversible inhibitor of EGFR, further demonstrate that these agents are synergistic in inhibiting growth of NSCLC cells harboring the activating EGFR(T790M) or EGFR(delE746-A750) mutants., Conclusions: These findings indicate that targeting MUC1-C inhibits mutant EGFR signaling and survival, and thus represents a potential approach alone and in combination for the treatment of NSCLCs resistant to EGFR kinase inhibitors., (©2014 American Association for Cancer Research.)
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- 2014
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11. Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinoma.
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Liao RG, Jung J, Tchaicha J, Wilkerson MD, Sivachenko A, Beauchamp EM, Liu Q, Pugh TJ, Pedamallu CS, Hayes DN, Gray NS, Getz G, Wong KK, Haddad RI, Meyerson M, and Hammerman PS
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- Animals, Carcinogenesis drug effects, Carcinogenesis genetics, Carcinogenesis metabolism, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell metabolism, Cell Transformation, Neoplastic drug effects, Cell Transformation, Neoplastic genetics, Dimerization, Humans, Indazoles, Interleukin-3 genetics, Interleukin-3 metabolism, Ligands, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Mice, Mice, Nude, NIH 3T3 Cells, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology, Receptor, Fibroblast Growth Factor, Type 2 metabolism, Receptor, Fibroblast Growth Factor, Type 3 metabolism, Sulfonamides pharmacology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Squamous Cell genetics, Lung Neoplasms genetics, Mutation, Receptor, Fibroblast Growth Factor, Type 2 genetics, Receptor, Fibroblast Growth Factor, Type 3 genetics
- Abstract
A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SCC) has recently been reported, enabling the identification of genomic events that contribute to the oncogenesis of this disease. In lung SCC, one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3, each of which are observed in 3% of samples, for a mutation rate of 6% across both genes. Using cell culture and xenograft models, we show that several of these mutations drive cellular transformation. Transformation can be reversed by small-molecule FGFR inhibitors currently being developed for clinical use. We also show that mutations in the extracellular domains of FGFR2 lead to constitutive FGFR dimerization. In addition, we report a patient with an FGFR2-mutated oral SCC who responded to the multitargeted tyrosine kinase inhibitor pazopanib. These findings provide new insights into driving oncogenic events in a subset of lung squamous cancers, and recommend future clinical studies with FGFR inhibitors in patients with lung and head and neck SCC.
- Published
- 2013
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