28 results on '"Allaj V"'
Search Results
2. OA07.01 Signatures of Plasticity and Immunosuppression in a Single-Cell Atlas of Human Small Cell Lung Cancer
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Chan, J., primary, Quintanal-Villalonga, A., additional, Gao, V., additional, Xie, Y., additional, Allaj, V., additional, Chaudhary, O., additional, Masilionis, I., additional, Egger, J., additional, Chow, A., additional, Walle, T., additional, Ciampricotti, M., additional, Offin, M., additional, Lai, V., additional, Bott, M., additional, Jones, D., additional, Hollmann, T., additional, Nawy, T., additional, Mazutis, L., additional, Sen, T., additional, Pe'Er, D., additional, and Rudin, C., additional
- Published
- 2021
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3. 2MO XPO1 inhibition strongly sensitizes to first-line and second-line therapy in small cell lung cancer
- Author
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Quintanal-Villalonga, Á., primary, Taniguchi, H., additional, Hao, Y., additional, Chow, A., additional, Zhan, Y.A., additional, Uddin, F., additional, Allaj, V., additional, Manoj, P., additional, Shah, N., additional, Chan, J.M., additional, Offin, M., additional, Ciampricotti, M., additional, Egger, J., additional, Qiu, J., additional, De Stanchina, E., additional, Hollmann, T.J., additional, Koche, R.P., additional, Sen, T., additional, Poirier, J.T., additional, and Rudin, C.M., additional
- Published
- 2021
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4. 1MO Multi-omic characterization of lung tumors identify AKT and EZH2 as potential therapeutic targets in adenocarcinoma-to-squamous transdifferentiation
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Quintanal-Villalonga, Á., primary, Taniguchi, H., additional, Zhan, Y.A., additional, Hasan, M.M., additional, Chavan, S.S., additional, Uddin, F., additional, Allaj, V., additional, Manoj, P., additional, Shah, N., additional, Ciampricotti, M., additional, Bhanot, U., additional, Egger, J., additional, Qiu, J., additional, De Stanchina, E., additional, Rekhtman, N., additional, Houck-Loomis, B., additional, Koche, R.P., additional, Yu, H.A., additional, Sen, T., additional, and Rudin, C.M., additional
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- 2021
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5. MA16.03 CRISPR Screen Reveals XPO1 as a Therapeutic Target Strongly Sensitizing to First and Second Line Therapy in Small Cell Lung Cancer
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Quintanal-Villalonga, A., primary, Taniguchi, H., additional, Hao, Y., additional, Chow, A., additional, Zhan, Y., additional, Chavan, S., additional, Uddin, F., additional, Allaj, V., additional, Manoj, P., additional, Shah, N., additional, Chan, J., additional, Offin, M., additional, Egger, J., additional, Bhanot, U., additional, Qiu, J., additional, De Stanchina, E., additional, Sen, T., additional, Poirier, J.t., additional, and Rudin, C., additional
- Published
- 2021
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6. 1800O Multi-omic characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation
- Author
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Quintanal-Villalonga, Á., primary, Taniguchi, H., additional, Zhan, Y.A., additional, Hasan, M.M., additional, Chavan, S.S., additional, Uddin, F., additional, Allaj, V., additional, Manoj, P., additional, Shah, N.S., additional, Chan, J.M., additional, Ciampricotti, M., additional, Chow, A., additional, Bhanot, U., additional, Egger, J., additional, Qiu, J., additional, De Stanchina, E., additional, Rekhtman, N., additional, Yu, H.A., additional, Sen, T., additional, and Rudin, C.M., additional
- Published
- 2021
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7. MA16.03 CRISPR Screen Reveals XPO1as a Therapeutic Target Strongly Sensitizing to First and Second Line Therapy in Small Cell Lung Cancer
- Author
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Quintanal-Villalonga, A., Taniguchi, H., Hao, Y., Chow, A., Zhan, Y., Chavan, S., Uddin, F., Allaj, V., Manoj, P., Shah, N., Chan, J., Offin, M., Egger, J., Bhanot, U., Qiu, J., De Stanchina, E., Sen, T., Poirier, J.t., and Rudin, C.
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- 2021
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8. Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade
- Author
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Pai, JA, primary, Hellmann, MD, additional, Sauter, JL, additional, Mattar, M, additional, Rizvi, H, additional, Woo, HJ, additional, Shah, N, additional, Ngyuen, EX, additional, Uddin, FZ, additional, Quintanal-Villalonga, A, additional, Chan, JM, additional, Manoj, P, additional, Allaj, V, additional, Baine, M, additional, Bhanot, UK, additional, Jain, M, additional, Linkov, I, additional, Meng, F, additional, Brown, D, additional, Chaft, JE, additional, Plodowski, AJ, additional, Gigoux, M, additional, Won, H, additional, Sen, T, additional, Wells, DK, additional, Donoghue, MTA, additional, de Stanchina, E, additional, Wolchok, JD, additional, Boolis, B, additional, Merghoub, T, additional, Rudin, CM, additional, Chow, A, additional, and Satpathy, AT, additional
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9. The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer
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Chow, A, primary, Uddin, FZ, additional, Liu, M, additional, Dobrin, A, additional, Nabet, BY, additional, Mangarin, L, additional, Lavin, Y, additional, Rizvi, H, additional, Tischfield, S, additional, Quintanal-Villalonga, A, additional, Chan, JM, additional, Shah, N, additional, Allaj, V, additional, Manoj, P, additional, Mattar, M, additional, Meneses, M, additional, Landau, R, additional, Ward, M, additional, Kulick, A, additional, Kwong, C, additional, Wierzbicki, M, additional, Yavner, J, additional, Egger, J, additional, Chavan, SS, additional, Farillas, A, additional, Holland, A, additional, Sridhar, H, additional, Ciampricotti, M, additional, Hirschhorn, D, additional, Guan, X, additional, Richards, AL, additional, Heller, G, additional, Mansilla-Soto, J, additional, Sadelain, M, additional, Klebanoff, CA, additional, Hellmann, MD, additional, Sen, T, additional, de Stanchina, E, additional, Wolchok, JD, additional, Merghoub, T, additional, and Rudin, CM, additional
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10. Early Circulating Tumor DNA Shedding Kinetics for Prediction of Platinum Sensitivity in Patients With Small Cell Lung Cancer.
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Murciano-Goroff YR, Hui AB, Araujo Filho JA, Hamilton EG, Chabon JJ, Moding EJ, Bonilla RF, Lebow ES, Gomez D, Rimner A, Ginsberg MS, Offin M, Kundra R, Allaj V, Norton L, Reis-Filho JS, Razavi P, Drilon A, Jones DR, Isbell JM, Lai WV, Rudin CM, Alizadeh AA, Li BT, and Diehn M
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Drug Resistance, Neoplasm genetics, Adult, Platinum therapeutic use, Antineoplastic Agents therapeutic use, Circulating Tumor DNA blood, Circulating Tumor DNA genetics, Small Cell Lung Carcinoma drug therapy, Small Cell Lung Carcinoma blood, Small Cell Lung Carcinoma genetics, Lung Neoplasms drug therapy, Lung Neoplasms blood, Lung Neoplasms genetics
- Abstract
Purpose: Small cell lung cancer (SCLC) is characterized by rapid progression after platinum resistance. Circulating tumor (ctDNA) dynamics early in treatment may help determine platinum sensitivity., Materials and Methods: Serial plasma samples were collected from patients receiving platinum-based chemotherapy for SCLC on the first 3 days of cycle one and on the first days of subsequent cycles with paired samples collected both before and again after infusions. Tumor-informed plasma analysis was carried out using CAncer Personalized Profiling by deep Sequencing (CAPP-Seq). The mean variant allele frequency (VAF) of all pretreatment mutations was tracked in subsequent blood draws and correlated with radiologic response., Results: ctDNA kinetics were assessed in 122 samples from 21 patients. Pretreatment VAF did not differ significantly between patients who did and did not respond to chemotherapy (mean 22.5% v 4.6%, P = .17). A slight increase in ctDNA on cycle 1, day 1 immediately post-treatment was seen in six of the seven patients with available draws (fold change from baseline: 1.01-1.44), half of whom achieved a response. All patients who responded had a >2-fold decrease in mean VAF on cycle 2 day 1 (C2D1). Progression-free survival (PFS) and overall survival (OS) were significantly longer in patients with a >2-fold decrease in mean VAF after one treatment cycle (6.8 v 2.6 months, log-rank P = .0004 and 21.7 v 6.4 months, log rank P = .04, respectively)., Conclusion: A >2-fold decrease in ctDNA concentration was observed by C2D1 in all patients who were sensitive to platinum-based therapy and was associated with longer PFS and OS.
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- 2024
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11. Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade.
- Author
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Pai JA, Hellmann MD, Sauter JL, Mattar M, Rizvi H, Woo HJ, Shah N, Nguyen EM, Uddin FZ, Quintanal-Villalonga A, Chan JM, Manoj P, Allaj V, Baine MK, Bhanot UK, Jain M, Linkov I, Meng F, Brown D, Chaft JE, Plodkowski AJ, Gigoux M, Won HH, Sen T, Wells DK, Donoghue MTA, de Stanchina E, Wolchok JD, Loomis B, Merghoub T, Rudin CM, Chow A, and Satpathy AT
- Subjects
- Humans, CD8-Positive T-Lymphocytes, Immune Checkpoint Inhibitors therapeutic use, Receptors, Antigen, T-Cell, Clone Cells, Tumor Microenvironment, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Paired single-cell RNA and T cell receptor sequencing (scRNA/TCR-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scRNA/TCR-seq analysis of 187,650 T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients with non-small cell lung cancer after immune checkpoint blockade (ICB). Regions with viable cancer cells are enriched for exhausted CD8
+ T cells, regulatory CD4+ T cells (Treg), and follicular helper CD4+ T cells (TFH). Tracking T cell clonotypes across tissues, combined with neoantigen specificity assays, reveals that TFH and tumor-specific exhausted CD8+ T cells are clonally linked to TCF7+ SELL+ progenitors in tumor draining LNs, and progressive exhaustion trajectories of CD8+ T, Treg, and TFH cells with proximity to the tumor microenvironment. Finally, longitudinal tracking of tumor-specific CD8+ and CD4+ T cell clones reveals persistence in the peripheral blood for years after ICB therapy., Competing Interests: Declaration of interests M.D.H. reports advisory/consulting fees from Achilles, Adagene, Adicet, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Da Volaterra, Eli Lilly, Genentech, Genzyme/Sanofi, Immunai, Instill Bio, Janssen, Mana Therapeutics, Merk, Mirati, Pact Pharma, Regeneron, Roche, and Shattuck Labs; research funding from Bristol Myers Squibb; stock interest with Arcus, Factorial, Immunai, and Shattuck Labs; a patent filed by Memorial Sloan Kettering related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from Personal Genome Diagnostics (PGDx); after the completion of this work, M.D.H .began as an employee (and equity holder) at AstraZeneca. J.D.W. has Equity in Apricity, Arsenal IO, Ascentage, Beigene, Imvaq, Linneaus, Georgiamune, Maverick, Tizona Pharmaceuticals, and Trieza. J.D.W. is a co-inventor on the following patent application: Xenogeneic (Canine) DNA vaccines, myeloid-derived suppressor cell (MDSC) assay, anti-PD1 antibody, anti-CTLA4 antibodies, anti-GITR antibodies and methods of use thereof, Newcastle disease viruses for cancer therapy, and prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment. J.D.W. and T.M. are co-inventors on patent applications related to CD40 and in situ vaccination (PCT/US2016/045970). T.M. is a consultant for Immunos Therapeutics and Pfizer. T.M. is a cofounder of and equity holder in IMVAQ Therapeutics. T.M. receives research funding from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus–based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo, and PharmaMar and is on the scientific advisory boards of Elucida, Bridge, and Harpoon. A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Merck Research Laboratories. The remaining authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
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12. The ectonucleotidase CD39 identifies tumor-reactive CD8 + T cells predictive of immune checkpoint blockade efficacy in human lung cancer.
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Chow A, Uddin FZ, Liu M, Dobrin A, Nabet BY, Mangarin L, Lavin Y, Rizvi H, Tischfield SE, Quintanal-Villalonga A, Chan JM, Shah N, Allaj V, Manoj P, Mattar M, Meneses M, Landau R, Ward M, Kulick A, Kwong C, Wierzbicki M, Yavner J, Egger J, Chavan SS, Farillas A, Holland A, Sridhar H, Ciampricotti M, Hirschhorn D, Guan X, Richards AL, Heller G, Mansilla-Soto J, Sadelain M, Klebanoff CA, Hellmann MD, Sen T, de Stanchina E, Wolchok JD, Merghoub T, and Rudin CM
- Subjects
- Humans, Immune Checkpoint Inhibitors therapeutic use, CD8-Positive T-Lymphocytes, Immunotherapy, Lung Neoplasms genetics, Carcinoma, Non-Small-Cell Lung genetics
- Abstract
Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8
+ T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8+ T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39+ CD8+ T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39+ CD8+ T cells. Higher baseline frequency of CD39+ CD8+ T cells conferred improved clinical outcomes from ICB therapy. Furthermore, a gene signature of CD39+ CD8+ T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. These findings highlight CD39 as a proxy of tumor-reactive CD8+ T cells in human lung cancer., Competing Interests: Declaration of interests C.A.K. received research funding support from Kite/Gilead and Intima Bioscience; is on the Scientific and/or Clinical Advisory Boards of Achilles Therapeutics, Aleta BioTherapeutics, Bellicum Pharmaceuticals, Catamaran Bio, Obsidian Therapeutics, and T-knife; and has performed consulting services for Bristol Myers Squibb, PACT Pharma, and Roche/Genentech. C.A.K. is a co-inventor on patent applications related to TCRs targeting public neoantigens unrelated to the current work. M.D.H. received a research grant from BMS; personal fees from Achilles, Arcus, AstraZeneca, Blueprint, BMS, Genentech/Roche, Genzyme, Immunai, Instil Bio, Janssen, Merck, Mirati, Natera, Nektar, Pact Pharma, Regeneron, Shattuck Labs, and Syndax; and equity options from Arcus, Factorial, Immunai, and Shattuck Labs. A patent filed by MSKCC related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) is pending and licensed by PGDx. J.D.W. is a consultant for Amgen, Apricity, Ascentage Pharma, Astellas, AstraZeneca, Bicara Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, CellCarta, Chugai, Daiichi Sankyo, Dragonfly, Georgiamune, Idera, Imvaq, Larkspur, Maverick Therapeutics, Merck, Psioxus, Recepta, Tizona, Trishula, Sellas, Surface Oncology, and Werewolf Therapeutics. J.D.W. receives grant/research support from Bristol Myers Squibb and Sephora. J.D.W. has equity in Apricity, Arsenal IO, Ascentage, Beigene, Imvaq, Linneaus, Georgiamune, Maverick, Tizona Pharmaceuticals, and Trieza. J.D.W. is a co-inventor on the following patent application: xenogeneic (canine) DNA vaccines, myeloid-derived suppressor cell (MDSC) assay, anti-PD1 antibody, anti-CTLA4 antibodies, anti-GITR antibodies and methods of use thereof, Newcastle disease viruses for cancer therapy, and prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment. J.D.W. and T.M. are co-inventors on patent applications related to CD40 and in situ vaccination (PCT/US2016/045970). T.M. is a consultant for Immunos Therapeutics and Pfizer. T.M. is a cofounder of and equity holder in IMVAQ Therapeutics. T.M. receives research funding from Bristol Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus-based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo, and PharmaMar and is on the scientific advisory boards of Elucida, Bridge, and Harpoon. B.Y.N. and X.G. are employees and stockholders of Genentech/Roche., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2023
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13. Genomic and transcriptomic analysis of a diffuse pleural mesothelioma patient-derived xenograft library.
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Offin M, Sauter JL, Tischfield SE, Egger JV, Chavan S, Shah NS, Manoj P, Ventura K, Allaj V, de Stanchina E, Travis W, Ladanyi M, Rimner A, Rusch VW, Adusumilli PS, Poirier JT, Zauderer MG, Rudin CM, and Sen T
- Subjects
- Animals, Humans, Xenograft Model Antitumor Assays, Heterografts, Proteomics, Genomics, Disease Models, Animal, Transcriptome, Mesothelioma drug therapy, Mesothelioma genetics
- Abstract
Background: Diffuse pleural mesothelioma (DPM) is an aggressive malignancy that, despite recent treatment advances, has unacceptably poor outcomes. Therapeutic research in DPM is inhibited by a paucity of preclinical models that faithfully recapitulate the human disease., Methods: We established 22 patient-derived xenografts (PDX) from 22 patients with DPM and performed multi-omic analyses to deconvolute the mutational landscapes, global expression profiles, and molecular subtypes of these PDX models and compared features to those of the matched primary patient tumors. Targeted next-generation sequencing (NGS; MSK-IMPACT), immunohistochemistry, and histologic subtyping were performed on all available samples. RNA sequencing was performed on all available PDX samples. Clinical outcomes and treatment history were annotated for all patients. Platinum-doublet progression-free survival (PFS) was determined from the start of chemotherapy until radiographic/clinical progression and grouped into < or ≥ 6 months., Results: PDX models were established from both treatment naïve and previously treated samples and were noted to closely resemble the histology, genomic landscape, and proteomic profiles of the parent tumor. After establishing the validity of the models, transcriptomic analyses demonstrated overexpression in WNT/β-catenin, hedgehog, and TGF-β signaling and a consistent suppression of immune-related signaling in PDXs derived from patients with worse clinical outcomes., Conclusions: These data demonstrate that DPM PDX models closely resemble the genotype and phenotype of parental tumors, and identify pathways altered in DPM for future exploration in preclinical studies., (© 2022. The Author(s).)
- Published
- 2022
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14. Protocol to dissociate, process, and analyze the human lung tissue using single-cell RNA-seq.
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Quintanal-Villalonga Á, Chan JM, Masilionis I, Gao VR, Xie Y, Allaj V, Chow A, Poirier JT, Pe'er D, Rudin CM, and Mazutis L
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- Humans, Sequence Analysis, RNA methods, RNA-Seq, Biopsy, Fine-Needle methods, Gene Expression Profiling methods, Lung
- Abstract
We report a protocol for obtaining high-quality single-cell transcriptomics data from human lung biospecimens acquired from core needle biopsies, fine-needle aspirates, surgical resection, and pleural effusions. The protocol relies upon the brief mechanical and enzymatic disruption of tissue, enrichment of live cells by fluorescence-activated cell sorting (FACS), and droplet-based single-cell RNA sequencing (scRNA-seq). The protocol also details a procedure for analyzing the scRNA-seq data. For complete details on the use and execution of this protocol, please refer to Chan et al. (2021)., Competing Interests: A.Q.V. reports honoraria from AstraZeneca. M.O. reports advisory roles for PharMar, Novartis, and Targeted Oncology and reports honoraria from Bristol-Myers Squibb and Merck Sharp & Dohme. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, Astra Zeneca, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Jazz, Lilly, Pfizer, PharmaMar, Syros, and Vavotek. C.M.R. serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics. L.M. is shareholder and scientific advisor of Droplet Genomics., (© 2022 The Author(s).)
- Published
- 2022
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15. Targeting Lysine-Specific Demethylase 1 Rescues Major Histocompatibility Complex Class I Antigen Presentation and Overcomes Programmed Death-Ligand 1 Blockade Resistance in SCLC.
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Nguyen EM, Taniguchi H, Chan JM, Zhan YA, Chen X, Qiu J, de Stanchina E, Allaj V, Shah NS, Uddin F, Manoj P, Liu M, Cai SF, Levine R, Quintanal-Villalonga Á, Sen T, Chow A, and Rudin CM
- Subjects
- Animals, Antigens, Neoplasm, B7-H1 Antigen, Genes, MHC Class I, Humans, Mice, Antigen Presentation, Histocompatibility Antigens Class I genetics, Histone Demethylases genetics, Histone Demethylases metabolism, Lung Neoplasms pathology, Small Cell Lung Carcinoma pathology
- Abstract
Introduction: SCLC is a highly aggressive neuroendocrine tumor that is characterized by early acquired therapeutic resistance and modest benefit from immune checkpoint blockade (ICB). Repression of the major histocompatibility complex class I (MHC-I) represents a key mechanism driving resistance to T cell-based immunotherapies., Methods: We evaluated the role of the lysine-specific demethylase 1 (LSD1) as a determinant of MHC-I expression, functional antigen presentation, and immune activation in SCLC in vitro and in vivo through evaluation of both human SCLC cell lines and immunocompetent mouse models., Results: We found that targeted inhibition of LSD1 in SCLC restores MHC-I cell surface expression and transcriptionally activates genes encoding the antigen presentation pathway. LSD1 inhibition further activates interferon signaling, induces tumor-intrinsic immunogenicity, and sensitizes SCLC cells to MHC-I-restricted T cell cytolysis. Combination of LSD1 inhibitor with ICB augments the antitumor immune response in refractory SCLC models. Together, these data define a role for LSD1 as a potent regulator of MHC-I antigen presentation and provide rationale for combinatory use of LSD1 inhibitors with ICB to improve therapeutic response in SCLC., Conclusions: Epigenetic silencing of MHC-I in SCLC contributes to its poor response to ICB. Our study identifies a previously uncharacterized role for LSD1 as a regulator of MHC-I antigen presentation in SCLC. LSD1 inhibition enables MHC-I-restricted T cell cytolysis, induces immune activation, and augments the antitumor immune response to ICB in SCLC., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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16. WEE1 inhibition enhances the antitumor immune response to PD-L1 blockade by the concomitant activation of STING and STAT1 pathways in SCLC.
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Taniguchi H, Caeser R, Chavan SS, Zhan YA, Chow A, Manoj P, Uddin F, Kitai H, Qu R, Hayatt O, Shah NS, Quintanal Villalonga Á, Allaj V, Nguyen EM, Chan J, Michel AO, Mukae H, de Stanchina E, Rudin CM, and Sen T
- Subjects
- Animals, Cell Line, Tumor, Drug Synergism, Immune Checkpoint Inhibitors pharmacology, Mice, Protein Kinase Inhibitors pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, B7-H1 Antigen antagonists & inhibitors, B7-H1 Antigen immunology, Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins metabolism, Lung Neoplasms drug therapy, Lung Neoplasms immunology, Lung Neoplasms metabolism, Lung Neoplasms pathology, Membrane Proteins metabolism, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases metabolism, STAT1 Transcription Factor metabolism, Small Cell Lung Carcinoma drug therapy, Small Cell Lung Carcinoma immunology, Small Cell Lung Carcinoma metabolism, Small Cell Lung Carcinoma pathology
- Abstract
Small cell lung cancers (SCLCs) have high mutational burden but are relatively unresponsive to immune checkpoint blockade (ICB). Using SCLC models, we demonstrate that inhibition of WEE1, a G2/M checkpoint regulator induced by DNA damage, activates the STING-TBK1-IRF3 pathway, which increases type I interferons (IFN-α and IFN-β) and pro-inflammatory chemokines (CXCL10 and CCL5), facilitating an immune response via CD8
+ cytotoxic T cell infiltration. We further show that WEE1 inhibition concomitantly activates the STAT1 pathway, increasing IFN-γ and PD-L1 expression. Consistent with these findings, combined WEE1 inhibition (AZD1775) and PD-L1 blockade causes remarkable tumor regression, activation of type I and II interferon pathways, and infiltration of cytotoxic T cells in multiple immunocompetent SCLC genetically engineered mouse models, including an aggressive model with stabilized MYC. Our study demonstrates cell-autonomous and immune-stimulating activity of WEE1 inhibition in SCLC models. Combined inhibition of WEE1 plus PD-L1 blockade represents a promising immunotherapeutic approach in SCLC., Competing Interests: Declaration of interests C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, Astra Zeneca, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Jazz, Lilly, Pfizer, PharmaMar, Syros, and Vavotek. C.M.R. serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics. T.S. has received research grant from Jazz Pharmaceuticals. A.O.M. is currently employed by Regeneron Pharmaceuticals; none of the work herein was funded or sponsored by Regeneron. H.M. has received a commercial research grant from Chugai Pharm and speaking honoraria from Astra Zeneca and MSD, a subsidiary of Merck & Co., Inc., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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17. Genomic and transcriptomic analysis of a library of small cell lung cancer patient-derived xenografts.
- Author
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Caeser R, Egger JV, Chavan S, Socci ND, Jones CB, Kombak FE, Asher M, Roehrl MH, Shah NS, Allaj V, Manoj P, Tischfield SE, Kulick A, Meneses M, Iacobuzio-Donahue CA, Lai WV, Bhanot U, Baine MK, Rekhtman N, Hollmann TJ, de Stanchina E, Poirier JT, Rudin CM, and Sen T
- Subjects
- Heterografts, Humans, Proteomics, Transcriptome genetics, Lung Neoplasms genetics, Lung Neoplasms pathology, Small Cell Lung Carcinoma genetics, Small Cell Lung Carcinoma pathology
- Abstract
Access to clinically relevant small cell lung cancer (SCLC) tissue is limited because surgical resection is rare in metastatic SCLC. Patient-derived xenografts (PDX) and circulating tumor cell-derived xenografts (CDX) have emerged as valuable tools to characterize SCLC. Here, we present a resource of 46 extensively annotated PDX/CDX models derived from 33 patients with SCLC. We perform multi-omic analyses, using targeted tumor next-generation sequencing, RNA-sequencing, and immunohistochemistry to deconvolute the mutational landscapes, global expression profiles, and molecular subtypes of these SCLC models. SCLC subtypes characterized by transcriptional regulators, ASCL1, NEUROD1 and POU2F3 are confirmed in this cohort. A subset of SCLC clinical specimens, including matched PDX/CDX and clinical specimen pairs, confirm that the primary features and genomic and proteomic landscapes of the tumors of origin are preserved in the derivative PDX models. This resource provides a powerful system to study SCLC biology., (© 2022. The Author(s).)
- Published
- 2022
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18. Inhibition of XPO1 Sensitizes Small Cell Lung Cancer to First- and Second-Line Chemotherapy.
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Quintanal-Villalonga A, Taniguchi H, Hao Y, Chow A, Zhan YA, Chavan SS, Uddin F, Allaj V, Manoj P, Shah NS, Chan JM, Offin M, Ciampricotti M, Ray-Kirton J, Egger J, Bhanot U, Linkov I, Asher M, Roehrl MH, Qiu J, de Stanchina E, Hollmann TJ, Koche RP, Sen T, Poirier JT, and Rudin CM
- Subjects
- Animals, Cell Line, Tumor, Humans, Lung Neoplasms pathology, Mice, Small Cell Lung Carcinoma pathology, Exportin 1 Protein, Karyopherins metabolism, Lung Neoplasms drug therapy, Receptors, Cytoplasmic and Nuclear metabolism, Small Cell Lung Carcinoma drug therapy
- Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis and extreme lethality. The backbone of SCLC treatment over the past several decades has been platinum-based doublet chemotherapy, with the recent addition of immunotherapy providing modest benefits in a subset of patients. However, nearly all patients treated with systemic therapy quickly develop resistant disease, and there is an absence of effective therapies for recurrent and progressive disease. Here we conducted CRISPR-Cas9 screens using a druggable genome library in multiple SCLC cell lines representing distinct molecular subtypes. This screen nominated exportin-1, encoded by XPO1 , as a therapeutic target. XPO1 was highly and ubiquitously expressed in SCLC relative to other lung cancer histologies and other tumor types. XPO1 knockout enhanced chemosensitivity, and exportin-1 inhibition demonstrated synergy with both first- and second-line chemotherapy. The small molecule exportin-1 inhibitor selinexor in combination with cisplatin or irinotecan dramatically inhibited tumor growth in chemonaïve and chemorelapsed SCLC patient-derived xenografts, respectively. Together these data identify exportin-1 as a promising therapeutic target in SCLC, with the potential to markedly augment the efficacy of cytotoxic agents commonly used in treating this disease. SIGNIFICANCE: CRISPR-Cas9 screening nominates exportin-1 as a therapeutic target in SCLC, and exportin-1 inhibition enhances chemotherapy efficacy in patient-derived xenografts, providing a novel therapeutic opportunity in this disease., (©2021 American Association for Cancer Research.)
- Published
- 2022
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19. Rlf-Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer.
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Ciampricotti M, Karakousi T, Richards AL, Quintanal-Villalonga À, Karatza A, Caeser R, Costa EA, Allaj V, Manoj P, Spainhower KB, Kombak FE, Sanchez-Rivera FJ, Jaspers JE, Zavitsanou AM, Maddalo D, Ventura A, Rideout WM, Akama-Garren EH, Jacks T, Donoghue MTA, Sen T, Oliver TG, Poirier JT, Papagiannakopoulos T, and Rudin CM
- Subjects
- Animals, Carcinogenesis genetics, Cell Line, Tumor, Gene Fusion, Genes, myc, Mice, Proto-Oncogene Proteins c-myc, Telomere-Binding Proteins, Lung Neoplasms genetics, Lung Neoplasms pathology, Small Cell Lung Carcinoma genetics, Small Cell Lung Carcinoma pathology
- Abstract
Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel therapeutic targets. Recurrent genomic rearrangements have been identified in SCLC, most notably an in-frame gene fusion between RLF and MYCL found in up to 7% of the predominant ASCL1-expressing subtype. To explore the role of this fusion in oncogenesis and tumor progression, we used CRISPR/Cas9 somatic editing to generate a Rlf-Mycl-driven mouse model of SCLC. RLF-MYCL fusion accelerated transformation and proliferation of murine SCLC and increased metastatic dissemination and the diversity of metastatic sites. Tumors from the RLF-MYCL genetically engineered mouse model displayed gene expression similarities with human RLF-MYCL SCLC. Together, our studies support RLF-MYCL as the first demonstrated fusion oncogenic driver in SCLC and provide a new preclinical mouse model for the study of this subtype of SCLC., Significance: The biological and therapeutic implications of gene fusions in SCLC, an aggressive metastatic lung cancer, are unknown. Our study investigates the functional significance of the in-frame RLF-MYCL gene fusion by developing a Rlf-Mycl-driven genetically engineered mouse model and defining the impact on tumor growth and metastasis. This article is highlighted in the In This Issue feature, p. 2945., (©2021 American Association for Cancer Research.)
- Published
- 2021
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20. Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer.
- Author
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Chan JM, Quintanal-Villalonga Á, Gao VR, Xie Y, Allaj V, Chaudhary O, Masilionis I, Egger J, Chow A, Walle T, Mattar M, Yarlagadda DVK, Wang JL, Uddin F, Offin M, Ciampricotti M, Qeriqi B, Bahr A, de Stanchina E, Bhanot UK, Lai WV, Bott MJ, Jones DR, Ruiz A, Baine MK, Li Y, Rekhtman N, Poirier JT, Nawy T, Sen T, Mazutis L, Hollmann TJ, Pe'er D, and Rudin CM
- Subjects
- Cell Plasticity, Humans, Neoplasm Metastasis, Prognosis, Sequence Analysis, RNA, Single-Cell Analysis, Survival Analysis, Gene Expression Profiling methods, Lung Neoplasms genetics, Phospholipase C gamma genetics, Small Cell Lung Carcinoma genetics
- Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively). To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 155,098 transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes. We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discover a PLCG2-high SCLC phenotype with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival. SCLC exhibits greater immune sequestration and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less immune infiltrate and greater T cell dysfunction than SCLC-A. We identify a profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors that is particularly associated with the recurrent, PLCG2-high subpopulation., Competing Interests: Declaration of interests J.M.C. reports an advisory role in VantAI. A.Q.-V. reports honoraria from AstraZeneca. M.O. reports advisory roles for PharMar, Novartis, and Targeted Oncology, and reports honoraria from Bristol-Myers Squibb and Merck Sharp & Dohme. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, AstraZeneca, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Jazz, Lilly, Pfizer, PharmaMar, Syros, and Vavotek. C.M.R. serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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21. Comprehensive molecular characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation.
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Quintanal-Villalonga A, Taniguchi H, Zhan YA, Hasan MM, Chavan SS, Meng F, Uddin F, Allaj V, Manoj P, Shah NS, Chan JM, Ciampricotti M, Chow A, Offin M, Ray-Kirton J, Egger JD, Bhanot UK, Linkov I, Asher M, Roehrl MH, Ventura K, Qiu J, de Stanchina E, Chang JC, Rekhtman N, Houck-Loomis B, Koche RP, Yu HA, Sen T, and Rudin CM
- Subjects
- Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung metabolism, Animals, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell metabolism, Cell Transdifferentiation, Humans, Mice, Inbred NOD, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-myc genetics, Signal Transduction, Transcriptome, Mice, Adenocarcinoma of Lung pathology, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell pathology, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-myc metabolism
- Abstract
Background: Lineage plasticity, the ability to transdifferentiate among distinct phenotypic identities, facilitates therapeutic resistance in cancer. In lung adenocarcinomas (LUADs), this phenomenon includes small cell and squamous cell (LUSC) histologic transformation in the context of acquired resistance to targeted inhibition of driver mutations. LUAD-to-LUSC transdifferentiation, occurring in up to 9% of EGFR-mutant patients relapsed on osimertinib, is associated with notably poor prognosis. We hypothesized that multi-parameter profiling of the components of mixed histology (LUAD/LUSC) tumors could provide insight into factors licensing lineage plasticity between these histologies., Methods: We performed genomic, epigenomics, transcriptomics and protein analyses of microdissected LUAD and LUSC components from mixed histology tumors, pre-/post-transformation tumors and reference non-transformed LUAD and LUSC samples. We validated our findings through genetic manipulation of preclinical models in vitro and in vivo and performed patient-derived xenograft (PDX) treatments to validate potential therapeutic targets in a LUAD PDX model acquiring LUSC features after osimertinib treatment., Results: Our data suggest that LUSC transdifferentiation is primarily driven by transcriptional reprogramming rather than mutational events. We observed consistent relative upregulation of PI3K/AKT, MYC and PRC2 pathway genes. Concurrent activation of PI3K/AKT and MYC induced squamous features in EGFR-mutant LUAD preclinical models. Pharmacologic inhibition of EZH1/2 in combination with osimertinib prevented relapse with squamous-features in an EGFR-mutant patient-derived xenograft model, and inhibition of EZH1/2 or PI3K/AKT signaling re-sensitized resistant squamous-like tumors to osimertinib., Conclusions: Our findings provide the first comprehensive molecular characterization of LUSC transdifferentiation, suggesting putative drivers and potential therapeutic targets to constrain or prevent lineage plasticity., (© 2021. The Author(s).)
- Published
- 2021
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22. Tim-4 + cavity-resident macrophages impair anti-tumor CD8 + T cell immunity.
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Chow A, Schad S, Green MD, Hellmann MD, Allaj V, Ceglia N, Zago G, Shah NS, Sharma SK, Mattar M, Chan J, Rizvi H, Zhong H, Liu C, Bykov Y, Zamarin D, Shi H, Budhu S, Wohlhieter C, Uddin F, Gupta A, Khodos I, Waninger JJ, Qin A, Markowitz GJ, Mittal V, Balachandran V, Durham JN, Le DT, Zou W, Shah SP, McPherson A, Panageas K, Lewis JS, Perry JSA, de Stanchina E, Sen T, Poirier JT, Wolchok JD, Rudin CM, and Merghoub T
- Subjects
- Animals, Apoptosis, Cell Proliferation, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Female, Humans, Membrane Proteins genetics, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Prognosis, Retrospective Studies, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, CD8-Positive T-Lymphocytes immunology, Colonic Neoplasms immunology, Gene Expression Regulation, Neoplastic, Macrophages immunology, Membrane Proteins metabolism, Tumor Microenvironment
- Abstract
Immune checkpoint blockade (ICB) has been a remarkable clinical advance for cancer; however, the majority of patients do not respond to ICB therapy. We show that metastatic disease in the pleural and peritoneal cavities is associated with poor clinical outcomes after ICB therapy. Cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), and this is associated with reduced numbers of CD8
+ T cells with tumor-reactive features in pleural effusions and peritoneal ascites from patients with cancer. We mechanistically demonstrate that viable and cytotoxic anti-tumor CD8+ T cells upregulate PS and this renders them susceptible to sequestration away from tumor targets and proliferation suppression by Tim-4+ macrophages. Tim-4 blockade abrogates this sequestration and proliferation suppression and enhances anti-tumor efficacy in models of anti-PD-1 therapy and adoptive T cell therapy in mice. Thus, Tim-4+ cavity-resident macrophages limit the efficacy of immunotherapies in these microenvironments., Competing Interests: Declaration of interests JDW is a consultant for Adaptive Biotech, Amgen, Apricity, Ascentage Pharma, Arsenal IO, Astellas, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chugai, Daiichi Sankyo, Dragonfly, Eli Lilly, Elucida, F Star, Georgiamune, Idera, Imvaq, Kyowa Hakko Kirin, Linneaus, Maverick Therapeutics, Merck, Neon Therapeutics, Polynoma, Psioxus, Recepta, Takara Bio, Trieza, Truvax, Trishula, Sellas, Serametrix, Surface Oncology, Syndax, Syntalogic, and Werewolf Therapeutics. JDW has received grant/research support from Bristol Myers Squibb; Sephora. JDW has equity in Tizona Pharmaceuticals, Adaptive Biotechnologies, Imvaq, Beigene, Linneaus, Apricity, Arsenal IO, and Georgiamune. JDW is a co-inventor on patent applications related to heteroclitic cancer vaccines and recombinant poxviruses for cancer immunotherapy. JDW and TM are co-inventors on patent applications related to CD40 and in situ vaccination (PCT/US2016/045970). TM is a consultant for Immunos Therapeutics and Pfizer. TM is a cofounder of and equity holder in IMVAQ Therapeutics. TM receives research funding from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics. TM is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus–based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo and PharmaMar and is on the scientific advisory boards of Elucida, Bridge and Harpoon. Unrelated to this work, D.Z. reports clinical research support to his institution from Astra Zeneca, Plexxikon, and Genentech; and personal/consultancy fees from Merck, Synlogic Therapeutics, GSK, Genentech, Xencor, Memgen, Immunos, CrownBio, and Agenus. D.Z. is an inventor on patents related to the use of Newcastle Disease Virus that has been licensed to Merck. MDH received research grant from BMS; personal fees from Achilles, Arcus, AstraZeneca, Blueprint, BMS, Genentech/Roche, Genzyme, Immunai, Instil Bio, Janssen, Merck, Mirati, Natera, Nektar, Pact Pharma, Regeneron, Shattuck Labs, Syndax, as well as equity options from Arcus, Factorial, Immunai, and Shattuck Labs. A patent filed by MSKCC related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) is pending and licensed by PGDx. DTL serves on advisory boards for Merck, Bristol Myers Squibb, and Janssen and has received research funding from Merck, Bristol Myers Squibb, Aduro Biotech, Curegenix, Medivir, and Nouscom. She has received speaking honoraria from Merck and is an inventor of licensed intellectual property related to technology for mismatch repair deficiency for diagnosis and therapy (WO2016077553A1) from Johns Hopkins University. SS is a shareholder of Canexia Health Inc., (Copyright © 2021. Published by Elsevier Inc.)- Published
- 2021
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23. Regenerative lineages and immune-mediated pruning in lung cancer metastasis.
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Laughney AM, Hu J, Campbell NR, Bakhoum SF, Setty M, Lavallée VP, Xie Y, Masilionis I, Carr AJ, Kottapalli S, Allaj V, Mattar M, Rekhtman N, Xavier JB, Mazutis L, Poirier JT, Rudin CM, Pe'er D, and Massagué J
- Subjects
- Animals, Bronchi metabolism, Cell Differentiation, Cell Lineage, Cluster Analysis, Databases, Genetic, Disease Progression, Endoderm metabolism, Female, Humans, Hydrogels chemistry, Killer Cells, Natural metabolism, Lung pathology, Mice, Phenotype, Pulmonary Alveoli metabolism, Regeneration, Signal Transduction, Adenocarcinoma immunology, Adenocarcinoma pathology, Immune System physiology, Lung Neoplasms immunology, Lung Neoplasms pathology, Neoplasm Metastasis
- Abstract
Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2 and SOX9, and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9-dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis.
- Published
- 2020
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24. Peptide-based PET quantifies target engagement of PD-L1 therapeutics.
- Author
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Kumar D, Lisok A, Dahmane E, McCoy M, Shelake S, Chatterjee S, Allaj V, Sysa-Shah P, Wharram B, Lesniak WG, Tully E, Gabrielson E, Jaffee EM, Poirier JT, Rudin CM, Gobburu JV, Pomper MG, and Nimmagadda S
- Subjects
- A549 Cells, Animals, CHO Cells, Copper Radioisotopes, Cricetulus, Female, Humans, Male, Mice, Mice, Inbred NOD, Antineoplastic Agents, Immunological pharmacology, B7-H1 Antigen antagonists & inhibitors, Models, Biological, Neoplasm Proteins antagonists & inhibitors, Neoplasms, Experimental diagnostic imaging, Neoplasms, Experimental drug therapy, Neoplasms, Experimental metabolism, Peptides chemistry, Peptides pharmacokinetics, Peptides pharmacology, Positron-Emission Tomography, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacokinetics, Radiopharmaceuticals pharmacology
- Abstract
Immune checkpoint therapies have shown tremendous promise in cancer therapy. However, tools to assess their target engagement, and hence the ability to predict their efficacy, have been lacking. Here, we show that target engagement and tumor-residence kinetics of antibody therapeutics targeting programmed death ligand-1 (PD-L1) can be quantified noninvasively. In computational docking studies, we observed that PD-L1-targeted monoclonal antibodies (atezolizumab, avelumab, and durvalumab) and a high-affinity PD-L1-binding peptide, WL12, have common interaction sites on PD-L1. Using the peptide radiotracer [64Cu]WL12 in vivo, we employed positron emission tomography (PET) imaging and biodistribution studies in multiple xenograft models and demonstrated that variable PD-L1 expression and its saturation by atezolizumab, avelumab, and durvalumab can be quantified independently of biophysical properties and pharmacokinetics of antibodies. Next, we used [64Cu]WL12 to evaluate the impact of time and dose on the unoccupied fraction of tumor PD-L1 during treatment. These quantitative measures enabled, by mathematical modeling, prediction of antibody doses needed to achieve therapeutically effective occupancy (defined as >90%). Thus, we show that peptide-based PET is a promising tool for optimizing dose and therapeutic regimens employing PD-L1 checkpoint antibodies, and can be used for improving therapeutic efficacy.
- Published
- 2019
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25. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis.
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Romero R, Sayin VI, Davidson SM, Bauer MR, Singh SX, LeBoeuf SE, Karakousi TR, Ellis DC, Bhutkar A, Sánchez-Rivera FJ, Subbaraj L, Martinez B, Bronson RT, Prigge JR, Schmidt EE, Thomas CJ, Goparaju C, Davies A, Dolgalev I, Heguy A, Allaj V, Poirier JT, Moreira AL, Rudin CM, Pass HI, Vander Heiden MG, Jacks T, and Papagiannakopoulos T
- Subjects
- Adenocarcinoma metabolism, Adenocarcinoma pathology, Adenocarcinoma of Lung, Animals, Clustered Regularly Interspaced Short Palindromic Repeats, Glutaminase antagonists & inhibitors, Humans, Hydrolysis, Lung Neoplasms metabolism, Lung Neoplasms pathology, Mice, Adenocarcinoma genetics, Genes, ras, Glutamine metabolism, Kelch-Like ECH-Associated Protein 1 genetics, Lung Neoplasms genetics
- Abstract
Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein. One approach to addressing this challenge is to define mutations that frequently co-occur with those in KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function mutations in the KEAP1 gene encoding Kelch-like ECH-associated protein 1 (refs. 2, 3, 4), a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response. The high frequency of mutations in KEAP1 suggests an important role for the oxidative stress response in lung tumorigenesis. Using a CRISPR-Cas9-based approach in a mouse model of KRAS-driven LUAD, we examined the effects of Keap1 loss in lung cancer progression. We show that loss of Keap1 hyperactivates NRF2 and promotes KRAS-driven LUAD in mice. Through a combination of CRISPR-Cas9-based genetic screening and metabolomic analyses, we show that Keap1- or Nrf2-mutant cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacological inhibition of glutaminase. Finally, we provide a rationale for stratification of human patients with lung cancer harboring KRAS/KEAP1- or KRAS/NRF2-mutant lung tumors as likely to respond to glutaminase inhibition.
- Published
- 2017
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26. Noninvasive Interrogation of DLL3 Expression in Metastatic Small Cell Lung Cancer.
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Sharma SK, Pourat J, Abdel-Atti D, Carlin SD, Piersigilli A, Bankovich AJ, Gardner EE, Hamdy O, Isse K, Bheddah S, Sandoval J, Cunanan KM, Johansen EB, Allaj V, Sisodiya V, Liu D, Zeglis BM, Rudin CM, Dylla SJ, Poirier JT, and Lewis JS
- Subjects
- A549 Cells, Animals, Cell Line, Tumor, Female, Heterografts, Humans, Immunoconjugates, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins immunology, Lung Neoplasms diagnostic imaging, Lung Neoplasms genetics, Lung Neoplasms pathology, Membrane Proteins genetics, Membrane Proteins immunology, Mice, Mice, Nude, Neoplasm Metastasis, Positron-Emission Tomography, Small Cell Lung Carcinoma diagnostic imaging, Small Cell Lung Carcinoma genetics, Small Cell Lung Carcinoma pathology, Intracellular Signaling Peptides and Proteins biosynthesis, Lung Neoplasms metabolism, Membrane Proteins biosynthesis, Small Cell Lung Carcinoma metabolism
- Abstract
The Notch ligand DLL3 has emerged as a novel therapeutic target expressed in small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas. Rovalpituzumab teserine (Rova-T; SC16LD6.5) is a first-in-class DLL3-targeted antibody-drug conjugate with encouraging initial safety and efficacy profiles in SCLC in the clinic. Here we demonstrate that tumor expression of DLL3, although orders of magnitude lower in surface protein expression than typical oncology targets of immunoPET, can serve as an imaging biomarker for SCLC. We developed
89 Zr-labeled SC16 antibody as a companion diagnostic agent to facilitate selection of patients for treatment with Rova-T based on a noninvasive interrogation of the in vivo status of DLL3 expression using PET imaging. Despite low cell-surface abundance of DLL3, immunoPET imaging with89 Zr-labeled SC16 antibody enabled delineation of subcutaneous and orthotopic SCLC tumor xenografts as well as distant organ metastases with high sensitivity. Uptake of the radiotracer in tumors was concordant with levels of DLL3 expression and, most notably, DLL3 immunoPET yielded rank-order correlation for response to SC16LD6.5 therapy in SCLC patient-derived xenograft models. Cancer Res; 77(14); 3931-41. ©2017 AACR ., (©2017 American Association for Cancer Research.)- Published
- 2017
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27. Quantitation of Murine Stroma and Selective Purification of the Human Tumor Component of Patient-Derived Xenografts for Genomic Analysis.
- Author
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Schneeberger VE, Allaj V, Gardner EE, Poirier JT, and Rudin CM
- Subjects
- Animals, Computational Biology methods, Disease Models, Animal, Heterografts, High-Throughput Nucleotide Sequencing, Humans, Mice, Stromal Cells pathology, Genomics methods, Neoplasms genetics, Neoplasms pathology, Stromal Cells metabolism
- Abstract
Patient-derived xenograft (PDX) mouse models are increasingly used for preclinical therapeutic testing of human cancer. A limitation in molecular and genetic characterization of PDX tumors is the presence of integral murine stroma. This is particularly problematic for genomic sequencing of PDX models. Rapid and dependable approaches for quantitating stromal content and purifying the malignant human component of these tumors are needed. We used a recently developed technique exploiting species-specific polymerase chain reaction (PCR) amplicon length (ssPAL) differences to define the fractional composition of murine and human DNA, which was proportional to the fractional composition of cells in a series of lung cancer PDX lines. We compared four methods of human cancer cell isolation: fluorescence-activated cell sorting (FACS), an immunomagnetic mouse cell depletion (MCD) approach, and two distinct EpCAM-based immunomagnetic positive selection methods. We further analyzed DNA extracted from the resulting enriched human cancer cells by targeted sequencing using a clinically validated multi-gene panel. Stromal content varied widely among tumors of similar histology, but appeared stable over multiple serial tumor passages of an individual model. FACS and MCD were superior to either positive selection approach, especially in cases of high stromal content, and consistently allowed high quality human-specific genomic profiling. ssPAL is a dependable approach to quantitation of murine stromal content, and MCD is a simple, efficient, and high yield approach to human cancer cell isolation for genomic analysis of PDX tumors., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2016
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28. Non-steroid anti-inflammatory drugs, prostaglandins, and cancer.
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Allaj V, Guo C, and Nie D
- Abstract
Fatty acids are involved in multiple pathways and play a pivotal role in health. Eicosanoids, derived from arachidonic acid, have received extensive attention in the field of cancer research. Following release from the phospholipid membrane, arachidonic acid can be metabolized into different classes of eicosanoids through cyclooxygenases, lipoxygenases, or p450 epoxygenase pathways. Non-steroid anti-inflammatory drugs (NSAIDs) are widely consumed as analgesics to relieve minor aches and pains, as antipyretics to reduce fever, and as anti-inflammatory medications. Most NSAIDs are nonselective inhibitors of cyclooxygenases, the rate limiting enzymes in the formation of prostaglandins. Long term use of some NSAIDs has been linked with reduced incidence and mortality in many cancers. In this review, we appraise the biological activities of prostanoids and their cognate receptors in the context of cancer biology. The existing literature supports that these lipid mediators are involved to a great extent in the occurrence and progression of cancer.
- Published
- 2013
- Full Text
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