61 results on '"Lidia Robert"'
Search Results
2. Phenotypic heterogeneity and evolution of melanoma cells associated with targeted therapy resistance.
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Yapeng Su, Marcus Bintz, Yezi Yang, Lidia Robert, Alphonsus H C Ng, Victoria Liu, Antoni Ribas, James R Heath, and Wei Wei
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Biology (General) ,QH301-705.5 - Abstract
Phenotypic plasticity is associated with non-genetic drug tolerance in several cancers. Such plasticity can arise from chromatin remodeling, transcriptomic reprogramming, and/or protein signaling rewiring, and is characterized as a cell state transition in response to molecular or physical perturbations. This, in turn, can confound interpretations of drug responses and resistance development. Using BRAF-mutant melanoma cell lines as the prototype, we report on a joint theoretical and experimental investigation of the cell-state transition dynamics associated with BRAF inhibitor drug tolerance. Thermodynamically motivated surprisal analysis of transcriptome data was used to treat the cell population as an entropy maximizing system under the influence of time-dependent constraints. This permits the extraction of an epigenetic potential landscape for drug-induced phenotypic evolution. Single-cell flow cytometry data of the same system were modeled with a modified Fokker-Planck-type kinetic model. The two approaches yield a consistent picture that accounts for the phenotypic heterogeneity observed over the course of drug tolerance development. The results reveal that, in certain plastic cancers, the population heterogeneity and evolution of cell phenotypes may be understood by accounting for the competing interactions of the epigenetic potential landscape and state-dependent cell proliferation. Accounting for such competition permits accurate, experimentally verifiable predictions that can potentially guide the design of effective treatment strategies.
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- 2019
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3. Supplementary Figure 3 from Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells
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Antoni Ribas, Siwen Hu-Lieskovan, Begoña Comin-Anduix, Thomas G. Graeber, Ashani T. Weeraratna, Marcus Bosenberg, Abibatou Ndoye, Katrina Meeth, Lidia Robert, Giulia Parisi, Jennifer Tsoi, Angel Garcia-Diaz, Jesse M. Zaretsky, and Blanca Homet Moreno
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IGV plot of RNA-Seq from YUMM1.1, YUMM1.7 and YUMM2.1; western blot analysis of cytoplasmic and nuclear beta-catenin in YUMM1.7 and YUMM2.1 cell lines with or without exposure to 10 uM 4HT for 48 hours; top-flash activity of total beta-catenin in YUMM1.7 and YUMM2.1 with or without exposure to 10uM 4HT for 48 hours; representative immunofluorescence of beta-catenin stained non-treated tumors.
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- 2023
4. Supplementary Figure 1 from Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells
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Antoni Ribas, Siwen Hu-Lieskovan, Begoña Comin-Anduix, Thomas G. Graeber, Ashani T. Weeraratna, Marcus Bosenberg, Abibatou Ndoye, Katrina Meeth, Lidia Robert, Giulia Parisi, Jennifer Tsoi, Angel Garcia-Diaz, Jesse M. Zaretsky, and Blanca Homet Moreno
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IGV plot exome sequencing from YUMM1.1, YUMM1.7 and YUMM2.1, tumor growth curve of YUMM1.7 and B16 with 4 mice in each group, analysis of the non-synonymous mutational load compared to a strain-matched normal with known dbSNP variants excluded.
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- 2023
5. Supplementary Figure 4 from Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells
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Antoni Ribas, Siwen Hu-Lieskovan, Begoña Comin-Anduix, Thomas G. Graeber, Ashani T. Weeraratna, Marcus Bosenberg, Abibatou Ndoye, Katrina Meeth, Lidia Robert, Giulia Parisi, Jennifer Tsoi, Angel Garcia-Diaz, Jesse M. Zaretsky, and Blanca Homet Moreno
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Gating strategy of CD11c+B220-, CD11c+B220+, CD11c+B220-CD8+ and CD11c+B220-CD103+ cells; gating strategy of CD11b+MHC-IIhigh DCs in CD11c+ cells; gating strategy of CD11b+F4/80+TAMs, CD11b+F4/80+MHC-IIlow TAMs and CD11b+F4/80+MHC-IIhigh TAMs; gating strategy of MO-MDSC (CD11b+Ly6ChighLy6Glow) and PMN-MDSC (CD11b+Ly6ClowLy6Ghigh); gating strategy of Tregs (CD4+CD25+FoxP3+); corresponding normalized enrichment scores (NES), P values and false discovery rates (FDR) of the GSEA plots for YUMM2.1 versus YUMM1.1 enriched pathways involved in immune response, cytokine production and inflammatory response.
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- 2023
6. Supplementary Figure 2 from Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells
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Antoni Ribas, Siwen Hu-Lieskovan, Begoña Comin-Anduix, Thomas G. Graeber, Ashani T. Weeraratna, Marcus Bosenberg, Abibatou Ndoye, Katrina Meeth, Lidia Robert, Giulia Parisi, Jennifer Tsoi, Angel Garcia-Diaz, Jesse M. Zaretsky, and Blanca Homet Moreno
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Quantification of CD3+CD8+ (CD8 T-cells) and (B) CD3+CD4+ (CD4 T-cells) in both tumors and spleens in YUMM2.1; gating strategy after exclusion of dead cells of CD3+CD8+ and CD3+CD4+ cells after gating for CD3+ cells; quantification of CD3+CD8+ (CD8 T-cells) in MC38 and YUMM2.1 spleens; CD3+CD4+ (CD4 T-cells) in MC38 and YUMM 2.1 spleens CD8 T-cells in both tumors and spleens in YUMM1.1.
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- 2023
7. Supplementary Data from Immunotherapy Resistance by Inflammation-Induced Dedifferentiation
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Antoni Ribas, Cristina Puig-Saus, Paul C. Tumeh, James S. Economou, Alistair J. Cochran, Beata Berent-Maoz, Begoña Comin-Anduix, Jennifer Tsoi, Lidia Robert, Yeon Joo Kim, and Arnav Mehta
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The supplementary data contains supplemental methods, figures, tables and the clinical trial protocol in which patients from this study were enrolled.
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- 2023
8. Data from Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells
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Antoni Ribas, Siwen Hu-Lieskovan, Begoña Comin-Anduix, Thomas G. Graeber, Ashani T. Weeraratna, Marcus Bosenberg, Abibatou Ndoye, Katrina Meeth, Lidia Robert, Giulia Parisi, Jennifer Tsoi, Angel Garcia-Diaz, Jesse M. Zaretsky, and Blanca Homet Moreno
- Abstract
The programmed cell death protein 1 (PD-1) limits effector T-cell functions in peripheral tissues, and its inhibition leads to clinical benefit in different cancers. To better understand how PD-1 blockade therapy modulates the tumor–host interactions, we evaluated three syngeneic murine tumor models, the BRAFV600E-driven YUMM1.1 and YUMM2.1 melanomas, and the carcinogen-induced murine colon adenocarcinoma MC38. The YUMM cell lines were established from mice with melanocyte-specific BRAFV600E mutation and PTEN loss (BRAFV600E/PTEN−/−). Anti–PD-1 or anti–PD-L1 therapy engendered strong antitumor activity against MC38 and YUMM2.1, but not YUMM1.1. PD-L1 expression did not differ between the three models at baseline or upon interferon stimulation. Whereas mutational load was high in MC38, it was lower in both YUMM models. In YUMM2.1, the antitumor activity of PD-1 blockade had a critical requirement for both CD4 and CD8 T cells, as well as CD28 and CD80/86 costimulation, with an increase in CD11c+CD11b+MHC-IIhigh dendritic cells and tumor-associated macrophages in the tumors after PD-1 blockade. Compared with YUMM1.1, YUMM2.1 exhibited a more inflammatory profile by RNA sequencing analysis, with an increase in expression of chemokine-trafficking genes that are related to immune cell recruitment and T-cell priming. In conclusion, response to PD-1 blockade therapy in tumor models requires CD4 and CD8 T cells and costimulation that is mediated by dendritic cells and macrophages. Cancer Immunol Res; 4(10); 845–57. ©2016 AACR.
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- 2023
9. Data from Immunotherapy Resistance by Inflammation-Induced Dedifferentiation
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Antoni Ribas, Cristina Puig-Saus, Paul C. Tumeh, James S. Economou, Alistair J. Cochran, Beata Berent-Maoz, Begoña Comin-Anduix, Jennifer Tsoi, Lidia Robert, Yeon Joo Kim, and Arnav Mehta
- Abstract
A promising arsenal of targeted and immunotherapy treatments for metastatic melanoma has emerged over the last decade. With these therapies, we now face new mechanisms of tumor-acquired resistance. We report here a patient whose metastatic melanoma underwent dedifferentiation as a resistance mechanism to adoptive T-cell transfer therapy (ACT) to the MART1 antigen, a phenomenon that had been observed only in mouse studies to date. After an initial period of tumor regression, the patient presented in relapse with tumors lacking melanocytic antigens (MART1, gp100) and expressing an inflammation-induced neural crest marker (NGFR). We demonstrate using human melanoma cell lines that this resistance phenotype can be induced in vitro by treatment with MART1 T cell receptor–expressing T cells or with TNFα, and that the phenotype is reversible with withdrawal of inflammatory stimuli. This supports the hypothesis that acquired resistance to cancer immunotherapy can be mediated by inflammation-induced cancer dedifferentiation.Significance: We report a patient whose metastatic melanoma underwent inflammation-induced dedifferentiation as a resistance mechanism to ACT to the MART1 antigen. Our results suggest that future melanoma ACT protocols may benefit from the simultaneous targeting of multiple tumor antigens, modulating the inflammatory response, and inhibition of inflammatory dedifferentiation-inducing signals. Cancer Discov; 8(8); 935–43. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 899
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- 2023
10. Supplementary figure legends from Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells
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Antoni Ribas, Siwen Hu-Lieskovan, Begoña Comin-Anduix, Thomas G. Graeber, Ashani T. Weeraratna, Marcus Bosenberg, Abibatou Ndoye, Katrina Meeth, Lidia Robert, Giulia Parisi, Jennifer Tsoi, Angel Garcia-Diaz, Jesse M. Zaretsky, and Blanca Homet Moreno
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Supplementary figure legends
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- 2023
11. Supplementary Figure 2 from CTLA4 Blockade Broadens the Peripheral T-Cell Receptor Repertoire
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Antoni Ribas, Harlan Robins, Thomas G. Graeber, Richard C. Koya, Begoña Comin-Anduix, Alistair J. Cochran, Rong Rong Huang, Stephen Mok, Thinle Chodon, Blanca Homet, Ryan Emerson, Xiaoyan Wang, Jennifer Tsoi, and Lidia Robert
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PDF file - 48KB, Lack of correlations between changes in ALC (x axis) and changes in the unique productive sequences (y axis) expressed in % of change both. Each dot corresponds to a GA patient.
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- 2023
12. Data from Effects of MAPK and PI3K Pathways on PD-L1 Expression in Melanoma
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Antoni Ribas, Begonya Comin-Anduix, Thomas G. Graeber, Thinle Chodon, Bjoern Titz, Michael Cerniglia, David Foulad, Lidia Robert, Deborah J.L. Wong, Amanda Lassen, Earl Avramis, and Mohammad Atefi
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Purpose: PD-L1 is the main ligand for the immune inhibitory receptor PD-1. This ligand is frequently expressed by melanoma cells. In this study, we investigated whether PD-L1 expression is controlled by melanoma driver mutations and modified by oncogenic signaling inhibition.Experimental Design: Expression of PD-L1 was investigated in a panel of 51 melanoma cell lines containing different oncogenic mutations, including cell lines with innate and acquired resistance to BRAF inhibitors (BRAFi). The effects of targeted therapy drugs on expression of PD-L1 by melanoma cells were investigated.Results: No association was found between the level of PD-L1 expression and mutations in BRAF, NRAS, PTEN, or amplification of AKT. Resistance to vemurafenib due to the activation of alternative signaling pathways was accompanied with the induction of PD-L1 expression, whereas the resistance due to the reactivation of the MAPK pathway had no effect on PD-L1 expression. In melanoma cell lines, the effects of BRAF, MEK, and PI3K inhibitors on expression of PD-L1 were variable from reduction to induction, particularly in the presence of INFγ. In PD-L1–exposed lymphocytes, vemurafenib paradoxically restored activity of the MAPK pathway and increased the secretion of cytokines.Conclusions: In melanoma cell lines, including BRAFi-resistant cells, PD-L1 expression is variably regulated by oncogenic signaling pathways. PD-L1–exposed lymphocytes decrease MAPK signaling, which is corrected by exposure to vemurafenib, providing potential benefits of combining this drug with immunotherapies. Clin Cancer Res; 20(13); 3446–57. ©2014 AACR.
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- 2023
13. Supplementary Figure 1 from CTLA4 Blockade Broadens the Peripheral T-Cell Receptor Repertoire
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Antoni Ribas, Harlan Robins, Thomas G. Graeber, Richard C. Koya, Begoña Comin-Anduix, Alistair J. Cochran, Rong Rong Huang, Stephen Mok, Thinle Chodon, Blanca Homet, Ryan Emerson, Xiaoyan Wang, Jennifer Tsoi, and Lidia Robert
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PDF file - 411KB, Scatter plots for all patients with a rank-rank analysis . For every GA patient a dot plot was generated ranking each single clone according to abundance in baseline (x axis) and post-treatment (y axis). Values range from highest frequency (0) to lowest frequency.
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- 2023
14. Data from CTLA4 Blockade Broadens the Peripheral T-Cell Receptor Repertoire
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Antoni Ribas, Harlan Robins, Thomas G. Graeber, Richard C. Koya, Begoña Comin-Anduix, Alistair J. Cochran, Rong Rong Huang, Stephen Mok, Thinle Chodon, Blanca Homet, Ryan Emerson, Xiaoyan Wang, Jennifer Tsoi, and Lidia Robert
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Purpose: To evaluate the immunomodulatory effects of cytotoxic T–lymphocyte-associated protein 4 (CTLA4) blockade with tremelimumab in peripheral blood mononuclear cells (PBMC).Experimental Design: We used next-generation sequencing to study the complementarity-determining region 3 (CDR3) from the rearranged T-cell receptor (TCR) variable beta (V-beta) in PBMCs of 21 patients, at baseline and 30 to 60 days after receiving tremelimumab.Results: After receiving tremelimumab, there was a median of 30% increase in unique productive sequences of TCR V-beta CDR3 in 19 out of 21 patients, and a median decrease of 30% in only 2 out of 21 patients. These changes were significant for richness (P = 0.01) and for Shannon index diversity (P = 0.04). In comparison, serially collected PBMCs from four healthy donors did not show a significant change in TCR V-beta CDR3 diversity over 1 year. There was a significant difference in the total unique productive TCR V-beta CDR3 sequences between patients experiencing toxicity with tremelimumab compared with patients without toxicity (P = 0.05). No relevant differences were noted between clinical responders and nonresponders.Conclusions: CTLA4 blockade with tremelimumab diversifies the peripheral T-cell pool, representing a pharmacodynamic effect of how this class of antibodies modulates the human immune system. Clin Cancer Res; 20(9); 2424–32. ©2014 AACR.
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- 2023
15. Supplementary Figure 1 from Effects of MAPK and PI3K Pathways on PD-L1 Expression in Melanoma
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Antoni Ribas, Begonya Comin-Anduix, Thomas G. Graeber, Thinle Chodon, Bjoern Titz, Michael Cerniglia, David Foulad, Lidia Robert, Deborah J.L. Wong, Amanda Lassen, Earl Avramis, and Mohammad Atefi
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PDF file - 247KB, MAPK pathway is almost inactive in resting PBMCs.
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- 2023
16. Supplementary Figure Legends, Tables 1 - 3 from CTLA4 Blockade Broadens the Peripheral T-Cell Receptor Repertoire
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Antoni Ribas, Harlan Robins, Thomas G. Graeber, Richard C. Koya, Begoña Comin-Anduix, Alistair J. Cochran, Rong Rong Huang, Stephen Mok, Thinle Chodon, Blanca Homet, Ryan Emerson, Xiaoyan Wang, Jennifer Tsoi, and Lidia Robert
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PDF file - 65KB, Table S1 Summary for TCR V-beta CDR3 sequence analysis. Table S2 Number of unique Productive Sequences in Top 25% abundance at four different timepoints. Table S3 Number of unique productive Sequences in Top 25% clones at baseline and at Day 30-60.
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- 2023
17. Supplementary Figure 2 from Effects of MAPK and PI3K Pathways on PD-L1 Expression in Melanoma
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Antoni Ribas, Begonya Comin-Anduix, Thomas G. Graeber, Thinle Chodon, Bjoern Titz, Michael Cerniglia, David Foulad, Lidia Robert, Deborah J.L. Wong, Amanda Lassen, Earl Avramis, and Mohammad Atefi
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PDF file - 206KB, Restoration of the MAPK pathway activity by vemurafenib in lymphocytes exposed to PD-L1.
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- 2023
18. Erratum to : Antitumor activity of the ERK inhibitor SCH722984 against BRAF mutant, NRAS mutant and wild-type melanoma
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Roger S. Lo, Amanda Lassen, David Foulad, Earl Avramis, Antoni Ribas, Jennifer Tsoi, Begonya Comin-Anduix, Lidia Robert, Deborah J.L. Wong, Thomas G. Graeber, Michael Cerniglia, Geetha Avarappatt, Mohammad Atefi, and Ahmed A. Samatar
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Neuroblastoma RAS viral oncogene homolog ,MAPK/ERK pathway ,Proto-Oncogene Proteins B-raf ,Cancer Research ,Indazoles ,Indoles ,Mutant ,Biology ,Piperazines ,GTP Phosphohydrolases ,Inhibitory Concentration 50 ,Cell Line, Tumor ,medicine ,Humans ,Molecular Targeted Therapy ,Protein Kinase Inhibitors ,Antitumor activity ,Sulfonamides ,Melanoma ,Wild type ,Membrane Proteins ,Drug Synergism ,medicine.disease ,Oncology ,Vemurafenib ,Drug Resistance, Neoplasm ,Mutation ,Cancer research ,Molecular Medicine ,Erratum ,Multiple Myeloma - Abstract
In melanoma, dysregulation of the MAPK pathway, usually via BRAF(V600) or NRAS(Q61) somatic mutations, leads to constitutive ERK signaling. While BRAF inhibitors are initially effective for BRAF-mutant melanoma, no FDA-approved targeted therapies exist for BRAF-inhibitor-resistant BRAF(V600), NRAS mutant, or wild-type melanoma.The 50% inhibitory concentration (IC50) of SCH772984, a novel inhibitor of ERK1/2, was determined in a panel of 50 melanoma cell lines. Effects on MAPK and AKT signaling by western blotting and cell cycle by flow cytometry were determined.Sensitivity fell into three groups: sensitive, 50% inhibitory concentration (IC50)1 μM; intermediately sensitive, IC50 1-2 μM; and resistant,2 μM. Fifteen of 21 (71%) BRAF mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH772984. All three (100%) BRAF/NRAS double mutants, 11 of 14 (78%) NRAS mutants and 5 of 7 (71%) wild-type melanomas were sensitive. Among BRAF(V600) mutants with in vitro acquired resistance to vemurafenib, those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH772984. SCH772984 caused G1 arrest and induced apoptosis.Combining vemurafenib and SCH722984 in BRAF mutant melanoma was synergistic in a majority of cell lines and significantly delayed the onset of acquired resistance in long term in vitro assays. Therefore, SCH772984 may be clinically applicable as a treatment for non-BRAF mutant melanoma or in BRAF-mutant melanoma with innate or acquired resistance, alone or in combination with BRAF inhibitors.
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- 2021
19. 259 Phase Ib/II open-label, randomized evaluation of atezolizumab (atezo) + selicrelumab (seli) + gemcitabine+nab-paclitaxel (gem+nabP) or bevacizumab (bev) vs control in MORPHEUS-PDAC, -TNBC and -CRC
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Seock-Ah Im, Jeffrey Xu, Carlos Gomez-Roca, Florence Dalenc, Xiaosong Zhang, Christelle Lenain, Sung-Bae Kim, Jeremy S. Kortmansky, Vincent Chung, Michel Ducreux, Gulam Abbas Manji, Nathan Bahary, Olivier Tredan, Danny Lu, Neil H. Segal, Jill Lacy, Kelly DuPree, Lidia Robert, and Olivera Cirovic
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Oncology ,medicine.medical_specialty ,Bevacizumab ,business.industry ,medicine.disease ,Interim analysis ,Gemcitabine ,Capecitabine ,chemistry.chemical_compound ,Breast cancer ,chemistry ,Atezolizumab ,Pharmacodynamics ,Internal medicine ,Regorafenib ,medicine ,business ,medicine.drug - Abstract
Background The MORPHEUS platform comprises multiple randomized Phase Ib/II trials to identify early safety and efficacy signals for treatment combinations across cancers. Seli interacts with CD40 on antigen presenting cells, resulting in activation and priming of CD8 T-cells. Atezo (anti-PD-L1)+seli (CD40 agonist) was evaluated with gem+nabP for pancreatic ductal adenocarcinoma (PDAC), or with bev for triple-negative breast cancer (TNBC) and colorectal cancer (CRC). Methods MORPHEUS-PDAC, MORPHEUS-TNBC and MORPHEUS-CRC enrolled 1L metastatic (m) PDAC, 2L locally advanced or mTNBC or 3L mCRC patients, respectively. Experimental arm patients received atezo (840 mg IV q2w) and seli (16 mg SC on D1 every 28-day cycle for C1-4 and every third cycle thereafter). Patients also received gem (1000 mg/m2) and nabP (1000 mg/m2, 125 mg/m2 respectively, IV on D1, 8, 15 every 28-day cycle) in PDAC or bev (10 mg/kg IV q2w) in TNBC and CRC. Control treatments were gem+nabP in PDAC, capecitabine in TNBC, and regorafenib in CRC. Primary endpoints were safety and objective response rate (ORR; investigator-assessed RECIST 1.1). PD-L1 and CD8/panCK IHC were tested in all biopsies. Results All treated patients were safety evaluable. MORPHEUS-PDAC (20-week interim analysis): 9 patients received atezo+seli+gem+nabP and 4 received control. Treatment-related adverse events (TRAEs) were seen in all. Treatment-related serious AEs (SAEs) occurred in 6 patients (67%) receiving atezo+seli+gem+nabP and 1 (25%) receiving control. Confirmed ORRs: 44% (95%CI:14–79) and 25% (95%CI:6–81), respectively. MORPHEUS-TNBC (27-week interim analysis): 6 patients received atezo+seli+bev and 24 received control. TRAEs were seen in 5 patients (83%) receiving atezo+seli+bev and 18 (75%) receiving control. Treatment-related SAEs occurred in 1 patient in each arm (17% and 4%, respectively). Confirmed ORRs: 17% (95%CI:0.4–64) and 21% (95%CI:7–42), respectively. All 6 patients receiving atezo+seli+bev were PD-L1 negative (SP142 IHC assay) at baseline; the only patient with partial response (PR) showed upregulation of PD-L1 expression at week 3. MORPHEUS-CRC (18-week interim analysis): 6 patients received atezo+seli+bev and 13 received control. TRAEs were seen in all patients receiving atezo+seli+bev and 12 (92%) receiving control. Treatment-related SAEs occurred in 3 patients (50%) receiving atezo+seli+bev and 1 (8%) receiving control. No responses occurred in either study arm. Paired biopsies for 3 patients (60%) receiving atezo+seli+bev suggest on-treatment increases in CD8 T-cell infiltration into tumors. Conclusions Toxicities related to the atezo+seli combinations were consistent with individual study treatments. Preliminary efficacy was observed for atezo+seli+gem+nabP in PDAC. Together with preliminary evidence of on-treatment pharmacodynamic effects in CRC and TNBC tumor samples, CD40 agonist strategies warrant further investigation. Trial Registration MORPHEUS-PDAC: NCT03193190; MORPHEUS-TNBC: NCT03424005; MORPHEUS-CRC: NCT03555149. Ethics Approval The trial was conducted according to the principles of the Declaration of Helsinki. All patients provided written informed consent. Protocol approval was obtained from independent review boards or ethics committees at each site.
- Published
- 2020
20. Multi-omic single-cell snapshots reveal multiple independent trajectories to drug tolerance in a melanoma cell line
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Jessica Wang, Luke Frankiw, Yapeng Su, Raphael D. Levine, Alexander M. Xu, Ronghui Zhu, Kaitlyn Takata, Wei Wei, Garry P. Nolan, Sylvia K. Plevritis, Guideng Li, Melissa E. Ko, Dan Yuan, David Baltimore, Jihoon W. Lee, Antoni Ribas, Stephanie Wong, Min Xue, Yue Lu, Hanjun Cheng, Sui Huang, James R. Heath, and Lidia Robert
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0301 basic medicine ,Models, Molecular ,Proteomics ,Cellular differentiation ,Microfluidics ,Druggability ,General Physics and Astronomy ,0302 clinical medicine ,Single-cell analysis ,Genes, Reporter ,Models ,lcsh:Science ,Melanoma ,Cancer ,education.field_of_study ,Multidisciplinary ,Tumor ,Lab-on-a-chip ,Genomics ,Drug Tolerance ,030220 oncology & carcinogenesis ,Single-Cell Analysis ,Proto-Oncogene Proteins B-raf ,Tumour heterogeneity ,Science ,1.1 Normal biological development and functioning ,Population ,Green Fluorescent Proteins ,Computational biology ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cell Line ,03 medical and health sciences ,Underpinning research ,Cell Line, Tumor ,Genetics ,Humans ,Metabolomics ,Epigenetics ,education ,neoplasms ,Reporter ,Microphthalmia-Associated Transcription Factor ,Reproducibility of Results ,Molecular ,General Chemistry ,digestive system diseases ,Computational biology and bioinformatics ,030104 developmental biology ,Genes ,lcsh:Q ,Generic health relevance - Abstract
The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge for understanding biological changes ranging from cellular differentiation to epigenetic responses of diseased cells upon drugging. We integrate experiments and theory to determine the trajectories that single BRAFV600E mutant melanoma cancer cells take between drug-naive and drug-tolerant states. Although single-cell omics tools can yield snapshots of the cell-state landscape, the determination of individual cell trajectories through that space can be confounded by stochastic cell-state switching. We assayed for a panel of signaling, phenotypic, and metabolic regulators at points across 5 days of drug treatment to uncover a cell-state landscape with two paths connecting drug-naive and drug-tolerant states. The trajectory a given cell takes depends upon the drug-naive level of a lineage-restricted transcription factor. Each trajectory exhibits unique druggable susceptibilities, thus updating the paradigm of adaptive resistance development in an isogenic cell population., Detailed understanding of how cancer cells transition from a drug sensitive to a tolerant state is lacking. Here, using single cell proteomic and metabolic data the authors uncover that isogenic BRAF mutant melanoma cells can take two distinct paths to become tolerant to BRAF inhibition.
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- 2020
21. Single-cell analysis resolves the cell state transition and signaling dynamics associated with melanoma drug-induced resistance
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Jungwoo Kim, Min Xue, Lidia Robert, Jihoon W. Lee, Jennifer Tsoi, James R. Heath, Begonya Comin-Anduix, Antoni Ribas, Wei Wei, Yapeng Su, Rachel Ng, Richard C. Koya, Angel Garcia-Diaz, Thomas G. Graeber, and Blanca Homet Moreno
- Subjects
Proteomics ,0301 basic medicine ,Proteome ,Drug Resistance ,cell state transition ,Transcriptome ,chemistry.chemical_compound ,Single-cell analysis ,single-cell analysis ,Melanoma ,Cancer ,Tumor ,Multidisciplinary ,Transition (genetics) ,NF-kappa B ,Biological Sciences ,Adaptation, Physiological ,Phenotype ,Markov Chains ,Single-Cell Analysis ,Growth inhibition ,Signal Transduction ,Proto-Oncogene Proteins B-raf ,MAP Kinase Signaling System ,Physiological ,Antineoplastic Agents ,Biology ,Cell Line ,03 medical and health sciences ,Cell Line, Tumor ,melanoma ,Genetics ,medicine ,Humans ,Adaptation ,adaptive resistance ,neoplasms ,Gene Expression Profiling ,Human Genome ,medicine.disease ,digestive system diseases ,030104 developmental biology ,Markov chain model ,chemistry ,Targeted drug delivery ,Drug Resistance, Neoplasm ,Cell culture ,Cancer research ,Neoplasm - Abstract
Continuous BRAF inhibition of BRAF mutant melanomas triggers a series of cell state changes that lead to therapy resistance and escape from immune control before establishing acquired resistance genetically. We used genome-wide transcriptomics and single-cell phenotyping to explore the response kinetics to BRAF inhibition for a panel of patient-derived BRAF^(V600)-mutant melanoma cell lines. A subset of plastic cell lines, which followed a trajectory covering multiple known cell state transitions, provided models for more detailed biophysical investigations. Markov modeling revealed that the cell state transitions were reversible and mediated by both Lamarckian induction and nongenetic Darwinian selection of drug-tolerant states. Single-cell functional proteomics revealed activation of certain signaling networks shortly after BRAF inhibition, and before the appearance of drug-resistant phenotypes. Drug targeting those networks, in combination with BRAF inhibition, halted the adaptive transition and led to prolonged growth inhibition in multiple patient-derived cell lines.
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- 2017
22. Trajectories from Snapshots: Integrated proteomic and metabolic single-cell assays reveal multiple independent adaptive responses to drug tolerance in a BRAF-mutant melanoma cell line
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Guideng Li, Sylvia K. Plevritis, Min Xue, David Baltimore, Jessica Wang, Alexander M. Xu, Stephanie Wong, Antoni Ribas, James R. Heath, Kaitlyn Takata, Garry P. Nolan, Jihoon W. Lee, Sui Huang, Lidia Robert, Melissa E. Ko, Wei Wei, Yapeng Su, Raphael D. Levine, Luke Frankiw, Ronghui Zhu, and Hanjun Cheng
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education.field_of_study ,Cellular differentiation ,Cell ,Population ,Druggability ,Computational biology ,Complex cell ,Biology ,Phenotype ,medicine.anatomical_structure ,medicine ,Epigenetics ,education ,Transcription factor - Abstract
The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge, with relevance towards understanding biological changes ranging from cellular differentiation to epigenetic (adaptive) responses of diseased cells to drugging. We report on a combined experimental and theoretic method for determining the trajectories that specific highly plastic BRAFV600E mutant patient-derived melanoma cancer cells take between drug-naïve and drug-tolerant states. Recent studies have implicated non-genetic, fast-acting resistance mechanisms are activated in these cells following BRAF inhibition. While single-cell highly multiplex omics tools can yield snapshots of the cell state space landscape sampled at any given time point, individual cell trajectories must be inferred from a kinetic series of snapshots, and that inference can be confounded by stochastic cell state switching. Using a microfludic-based single-cell integrated proteomic and metabolic assay, we assayed for a panel of signaling, phenotypic, and metabolic regulators at four time points during the first five days of drug treatment. Dimensional reduction of the resultant data set, coupled with information theoretic analysis, uncovered a complex cell state landscape and identified two distinct paths connecting drug-naïve and drug-tolerant states. Cells are shown to exclusively traverse one of the two pathways depending on the level of the lineage restricted transcription factor MITF in the drug-naïve cells. The two trajectories are associated with distinct signaling and metabolic susceptibilities, and are independently druggable. Our results update the paradigm of adaptive resistance development in an isogenic cell population and offer insight into the design of more effective combination therapies.
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- 2019
23. Kinetic Inference Resolves Epigenetic Mechanism of Drug Resistance in Melanoma
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Xiwei Wu, Yan Kong, Lidia Robert, Victoria Liu, Zhuo Wang, Yi-Teng Xu, Raphael D. Levine, Jihoon W. Lee, Yapeng Su, Guangrong Qin, Hanjun Cheng, Ilya Shmulevich, Qihui Shi, Jingchuan Guo, Charles Warden, Songming Peng, Jiahuan Chen, Alphonsus H. C. Ng, Y. Yapeng, James R. Heath, David Baltimore, C. Liu, Min Xue, Rachel Ng, Stephanie Wong, Antoni Ribas, Wei Wei, Jessica Wang, Dazy Johnson, Xiang Lu, and Guideng Li
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MAPK/ERK pathway ,010407 polymers ,0303 health sciences ,biology ,Melanoma ,Systems biology ,Epigenome ,medicine.disease ,01 natural sciences ,Phenotype ,Chromatin remodeling ,3. Good health ,0104 chemical sciences ,Cell biology ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Histone ,030220 oncology & carcinogenesis ,Cancer cell ,medicine ,biology.protein ,Epigenetics ,030304 developmental biology - Abstract
SummaryWe resolved a mechanism connecting tumor epigenetic plasticity with non-genetic adaptive resistance to therapy, with MAPK inhibition ofBRAF-mutant melanomas providing the model. These cancer cells undergo multiple, reversible drug-induced cell-state transitions, ultimately yielding a drug-resistant mesenchymal-like phenotype. A kinetic series of transcriptome and epigenome data, collected over two months of drug treatment and release, revealed changing levels of thousands of genes and extensive chromatin remodeling. However, a 3-step computational algorithm greatly simplified the interpretation of these changes, and revealed that the whole adaptive process was controlled by a gene module activated within just three days of treatment, with RelA driving chromatin remodeling to establish an epigenetic program encoding long-term phenotype changes. These findings were confirmed across several patient-derived cell lines and in melanoma patients under MAPK inhibitor treatment. Co-targeting BRAF and histone-modifying enzymes arrests adaptive transitions towards drug tolerance in epigenetically plastic melanoma cells and may be exploited therapeutically.
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- 2019
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24. Phenotypic heterogeneity and evolution of melanoma cells associated with targeted therapy resistance
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Antoni Ribas, Yapeng Su, Marcus Bintz, Alphonsus H. C. Ng, Lidia Robert, Yezi Yang, Wei Wei, Victoria Liu, James R. Heath, and Tanay, Amos
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0301 basic medicine ,Entropy ,Population Dynamics ,Drug Resistance ,Gene Expression ,Mathematical Sciences ,Transcriptome ,0302 clinical medicine ,Spectrum Analysis Techniques ,Models ,Medicine and Health Sciences ,Biology (General) ,Melanoma ,Free Energy ,Cancer ,Cultured Tumor Cells ,education.field_of_study ,Tumor ,Ecology ,Pharmaceutics ,Physics ,Genomics ,Biological Sciences ,Flow Cytometry ,Phenotype ,Computational Theory and Mathematics ,Spectrophotometry ,5.1 Pharmaceuticals ,Modeling and Simulation ,Physical Sciences ,Thermodynamics ,Melanoma Cells ,Cytophotometry ,Biological Cultures ,Development of treatments and therapeutic interventions ,Reprogramming ,Transcriptome Analysis ,Research Article ,QH301-705.5 ,Evolution ,Bioinformatics ,Population ,Antineoplastic Agents ,Computational biology ,Biology ,Research and Analysis Methods ,Models, Biological ,Chromatin remodeling ,Cell Line ,Evolution, Molecular ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Drug Therapy ,Cell Line, Tumor ,Information and Computing Sciences ,Genetics ,Humans ,Epigenetics ,education ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Cell Proliferation ,Phenotypic plasticity ,Population Biology ,Genetic heterogeneity ,Human Genome ,Biology and Life Sciences ,Computational Biology ,Molecular ,Cell Cultures ,Genome Analysis ,Biological ,030104 developmental biology ,Drug Resistance, Neoplasm ,Neoplasm ,030217 neurology & neurosurgery - Abstract
Phenotypic plasticity is associated with non-genetic drug tolerance in several cancers. Such plasticity can arise from chromatin remodeling, transcriptomic reprogramming, and/or protein signaling rewiring, and is characterized as a cell state transition in response to molecular or physical perturbations. This, in turn, can confound interpretations of drug responses and resistance development. Using BRAF-mutant melanoma cell lines as the prototype, we report on a joint theoretical and experimental investigation of the cell-state transition dynamics associated with BRAF inhibitor drug tolerance. Thermodynamically motivated surprisal analysis of transcriptome data was used to treat the cell population as an entropy maximizing system under the influence of time-dependent constraints. This permits the extraction of an epigenetic potential landscape for drug-induced phenotypic evolution. Single-cell flow cytometry data of the same system were modeled with a modified Fokker-Planck-type kinetic model. The two approaches yield a consistent picture that accounts for the phenotypic heterogeneity observed over the course of drug tolerance development. The results reveal that, in certain plastic cancers, the population heterogeneity and evolution of cell phenotypes may be understood by accounting for the competing interactions of the epigenetic potential landscape and state-dependent cell proliferation. Accounting for such competition permits accurate, experimentally verifiable predictions that can potentially guide the design of effective treatment strategies., Author summary Cancer cells exhibit varied degrees of phenotypic heterogeneity. These phenotypes, each of them with unique molecular and functional profiles, display dynamic interconversion in response to drug perturbations, and can evolve to form new drug-tolerant phenotypes. Such phenotypic plasticity, in turn, renders tumor cells extremely difficult to treat. To get a quantitative biophysical understanding of the origins of the phenotypic equilibrium and evolution associated with drug tolerance development in highly plastic patient-derived melanoma cells, we employed joint experimental and computational approaches, using either bulk or single cell measurements as input, to interrogate the epigenetic landscape of the phenotypic evolution. We found that the observed phenotypic equilibria were established via competition between state-dependent net proliferation rates and landscape potential. The results reveal how the tumor cells maintain a phenotypic heterogeneity that facilitates appropriate responses to external cues. They implicate that, in certain phenotypically plastic tumor cells, drug targeting the driver oncogenes may not have sustained efficacy unless the phenotypic plasticity of the tumor is co-targeted.
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- 2019
25. Abstract 6585: Systems biology for investigating drug resistance mechanism of melanoma
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Melissa E. Ko, Raphael D. Levine, Antoni Ribas, Sylvia K. Plevritis, Hanjun Cheng, Yapeng Su, Lidia Robert, Min Xue, David Baltimore, James R. Heath, Wei Wei, Ronghui Zhu, Guideng Li, and Garry P. Nolan
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Cancer Research ,education.field_of_study ,Mechanism (biology) ,Melanoma ,Systems biology ,Population ,Druggability ,Computational biology ,Biology ,medicine.disease ,Microphthalmia-associated transcription factor ,Phenotype ,Oncology ,medicine ,education ,Transcription factor - Abstract
Integrated proteomic and metabolic single-cell assays reveal multiple independent adaptive responses to drug tolerance in a BRAF-mutant melanoma cell line Cancers commonly develop resistance against chemotherapeutics or targeted therapies through various types of genetic or non-genetic mechanisms. Non-genetic mechanisms have been shown to occur early on and can provide a latent reservoir of cells for the emergence of various different type of mechanisms, yet very limited understanding of process were resolve main from bulk analysis. Considering the heterogeneous nature of the tumor cells, a single-cell level characterization of the process worth detailed further investigation. Using MAPK inhibition of BRAF-mutant melanomas as a model system, we resolved that cells take different paths to go from drug-sensitive to drug-resistant state. Using a microfludic-based single-cell integrated proteomic and metabolic assay, we assayed for a panel of signaling, phenotypic, and metabolic regulators at four time points during the first five days of drug treatment. Dimensional reduction of the resultant data set, coupled with information theoretic analysis, uncovered a complex cell state landscape and identified two distinct paths connecting drug-naïve and drug-tolerant states. Cells are shown to exclusively traverse one of the two pathways depending on the level of the lineage restricted transcription factor MITF in the drug-naïve cells. The two trajectories are associated with distinct signaling and metabolic susceptibilities, and are independently druggable. Our results update the paradigm of adaptive resistance development in an isogenic cell population and offer insight into the design of more effective combination therapies. Citation Format: Yapeng Su, Guideng Li, Melissa Ko, Hanjun Cheng, Ronghui Zhu, Min Xue, Lidia Robert, Raphael Levine, Antoni Ribas, Garry Nolan, Wei Wei, Sylvia Plevritis, David Baltimore, James R. Heath. Systems biology for investigating drug resistance mechanism of melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6585.
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- 2020
26. Immunotherapy Resistance by Inflammation-Induced Dedifferentiation
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Beata Berent-Maoz, Antoni Ribas, James S. Economou, Paul C. Tumeh, Yeon Joo Kim, Jennifer Tsoi, Lidia Robert, Arnav Mehta, Alistair J. Cochran, Cristina Puig-Saus, and Begoña Comin-Anduix
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0301 basic medicine ,Male ,medicine.medical_treatment ,Adoptive ,Drug Resistance ,Drug resistance ,Immunotherapy, Adoptive ,Cancer immunotherapy ,Recurrence ,Receptors ,Nerve Growth Factor ,Medicine ,Neoplasm ,2.1 Biological and endogenous factors ,Neoplasm Metastasis ,Aetiology ,Melanoma ,Cancer ,Nevus, Pigmented ,Receptors, Chimeric Antigen ,Tumor ,Middle Aged ,medicine.anatomical_structure ,Oncology ,5.1 Pharmaceuticals ,Tumor necrosis factor alpha ,Immunotherapy ,Development of treatments and therapeutic interventions ,T cell ,Oncology and Carcinogenesis ,Nerve Tissue Proteins ,Receptors, Nerve Growth Factor ,Article ,Cell Line ,Vaccine Related ,03 medical and health sciences ,MART-1 Antigen ,Antigen ,Pigmented ,Cell Line, Tumor ,Humans ,neoplasms ,Nevus ,business.industry ,Chimeric Antigen ,Cell Dedifferentiation ,medicine.disease ,Coculture Techniques ,030104 developmental biology ,Drug Resistance, Neoplasm ,Cancer research ,Immunization ,business - Abstract
A promising arsenal of targeted and immunotherapy treatments for metastatic melanoma has emerged over the last decade. With these therapies, we now face new mechanisms of tumor-acquired resistance. We report here a patient whose metastatic melanoma underwent dedifferentiation as a resistance mechanism to adoptive T-cell transfer therapy (ACT) to the MART1 antigen, a phenomenon that had been observed only in mouse studies to date. After an initial period of tumor regression, the patient presented in relapse with tumors lacking melanocytic antigens (MART1, gp100) and expressing an inflammation-induced neural crest marker (NGFR). We demonstrate using human melanoma cell lines that this resistance phenotype can be induced in vitro by treatment with MART1 T cell receptor–expressing T cells or with TNFα, and that the phenotype is reversible with withdrawal of inflammatory stimuli. This supports the hypothesis that acquired resistance to cancer immunotherapy can be mediated by inflammation-induced cancer dedifferentiation. Significance: We report a patient whose metastatic melanoma underwent inflammation-induced dedifferentiation as a resistance mechanism to ACT to the MART1 antigen. Our results suggest that future melanoma ACT protocols may benefit from the simultaneous targeting of multiple tumor antigens, modulating the inflammatory response, and inhibition of inflammatory dedifferentiation-inducing signals. Cancer Discov; 8(8); 935–43. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 899
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- 2018
27. Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress
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Katherine M. Sheu, Deborah J.L. Wong, Johnson Lay, Catherine S. Grasso, Antoni Ribas, Jennifer Tsoi, Xiaoyan Wang, Lidia Robert, Kim H. T. Paraiso, Thomas G. Graeber, Nicolaos Palaskas, Mohammad Atefi, Roksana Shirazi, Carlos Galvan, and Daniel Braas
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0301 basic medicine ,Cancer Research ,Programmed cell death ,Cell Survival ,medicine.medical_treatment ,Iron ,Biology ,medicine.disease_cause ,Article ,Piperazines ,Malignant transformation ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Humans ,Gene Regulatory Networks ,Protein kinase A ,Receptor ,Melanoma ,Gene Expression Profiling ,Cell Biology ,Immunotherapy ,Cell Dedifferentiation ,DNA Methylation ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Oxidative Stress ,030104 developmental biology ,Oncology ,Vemurafenib ,Cell culture ,Drug Resistance, Neoplasm ,Cancer research ,Oxidative stress ,Signal Transduction - Abstract
Malignant transformation can result in melanoma cells that resemble different stages of their embryonic development. Our gene expression analysis of human melanoma cell lines and patient tumors revealed that melanoma follows a two-dimensional differentiation trajectory that can be subclassified into four progressive subtypes. This differentiation model is associated with subtype-specific sensitivity to iron-dependent oxidative stress and cell death known as ferroptosis. Receptor tyrosine kinase-mediated resistance to mitogen-activated protein kinase targeted therapies and activation of the inflammatory signaling associated with immune therapy involves transitions along this differentiation trajectory, which lead to increased sensitivity to ferroptosis. Therefore, ferroptosis-inducing drugs present an orthogonal therapeutic approach to target the differentiation plasticity of melanoma cells to increase the efficacy of targeted and immune therapies.
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- 2018
28. Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors
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Thomas S. Rush, Hussein Tawbi, Yongqi Deng, Wen-Jen Hwu, Paul Kirschmeier, Ryan J. Sullivan, Joseph Rubino, Ahmed A. Samatar, Lidia Robert, Gerald W. Shipps, Keith T. Flaherty, Donna Carr, Peter C.C. Fong, Antoni Ribas, Patrick Chun, Brian Long, Eric H. Rubin, Priya Dayananth, Ramesh K. Ramanathan, Ronnie Shapira-Frommer, Stergios J. Moschos, Blanca Homet Moreno, W. Robert Bishop, Alan B. Cooper, James E. Schiller, Alex A. Adjei, Nathan R. Miselis, and Da Zhang
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0301 basic medicine ,Male ,Pyrrolidines ,Pyridines ,Drug Evaluation, Preclinical ,Administration, Oral ,Phases of clinical research ,lcsh:Medicine ,Pharmacology ,Signal transduction ,Mice ,0302 clinical medicine ,Clinical trials ,Neoplasms ,Medicine ,Melanoma ,Fatigue ,Cancer ,Mitogen-Activated Protein Kinase 1 ,Tumor ,Mitogen-Activated Protein Kinase 3 ,Nausea ,General Medicine ,Middle Aged ,Preclinical ,Tolerability ,Oncology ,030220 oncology & carcinogenesis ,6.1 Pharmaceuticals ,Toxicity ,Administration ,Female ,Drug Eruptions ,Drug ,Diarrhea ,Oral ,Adult ,Indazoles ,Maximum Tolerated Dose ,MAP Kinase Signaling System ,Clinical Trials and Supportive Activities ,Biological Availability ,Cell Line ,Dose-Response Relationship ,03 medical and health sciences ,Young Adult ,Dogs ,Pharmacokinetics ,Clinical Research ,Cell Line, Tumor ,Animals ,Humans ,Clinical Trials ,Adverse effect ,Protein Kinase Inhibitors ,Neoplasm Staging ,Dose-Response Relationship, Drug ,business.industry ,lcsh:R ,Evaluation of treatments and therapeutic interventions ,Triazoles ,medicine.disease ,Xenograft Model Antitumor Assays ,Rats ,Clinical trial ,030104 developmental biology ,Pharmacodynamics ,Drug Evaluation ,Clinical Medicine ,business - Abstract
BACKGROUND. Constitutive activation of ERK1/2 occurs in various cancers, and its reactivation is a well-described resistance mechanism to MAPK inhibitors. ERK inhibitors may overcome the limitations of MAPK inhibitor blockade. The dual mechanism inhibitor SCH772984 has shown promising preclinical activity across various BRAFV600/RAS-mutant cancer cell lines and human cancer xenografts. METHODS. We have developed an orally bioavailable ERK inhibitor, MK-8353; conducted preclinical studies to demonstrate activity, pharmacodynamic endpoints, dosing, and schedule; completed a study in healthy volunteers (P07652); and subsequently performed a phase I clinical trial in patients with advanced solid tumors (MK-8353-001). In the P07652 study, MK-8353 was administered as a single dose in 10- to 400-mg dose cohorts, whereas in the MK-8353-001 study, MK-8353 was administered in 100- to 800-mg dose cohorts orally twice daily. Safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity were analyzed. RESULTS. MK-8353 exhibited comparable potency with SCH772984 across various preclinical cancer models. Forty-eight patients were enrolled in the P07652 study, and twenty-six patients were enrolled in the MK-8353-001 study. Adverse events included diarrhea (44%), fatigue (40%), nausea (32%), and rash (28%). Dose-limiting toxicity was observed in the 400-mg and 800-mg dose cohorts. Sufficient exposure to MK-8353 was noted that correlated with biological activity in preclinical data. Three of fifteen patients evaluable for treatment response in the MK-8353-001 study had partial response, all with BRAFV600-mutant melanomas. CONCLUSION. MK-8353 was well tolerated up to 400 mg twice daily and exhibited antitumor activity in patients with BRAFV600-mutant melanoma. However, antitumor activity was not particularly correlated with pharmacodynamic parameters. TRIAL REGISTRATION. ClinicalTrials.gov NCT01358331. FUNDING. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and NIH (P01 CA168585 and R35 CA197633).
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- 2018
29. MAPK pathway inhibition induces MET and GAB1 levels, priming BRAF mutant melanoma for rescue by hepatocyte growth factor
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Keegan Cooke, Blanca Homet Moreno, Sean Caenepeel, Sarah Wadsworth, Giulia Parisi, Lidia Robert, Angela Coxon, Antoni Ribas, Richard Kendall, Paul E. Hughes, Elaina Cajulis, Guo Huang, and Pedro J. Beltran
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0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,MAPK/ERK pathway ,Indoles ,medicine.medical_treatment ,Nude ,Drug Resistance ,GAB1 ,Apoptosis ,Targeted therapy ,Mice ,0302 clinical medicine ,HGF ,Cancer ,Sulfonamides ,Tumor ,Hepatocyte Growth Factor ,Melanoma ,Adaptor Proteins ,Dipeptides ,Proto-Oncogene Proteins c-met ,Oncology ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Benzamides ,MET ,Hepatocyte growth factor ,Female ,Development of treatments and therapeutic interventions ,Tyrosine kinase ,Research Paper ,medicine.drug ,Proto-Oncogene Proteins B-raf ,Combination therapy ,Pyridones ,MAP Kinase Signaling System ,Oncology and Carcinogenesis ,Mice, Nude ,Antineoplastic Agents ,Cell Line ,BRAF ,resistance ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,melanoma ,Animals ,Humans ,neoplasms ,Protein Kinase Inhibitors ,Adaptor Proteins, Signal Transducing ,business.industry ,Diphenylamine ,Signal Transducing ,Triazoles ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Vemurafenib ,Drug Resistance, Neoplasm ,Immunology ,Cancer research ,Neoplasm ,business - Abstract
Therapeutic resistance is a major obstacle to achieving durable clinical responses with targeted therapies, highlighting a need to elucidate the underlying mechanisms responsible for resistance and identify strategies to overcome this challenge. An emerging body of data implicates the tyrosine kinase MET in mediating resistance to BRAF inhibitors in BRAFV600E mutant melanoma. In this study we observed a dominant role for the HGF/MET axis in mediating resistance to BRAF and MEK inhibitors in models of BRAFV600E and NRAS mutant melanoma. In addition, we showed that MAPK pathway inhibition induced rapid increases in MET and GAB1 levels, providing novel mechanistic insight into how BRAFV600E mutant melanoma is primed for HGF-mediated rescue. We also determined that tumor-derived HGF, not systemic HGF, may be required to convey resistance to BRAF inhibition in vivo and that resistance could be reversed following treatment with AMG 337, a selective MET inhibitor. In summary, these findings support the clinical evaluation of MET-directed targeted therapy to circumvent resistance to BRAF and MEK inhibitors in BRAFV600E mutant melanoma. In addition, the induction of MET following treatment with BRAF and MEK inhibitors has the potential to serve as a predictive biomarker for identifying patients best suited for MET inhibitor combination therapy.
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- 2017
30. Abstract 553: Melanoma subtypes that emerge during adaptive resistance to therapy are targets for bispecific T cell engager (BiTE®) antibody constructs directed to CDH19 and DLL3
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Giffin Michael John, Lidia Robert, Antoni Ribas, Fei Lee, Paul E. Hughes, Angela Coxon, Thomas G. Graeber, Julie M. Bailis, and Jennifer Tsoi
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Cancer Research ,business.industry ,Melanoma ,medicine.medical_treatment ,T cell ,Immunotherapy ,medicine.disease ,Immune checkpoint ,Targeted therapy ,Cell killing ,medicine.anatomical_structure ,Oncology ,Cancer cell ,Cancer research ,medicine ,Cytotoxic T cell ,business - Abstract
The treatment landscape for metastatic melanoma has changed considerably over the last several years with the approval of targeted therapy, such as BRAF inhibitors, and immunotherapy, such as immune checkpoint inhibitors that block cytotoxic T lymphocyte associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1). However, approximately 40% of patients do not respond to the current standard of care, and up to one-third of patients who initially respond to therapy can relapse. Novel therapies that act by a distinct mechanism of action may be needed to increase durable response rates in metastatic melanoma. Bispecific T cell engager (BiTE®) antibody constructs directly connect T cells to tumor cells and redirect T cell lysis to achieve tumor cell killing. BiTE®-mediated cytotoxicity is not dependent on a specific T cell receptor or peptide-MHC complex and has the potential to circumvent common immune resistance mechanisms. We have generated a BiTE® with half-life extension (HLE) that targets the atypical cadherin CDH19 on melanoma cells and CD3 on T cells (anti-CDH19/CD3 HLE BiTE®). We have also generated an HLE BiTE® that targets delta-like ligand 3 (DLL3) on tumor cells and CD3 on T cells, anti-DLL3/CD3 HLE BiTE®, or AMG 757. CDH19 and DLL3 are expressed on about half of primary and metastatic melanoma tumors prior to treatment. In this study, we investigated the expression of CDH19 and DLL3 and the activity of the corresponding BiTE® antibody constructs in a panel of 14 melanoma cell lines that were derived from patients that were resistant to either targeted therapy or immune checkpoint therapy and expanded the spectrum of recently defined multistage differentiation melanoma subtypes from melanocytic, transitional, neural crest-like and de-differentiated subtypes (Tsoi et al. Cancer Cell 2017). The cell surface expression of CDH19 and DLL3 was determined by flow cytometry. We then used T cell-dependent cytotoxicity (TDCC) assays to assess the activity of the anti-CDH19/CD3 HLE BiTE® and AMG 757 against the cell lines. 13/14 (93%) of the treatment-resistant melanoma cell lines expressed CDH19 on the cell surface, and 9/14 (64%) of the cell lines expressed cell surface DLL3. The anti-CDH19/CD3 HLE BiTE® and AMG 757 demonstrated potent cell killing of CDH19-positive or DLL3-positive melanoma cells, respectively, in TDCC assays, with EC50 values in the low picomolar range. These data show that melanoma cells that become resistant to targeted therapy and/or immune checkpoint blockade can be effectively targeted with BiTE® antibody constructs and suggest that the anti-CDH19/CD3 HLE BiTE® and AMG 757 may be potential novel therapies for treatment of relapsed and/or refractory metastatic melanoma. Citation Format: Julie M. Bailis, Fei Lee, Michael Giffin, Paul Hughes, Jennifer Tsoi, Lidia Robert, Thomas G. Graeber, Antoni Ribas, Angela Coxon. Melanoma subtypes that emerge during adaptive resistance to therapy are targets for bispecific T cell engager (BiTE®) antibody constructs directed to CDH19 and DLL3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 553.
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- 2019
31. Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells
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Marcus Bosenberg, Siwen Hu-Lieskovan, Jennifer Tsoi, Jesse M. Zaretsky, Abibatou Ndoye, Lidia Robert, Ashani T. Weeraratna, Antoni Ribas, Angel Garcia-Diaz, Begoña Comin-Anduix, Thomas G. Graeber, Blanca Homet Moreno, Giulia Parisi, and Katrina Meeth
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0301 basic medicine ,CD4-Positive T-Lymphocytes ,Cancer Research ,Programmed Cell Death 1 Receptor ,Priming (immunology) ,CD8-Positive T-Lymphocytes ,Inbred C57BL ,Mice ,Interferon ,Monoclonal ,Cytotoxic T cell ,2.1 Biological and endogenous factors ,Lymphocytes ,Aetiology ,Melanoma ,Humanized ,Cancer ,Tumor ,CD28 ,Antibodies, Monoclonal ,Pharmacology and Pharmaceutical Sciences ,medicine.drug ,Proto-Oncogene Proteins B-raf ,Immunology ,Oncology and Carcinogenesis ,CD11c ,Antineoplastic Agents ,Biology ,Antibodies, Monoclonal, Humanized ,Article ,Antibodies ,Cell Line ,03 medical and health sciences ,Interferon-gamma ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Cell Line, Tumor ,medicine ,Animals ,Tumor-Infiltrating ,Macrophages ,Dendritic Cells ,Xenograft Model Antitumor Assays ,Blockade ,Mice, Inbred C57BL ,030104 developmental biology ,Mutation ,Cancer research ,CD80 - Abstract
The programmed cell death protein 1 (PD-1) limits effector T-cell functions in peripheral tissues, and its inhibition leads to clinical benefit in different cancers. To better understand how PD-1 blockade therapy modulates the tumor–host interactions, we evaluated three syngeneic murine tumor models, the BRAFV600E-driven YUMM1.1 and YUMM2.1 melanomas, and the carcinogen-induced murine colon adenocarcinoma MC38. The YUMM cell lines were established from mice with melanocyte-specific BRAFV600E mutation and PTEN loss (BRAFV600E/PTEN−/−). Anti–PD-1 or anti–PD-L1 therapy engendered strong antitumor activity against MC38 and YUMM2.1, but not YUMM1.1. PD-L1 expression did not differ between the three models at baseline or upon interferon stimulation. Whereas mutational load was high in MC38, it was lower in both YUMM models. In YUMM2.1, the antitumor activity of PD-1 blockade had a critical requirement for both CD4 and CD8 T cells, as well as CD28 and CD80/86 costimulation, with an increase in CD11c+CD11b+MHC-IIhigh dendritic cells and tumor-associated macrophages in the tumors after PD-1 blockade. Compared with YUMM1.1, YUMM2.1 exhibited a more inflammatory profile by RNA sequencing analysis, with an increase in expression of chemokine-trafficking genes that are related to immune cell recruitment and T-cell priming. In conclusion, response to PD-1 blockade therapy in tumor models requires CD4 and CD8 T cells and costimulation that is mediated by dendritic cells and macrophages. Cancer Immunol Res; 4(10); 845–57. ©2016 AACR.
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- 2016
32. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma
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John B. A. G. Haanen, Jennifer Tsoi, Chunying Song, Christian U. Blank, Roger S. Lo, Antoni Ribas, Colin R. Goding, Lidia Robert, Willy Hugo, Oscar Krijgsman, Daniel S. Peeper, Marnix H Geukes Foppen, Xiangju Kong, Paulien Cornelissen-Steijger, Ultan McDermott, Thomas G. Graeber, Kristel Kemper, Judith Müller, Patricia A. Possik, Pathology, and CCA - Innovative therapy
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Neuroblastoma RAS viral oncogene homolog ,MAPK/ERK pathway ,Indoles ,Skin Neoplasms ,Drug Resistance ,General Physics and Astronomy ,Aminopyridines ,Drug resistance ,Receptor tyrosine kinase ,Piperazines ,Mice ,0302 clinical medicine ,Oximes ,Vemurafenib ,Extracellular Signal-Regulated MAP Kinases ,Melanoma ,Cancer ,0303 health sciences ,Sulfonamides ,Multidisciplinary ,Tumor ,biology ,integumentary system ,Imidazoles ,Microphthalmia-associated transcription factor ,Prognosis ,Gene Expression Regulation, Neoplastic ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Benzamides ,Imatinib Mesylate ,Development of treatments and therapeutic interventions ,medicine.drug ,Signal Transduction ,Proto-Oncogene Proteins B-raf ,MAP Kinase Signaling System ,Pyridones ,Antineoplastic Agents ,Pyrimidinones ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cell Line ,03 medical and health sciences ,Clinical Research ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,neoplasms ,Protein Kinase Inhibitors ,030304 developmental biology ,Neoplastic ,Microphthalmia-Associated Transcription Factor ,NF-kappa B p50 Subunit ,Receptor Protein-Tyrosine Kinases ,General Chemistry ,medicine.disease ,Xenograft Model Antitumor Assays ,Axl Receptor Tyrosine Kinase ,body regions ,Imatinib mesylate ,Pyrimidines ,Gene Expression Regulation ,Drug Resistance, Neoplasm ,Cancer research ,biology.protein ,Neoplasm - Abstract
Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.
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- 2016
33. RASMutations in Cutaneous Squamous-Cell Carcinomas in Patients Treated with BRAF Inhibitors
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Holly Hilton, Nicholas Otte, Julie S. Hang, Ion Niculescu-Duvaz, Felipe C. Geyer, Lidia Robert, K. B. Nolop, Jorge S. Reis-Filho, Luc Andries, Alfonso Zambon, Gideon Bollag, Rene Gonzalez, Natasha Preece, Paul B. Chapman, Damien Kee, Min Jung Kim, Kerstin Trunzer, Dan Niculescu-Duvaz, Stephen Mok, Brian Lestini, Roger S. Lo, Gaston Habets, Amaya Viros, James L. Troy, Caroline J. Springer, Mark M. Kockx, Yan Ma, Igor Puzanov, Carla Milagre, Robert Hayward, Elizabeth A. Burton, Antoni Ribas, Xiangju Kong, Chao Zhang, Matthew J. Martin, Maryou B K Lambros, Andrew K. Joe, Richard C. Koya, Jeffrey A. Sosman, Olivia Spleiss, Johannes Noe, Bartosz Chmielowski, Hoa Nguyen, Richard J. Lee, Keith T. Flaherty, Richard Marais, Nathalie Dhomen, Hong Yang, Bernice Wong, Qiongqing Wang, Grant A. McArthur, Fei Su, and Thomas E. Hutson
- Subjects
Male ,Proto-Oncogene Proteins B-raf ,Neuroblastoma RAS viral oncogene homolog ,Indoles ,Skin Neoplasms ,Gene Expression ,medicine.disease_cause ,Mice ,chemistry.chemical_compound ,CDKN2A ,Animals ,Humans ,Medicine ,HRAS ,Vemurafenib ,Protein Kinase Inhibitors ,Aged ,Aged, 80 and over ,Mitogen-Activated Protein Kinase Kinases ,Cobimetinib ,Sulfonamides ,business.industry ,Melanoma ,General Medicine ,Middle Aged ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Genes, ras ,chemistry ,Mutation ,Carcinoma, Squamous Cell ,Cancer research ,Female ,KRAS ,business ,Carcinogenesis ,medicine.drug - Abstract
Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors.We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed.Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L-mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)-pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L-mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor.Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann-La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.).
- Published
- 2012
34. Combining targeted therapy with immunotherapy. Can 1+1 equal more than 2?
- Author
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Lidia Robert, Siwen Hu-Lieskovan, and Antoni Ribas
- Subjects
0301 basic medicine ,Oncology ,Adoptive cell transfer ,Receptor, ErbB-2 ,medicine.medical_treatment ,Adoptive ,Angiogenesis Inhibitors ,Immunotherapy, Adoptive ,Targeted therapy ,0302 clinical medicine ,ErbB-2 ,Neoplasms ,Tumor Microenvironment ,Immunology and Allergy ,Molecular Targeted Therapy ,Cancer ,Clinical Trials as Topic ,food and beverages ,Combined Modality Therapy ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,6.1 Pharmaceuticals ,Neoplastic Stem Cells ,Immunotherapy ,Development of treatments and therapeutic interventions ,Receptor ,medicine.medical_specialty ,Combination therapy ,Immunology ,Antineoplastic Agents ,Cancer Vaccines ,Article ,Vaccine Related ,03 medical and health sciences ,Cancer stem cell ,Clinical Research ,Internal medicine ,medicine ,Humans ,Protein Kinase Inhibitors ,Tumor microenvironment ,5.2 Cellular and gene therapies ,business.industry ,fungi ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,Stem Cell Research ,Immune checkpoint ,Histone Deacetylase Inhibitors ,030104 developmental biology ,Immunization ,business ,Immune checkpoint blockade - Abstract
Targeted therapies have induced high response rates and improved survival in patients with cancer. However, the long-term effectiveness of targeted therapies has been limited by the development of acquired resistance in the majority of patients. On the other hand, the modern immunotherapy strategies have been associated with durable responses but in limited number of patients. Accordingly, research efforts have been focused on examining the effects of combinations of targeted therapy and immunotherapy in several different histological subtypes of cancer. There has been accumulated evidence to suggest that targeted therapy can induce immune effects in the tumor cells, the host immune system, and the tumor microenvironment. Subsequently, clinical trials have been designed to examine the efficacy of combining immune checkpoint blockade or adoptive cell transfer with tyrosine kinase inhibitors, HER family blockade, anti-angiogenic agents, histone deacetylase inhibitors, and cancer stem cell inhibitors. To date, the combination of immunotherapy with targeted therapy has demonstrated potential as a cancer treatment strategy, but further optimizations are required and caution must be taken to avoid toxicity. The current review summarizes existing evidence and provides rationale supporting the use of combined targeted and immune-therapy approaches in patients with different types of cancer.
- Published
- 2015
35. Anti-PD-1 therapy in melanoma
- Author
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Antoni Ribas, Lidia Robert, Giulia Parisi, and Blanca Homet Moreno
- Subjects
Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Antineoplastic Agents ,Pembrolizumab ,Pidilizumab ,Cancer immunotherapy ,Internal medicine ,medicine ,Animals ,Humans ,Immunologic Factors ,Molecular Targeted Therapy ,Melanoma ,business.industry ,Cancer ,Hematology ,Immunotherapy ,medicine.disease ,Clinical trial ,Immunology ,Nivolumab ,business - Abstract
Immune-regulatory mechanisms are used by cancer to hide from the immune system. Advances and in-depth understanding of the biology of melanoma and its interaction with the immune system have led to the development of some of antagonistic antibodies to the programmed death 1 pathway (PD-1) and one of its ligands, programmed death ligand 1 (PD-L1), which are demonstrating high clinical benefit rates and tolerability. Blocking the immune-regulatory checkpoints that limit T-cell responses to melanoma upon PD-1/PD-L1 modulation has provided clinically validated targets for cancer immunotherapy. Combinations with other anti-melanoma agents may result in additional benefits. Nivolumab, pembrolizumab (formerly known as MK-3475 and lambrolizumab), and pidilizumab are anti-PD-1 antibodies in clinical development for melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancers, lymphoma, and several other cancers. Long-term survivors already have been reported with these therapies. In this review, we discuss the current state of anti-PD-1 agents, the evidence in the literature to support the combination of anti-PD-1 antibodies with other anti-cancer agents and discuss the future directions for rational design of clinical trials that keep on increasing the number of long-term survivors.
- Published
- 2015
36. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF V600E melanoma
- Author
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Begoña Comin-Anduix, Elaine M. Pinheiro, Lidia Robert, Richard C. Koya, Siwen Hu-Lieskovan, Stephen Mok, Lucas Goedert, Blanca Homet Moreno, Thomas G. Graeber, Antoni Ribas, and Jennifer Tsoi
- Subjects
Proto-Oncogene Proteins B-raf ,MAPK/ERK pathway ,Skin Neoplasms ,Cell Survival ,Pyridones ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Antineoplastic Agents ,Mice, Transgenic ,Pyrimidinones ,Article ,Targeted therapy ,Major Histocompatibility Complex ,Mice ,Antigens, Neoplasm ,Cell Line, Tumor ,Oximes ,medicine ,Animals ,Humans ,CTLA-4 Antigen ,Vemurafenib ,Melanoma ,Protein Kinase Inhibitors ,neoplasms ,Trametinib ,business.industry ,MEK inhibitor ,Imidazoles ,Dabrafenib ,General Medicine ,MAP Kinase Kinase Kinases ,medicine.disease ,Mice, Inbred C57BL ,Cancer research ,Immunotherapy ,business ,V600E ,medicine.drug - Abstract
Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA4 antibody ipilimumab was terminated early because of substantial liver toxicities. MEK [MAPK (mitogen-activated protein kinase) kinase] inhibitors can potentiate the MAPK inhibition in BRAF mutant cells while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild-type cells that lead to side effects when using BRAF inhibitors alone. However, there is the concern of MEK inhibitors being detrimental to T cell functionality. Using a mouse model of syngeneic BRAF(V600E)-driven melanoma, SM1, we tested whether addition of the MEK inhibitor trametinib would enhance the antitumor activity of combined immunotherapy with the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression, increased T cell infiltration into tumors, and improved in vivo cytotoxicity. Single-agent dabrafenib increased tumor-associated macrophages and T regulatory cells (Tregs) in tumors, which decreased with the addition of trametinib. The triple combination therapy resulted in increased melanosomal antigen and major histocompatibility complex (MHC) expression and global immune-related gene up-regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested the combination of dabrafenib, trametinib, and anti-PD1 therapy in SM1 tumors, and observed superior antitumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAF(V600E) mutant metastatic melanoma.
- Published
- 2015
37. MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells
- Author
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Thomas G. Graeber, Antoni Ribas, Diego Ploper, Lidia Robert, Brian S. Perez, Hsiao-Wang Chen, Edward M. De Robertis, Vincent F. Taelman, Björn Titz, and Erika von Euw
- Subjects
Wnt signalosome ,Wnt-STOP ,macromolecular substances ,Endosomes ,Biology ,multivesicular body ,Cell Line ,Glycogen Synthase Kinase 3 ,GSK-3 ,Cell Line, Tumor ,Genetics ,melanoma ,2.1 Biological and endogenous factors ,Humans ,Aetiology ,Phosphorylation ,Transcription factor ,Cancer ,Microphthalmia-Associated Transcription Factor ,MITF ,Multidisciplinary ,Tumor ,integumentary system ,Wnt signaling pathway ,LRP6 ,LRP5 ,Microphthalmia-associated transcription factor ,Cell biology ,Wnt Proteins ,HEK293 Cells ,PNAS Plus ,Cancer research ,lysosome ,TFEB ,Lysosomes ,Signal Transduction - Abstract
Canonical Wnt signaling plays an important role in development and disease, regulating transcription of target genes and stabilizing many proteins phosphorylated by glycogen synthase kinase 3 (GSK3). We observed that the MiT family of transcription factors, which includes the melanoma oncogene MITF (micropthalmiaassociated transcription factor) and the lysosomal master regulator TFEB, had the highest phylogenetic conservation of three consecutive putative GSK3 phosphorylation sites in animal proteomes. This finding prompted us to examine the relationship between MITF, endolysosomal biogenesis, and Wnt signaling. Here we report that MITF expression levels correlated with the expression of a large subset of lysosomal genes in melanoma cell lines. MITF expression in the tetracycline-inducible C32 melanoma model caused a marked increase in vesicular structures, and increased expression of late endosomal proteins, such as Rab7, LAMP1, and CD63. These late endosomes were not functional lysosomes as they were less active in proteolysis, yet were able to concentrate Axin1, phospho-LRP6, phospho-β-catenin, and GSK3 in the presence of Wnt ligands. This relocalization significantly enhanced Wnt signaling by increasing the number of multivesicular bodies into which the Wnt signalosome/ destruction complex becomes localized upon Wnt signaling. We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here. MITF stabilization caused an increase in multivesicular body biosynthesis, which in turn increased Wnt signaling, generating a positive-feedback loop that may function during the proliferative stages of melanoma. The results underscore the importance of misregulated endolysosomal biogenesis in Wnt signaling and cancer. MITF Wnt-STOP lysosome melanoma multivesicular body.
- Published
- 2015
38. PD-1 blockade induces responses by inhibiting adaptive immune resistance
- Author
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Harlan Robins, Christine Kivork, Gorana Tomasic, Lidia Robert, I. Peter Shintaku, Grace Cherry, Caroline Robert, Tristan Grogan, Elizabeth Seja, Ryan O. Emerson, David Elashoff, Paul C. Tumeh, Christine Mateus, Antoni Ribas, Emma Taylor, Marko Spasic, Voicu Ciobanu, Robert H. Pierce, Bartosz Chmielowski, Gina Henry, Antonio Gutierrez, John A. Glaspy, Jennifer H. Yearley, Manuel Carmona, Christina L. Harview, and Alisha N. West
- Subjects
Male ,Aging ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Pembrolizumab ,CD8-Positive T-Lymphocytes ,Adaptive Immunity ,Neurodegenerative ,0302 clinical medicine ,Models ,80 and over ,Melanoma ,Cancer ,Aged, 80 and over ,0303 health sciences ,Multidisciplinary ,Parkinson's Disease ,Middle Aged ,Acquired immune system ,3. Good health ,Gene Expression Regulation, Neoplastic ,Treatment Outcome ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Female ,Immunotherapy ,Development of treatments and therapeutic interventions ,General Science & Technology ,and over ,Biology ,Models, Biological ,Article ,03 medical and health sciences ,Immune system ,medicine ,Humans ,030304 developmental biology ,Cell Proliferation ,Aged ,Neoplastic ,Neurosciences ,medicine.disease ,Biological ,Brain Disorders ,Gene Expression Regulation ,Immunology ,Multivariate Analysis ,Checkpoint Blockade Immunotherapy ,CD8 ,Biomarkers - Abstract
Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8(+) T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.
- Published
- 2014
39. Chemical dissection of the cell cycle: probes for cell biology and anti-cancer drug development
- Author
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Robert Damoiseaux, Michael A. Teitell, Antoni Ribas, M K Summers, Lidia Robert, Thomas A. Zangle, Jorge Z. Torres, Silvia Senese, Yu-Chen Lo, Ankur A. Gholkar, Blanca Homet, and Dian Huang
- Subjects
Cancer Research ,Programmed cell death ,M Phase Cell Cycle Checkpoints ,Cell division ,1.1 Normal biological development and functioning ,Immunology ,Oncology and Carcinogenesis ,Mitosis ,Antineoplastic Agents ,Polymerization ,Small Molecule Libraries ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Underpinning research ,Tubulin ,Neoplasms ,Drug Discovery ,Genetics ,Humans ,030304 developmental biology ,Cancer ,0303 health sciences ,biology ,Cell Death ,Cell Cycle ,Cell Biology ,Cell cycle ,3. Good health ,Cell biology ,High-Throughput Screening Assays ,Spindle checkpoint ,Phenotype ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Hela Cells ,Molecular Probes ,Cancer cell ,biology.protein ,Original Article ,Biochemistry and Cell Biology ,Development of treatments and therapeutic interventions ,HeLa Cells ,Biotechnology - Abstract
Cancer cell proliferation relies on the ability of cancer cells to grow, transition through the cell cycle, and divide. To identify novel chemical probes for dissecting the mechanisms governing cell cycle progression and cell division, and for developing new anti-cancer therapeutics, we developed and performed a novel cancer cell-based high-throughput chemical screen for cell cycle modulators. This approach identified novel G1, S, G2, and M-phase specific inhibitors with drug-like properties and diverse chemotypes likely targeting a broad array of processes. We further characterized the M-phase inhibitors and highlight the most potent M-phase inhibitor MI-181, which targets tubulin, inhibits tubulin polymerization, activates the spindle assembly checkpoint, arrests cells in mitosis, and triggers a fast apoptotic cell death. Importantly, MI-181 has broad anti-cancer activity, especially against BRAFV600E melanomas.
- Published
- 2014
40. Antitumor activity of the ERK inhibitor SCH722984 against BRAF mutant, NRAS mutant and wild-type melanoma
- Author
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Lidia Robert, Antoni Ribas, Jennifer Tsoi, David Foulad, Michael Cerniglia, Begonya Comin-Anduix, Roger S. Lo, Amanda Lassen, Earl Avramis, Geetha Avarappatt, Thomas G. Graeber, Mohammad Atefi, Ahmed A. Samatar, and Deborah J.L. Wong
- Subjects
Neuroblastoma RAS viral oncogene homolog ,MAPK/ERK pathway ,BRAF inhibitor ,Cancer Research ,endocrine system diseases ,Mutant ,Biology ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Vemurafenib ,Protein kinase B ,neoplasms ,Melanoma ,030304 developmental biology ,0303 health sciences ,Research ,Wild type ,Cell cycle ,medicine.disease ,digestive system diseases ,3. Good health ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Molecular Medicine ,Acquired resistance ,ERK inhibitor ,medicine.drug - Abstract
Background In melanoma, dysregulation of the MAPK pathway, usually via BRAFV600 or NRASQ61 somatic mutations, leads to constitutive ERK signaling. While BRAF inhibitors are initially effective for BRAF-mutant melanoma, no FDA-approved targeted therapies exist for BRAF-inhibitor-resistant BRAFV600, NRAS mutant, or wild-type melanoma. Methods The 50% inhibitory concentration (IC50) of SCH772984, a novel inhibitor of ERK1/2, was determined in a panel of 50 melanoma cell lines. Effects on MAPK and AKT signaling by western blotting and cell cycle by flow cytometry were determined. Results Sensitivity fell into three groups: sensitive, 50% inhibitory concentration (IC50) 2 μM. Fifteen of 21 (71%) BRAF mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH772984. All three (100%) BRAF/NRAS double mutants, 11 of 14 (78%) NRAS mutants and 5 of 7 (71%) wild-type melanomas were sensitive. Among BRAFV600 mutants with in vitro acquired resistance to vemurafenib, those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH772984. SCH772984 caused G1 arrest and induced apoptosis. Conclusions Combining vemurafenib and SCH722984 in BRAF mutant melanoma was synergistic in a majority of cell lines and significantly delayed the onset of acquired resistance in long term in vitro assays. Therefore, SCH772984 may be clinically applicable as a treatment for non-BRAF mutant melanoma or in BRAF-mutant melanoma with innate or acquired resistance, alone or in combination with BRAF inhibitors. Electronic supplementary material The online version of this article (doi:10.1186/1476-4598-13-194) contains supplementary material, which is available to authorized users.
- Published
- 2014
41. Combining targeted therapy with immunotherapy in BRAF-mutant melanoma: promise and challenges
- Author
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Blanca Homet Moreno, Antoni Ribas, Siwen Hu-Lieskovan, and Lidia Robert
- Subjects
Proto-Oncogene Proteins B-raf ,Cancer Research ,medicine.medical_treatment ,Ipilimumab ,Targeted therapy ,Immune system ,Biology of Neoplasia ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Molecular Targeted Therapy ,Vemurafenib ,neoplasms ,Melanoma ,Protein Kinase Inhibitors ,business.industry ,Cancer ,Immunotherapy ,medicine.disease ,Prognosis ,Clinical trial ,Oncology ,Immunology ,Mutation ,Cancer research ,business ,medicine.drug - Abstract
Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAFV600-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non–BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.
- Published
- 2014
42. Distinct immunological mechanisms of CTLA-4 and PD-1 blockade revealed by analyzing TCR usage in blood lymphocytes
- Author
-
Stephen Mok, Paul C. Tumeh, Lidia Robert, Ryan O. Emerson, Begonya Comin-Anduix, Antoni Ribas, Christina L. Harview, Richard C. Koya, Xiaoyan Wang, Harlan Robins, and Blanca Homet
- Subjects
Immunology ,Oncology and Carcinogenesis ,chemical and pharmacologic phenomena ,Peripheral blood mononuclear cell ,Immune system ,PD-1 ,medicine ,Immunology and Allergy ,Author's View ,business.industry ,T-cell receptor ,PBMC ,Inhibitory receptors ,Cancer ,sequencing ,medicine.disease ,Oncology ,CTLA-4 ,Pd 1 blockade ,MK-3475 ,business ,Tremelimumab ,TCR ,medicine.drug - Abstract
Targeting immune inhibitory receptors has brought excitement, innovation and hope to cancer patients. Our recent work revealed the immunological effects of blocking the CTLA4 and PD-1 immune checkpoints on T cell receptor usage among peripheral blood cells, and further uncovers how the expansion of the T cell repertoire matches the immunotoxicity profile of the therapy.
- Published
- 2014
43. Effects of MAPK and PI3K Pathways on PD-L1 Expression in Melanoma
- Author
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Amanda Lassen, Begoña Comin-Anduix, Thomas G. Graeber, Lidia Robert, Michael Cerniglia, Earl Avramis, Deborah J.L. Wong, Antoni Ribas, David Foulad, Bjoern Titz, Thinle Chodon, and Mohammad Atefi
- Subjects
Neuroblastoma RAS viral oncogene homolog ,MAPK/ERK pathway ,Proto-Oncogene Proteins B-raf ,Cancer Research ,Indoles ,Cells ,Oncology and Carcinogenesis ,Drug Resistance ,Article ,B7-H1 Antigen ,Cell Line ,Phosphatidylinositol 3-Kinases ,Cell Line, Tumor ,medicine ,PTEN ,Humans ,Oncology & Carcinogenesis ,Lymphocytes ,Vemurafenib ,Protein kinase B ,Melanoma ,PI3K/AKT/mTOR pathway ,Cells, Cultured ,Cancer ,Sulfonamides ,Cultured ,Tumor ,biology ,medicine.disease ,Coculture Techniques ,Oncology ,5.1 Pharmaceuticals ,Drug Resistance, Neoplasm ,Mutation ,biology.protein ,Cancer research ,Neoplasm ,Cytokines ,Development of treatments and therapeutic interventions ,Signal transduction ,Mitogen-Activated Protein Kinases ,medicine.drug ,Signal Transduction - Abstract
Purpose: PD-L1 is the main ligand for the immune inhibitory receptor PD-1. This ligand is frequently expressed by melanoma cells. In this study, we investigated whether PD-L1 expression is controlled by melanoma driver mutations and modified by oncogenic signaling inhibition. Experimental Design: Expression of PD-L1 was investigated in a panel of 51 melanoma cell lines containing different oncogenic mutations, including cell lines with innate and acquired resistance to BRAF inhibitors (BRAFi). The effects of targeted therapy drugs on expression of PD-L1 by melanoma cells were investigated. Results: No association was found between the level of PD-L1 expression and mutations in BRAF, NRAS, PTEN, or amplification of AKT. Resistance to vemurafenib due to the activation of alternative signaling pathways was accompanied with the induction of PD-L1 expression, whereas the resistance due to the reactivation of the MAPK pathway had no effect on PD-L1 expression. In melanoma cell lines, the effects of BRAF, MEK, and PI3K inhibitors on expression of PD-L1 were variable from reduction to induction, particularly in the presence of INFγ. In PD-L1–exposed lymphocytes, vemurafenib paradoxically restored activity of the MAPK pathway and increased the secretion of cytokines. Conclusions: In melanoma cell lines, including BRAFi-resistant cells, PD-L1 expression is variably regulated by oncogenic signaling pathways. PD-L1–exposed lymphocytes decrease MAPK signaling, which is corrected by exposure to vemurafenib, providing potential benefits of combining this drug with immunotherapies. Clin Cancer Res; 20(13); 3446–57. ©2014 AACR.
- Published
- 2014
44. CTLA4 blockade broadens the peripheral T-cell receptor repertoire
- Author
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Thomas G. Graeber, Stephen Mok, Harlan Robins, Thinle Chodon, Alistair J. Cochran, Xiaoyan Wang, Begonya Comin-Anduix, Blanca Homet, Lidia Robert, Antoni Ribas, Ryan O. Emerson, Richard C. Koya, Jennifer Tsoi, and Rong R. Huang
- Subjects
Male ,Cancer Research ,Cytotoxic ,T-Lymphocytes ,Receptors, Antigen, T-Cell, alpha-beta ,Receptors ,Monoclonal ,Leukocytes ,Cytotoxic T cell ,Cluster Analysis ,CTLA-4 Antigen ,Lymphocytes ,Neoplasm Metastasis ,Humanized ,Melanoma ,alpha-beta ,Antibodies, Monoclonal ,hemic and immune systems ,Middle Aged ,medicine.anatomical_structure ,Treatment Outcome ,Oncology ,Antigen ,Female ,Sequence Analysis ,medicine.drug ,Adult ,T cell ,Mononuclear ,Oncology and Carcinogenesis ,Receptors, Antigen, T-Cell ,chemical and pharmacologic phenomena ,Antineoplastic Agents ,Biology ,Antibodies, Monoclonal, Humanized ,Peripheral blood mononuclear cell ,Antibodies ,Article ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Clinical Research ,medicine ,Humans ,Tumor-Infiltrating ,Oncology & Carcinogenesis ,Lymphocyte Count ,Aged ,Neoplasm Staging ,T-cell receptor ,Computational Biology ,Genetic Variation ,DNA ,Sequence Analysis, DNA ,T-Cell ,Complementarity Determining Regions ,Blockade ,Immunology ,Leukocytes, Mononuclear ,Tremelimumab ,T-Lymphocytes, Cytotoxic - Abstract
Purpose: To evaluate the immunomodulatory effects of cytotoxic T–lymphocyte-associated protein 4 (CTLA4) blockade with tremelimumab in peripheral blood mononuclear cells (PBMC). Experimental Design: We used next-generation sequencing to study the complementarity-determining region 3 (CDR3) from the rearranged T-cell receptor (TCR) variable beta (V-beta) in PBMCs of 21 patients, at baseline and 30 to 60 days after receiving tremelimumab. Results: After receiving tremelimumab, there was a median of 30% increase in unique productive sequences of TCR V-beta CDR3 in 19 out of 21 patients, and a median decrease of 30% in only 2 out of 21 patients. These changes were significant for richness (P = 0.01) and for Shannon index diversity (P = 0.04). In comparison, serially collected PBMCs from four healthy donors did not show a significant change in TCR V-beta CDR3 diversity over 1 year. There was a significant difference in the total unique productive TCR V-beta CDR3 sequences between patients experiencing toxicity with tremelimumab compared with patients without toxicity (P = 0.05). No relevant differences were noted between clinical responders and nonresponders. Conclusions: CTLA4 blockade with tremelimumab diversifies the peripheral T-cell pool, representing a pharmacodynamic effect of how this class of antibodies modulates the human immune system. Clin Cancer Res; 20(9); 2424–32. ©2014 AACR.
- Published
- 2014
45. Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy
- Author
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Richard C. Koya, Gideon Bollag, Lily Wu, Lidia Robert, Antoni Ribas, Thomas G. Graeber, Jingying Xu, Christopher Tsui, Stephen Mok, and Brian L. West
- Subjects
Cancer Research ,Adoptive cell transfer ,Cell Survival ,medicine.medical_treatment ,Adoptive ,Oncology and Carcinogenesis ,Mice, Transgenic ,Receptor, Macrophage Colony-Stimulating Factor ,Biology ,Inbred C57BL ,Immunotherapy, Adoptive ,Article ,Transgenic ,Cell Line ,Vaccine Related ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Oncology & Carcinogenesis ,Receptor ,Melanoma ,Protein Kinase Inhibitors ,030304 developmental biology ,Cancer ,0303 health sciences ,Tumor ,Macrophage Colony-Stimulating Factor ,Immunotherapy ,medicine.disease ,3. Good health ,Mice, Inbred C57BL ,Oncology ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Myeloid-derived Suppressor Cell ,Cancer research ,Immunization ,Development of treatments and therapeutic interventions ,Tyrosine kinase - Abstract
Colony stimulating factor 1 (CSF-1) recruits tumor-infiltrating myeloid cells (TIM) that suppress tumor immunity, including M2 macrophages and myeloid-derived suppressor cells (MDSC). The CSF-1 receptor (CSF-1R) is a tyrosine kinase that is targetable by small molecule inhibitors such as PLX3397. In this study, we used a syngeneic mouse model of BRAFV600E-driven melanoma to evaluate the ability of PLX3397 to improve the efficacy of adoptive cell therapy (ACT). In this model, we found that combined treatment produced superior antitumor responses compared with single treatments. In mice receiving the combined treatment, a dramatic reduction of TIMs and a skewing of MHCIIlow to MHCIIhi macrophages were observed. Furthermore, mice receiving the combined treatment exhibited an increase in tumor-infiltrating lymphocytes (TIL) and T cells, as revealed by real-time imaging in vivo. In support of these observations, TILs from these mice released higher levels of IFN-γ. In conclusion, CSF-1R blockade with PLX3397 improved the efficacy of ACT immunotherapy by inhibiting the intratumoral accumulation of immunosuppressive macrophages. Cancer Res; 74(1); 153–61. ©2013 AACR.
- Published
- 2014
46. Lytic lesions in a patient with past history of renal cancer
- Author
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Ana, Sebio, Lidia, Robert, Diana, Ovejero, Paola, Murata, Ivana, Sullivan, Agostina, Stradella, and Pablo, Maroto
- Subjects
Diagnosis, Differential ,Hyperparathyroidism ,Osteitis Fibrosa Cystica ,Humans ,Kidney Neoplasms - Abstract
To study lytic lesions in a patient with past history of renal cancer.A 62 year-old man was admitted to hospital for investigation of the cause of polyostotic bone pain.Brown tumors due to hyperparathyroidism turned out to be the cause of bone pain.Differential diagnosis is important in daily practice in order to provide a correct treatment for each condition.
- Published
- 2013
47. Abstract 879: Single cell analysis resolves combinatory targeted therapy for arresting the BRAFi-induced cellular dedifferentiation of metastatic melanomas
- Author
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James R. Heath, Wei Wei, Antoni Ribas, Thomas G. Graeber, Jennifer Tsoi, Lidia Robert, Min Xue, and Yapeng Su
- Subjects
Cancer Research ,Cellular Dedifferentiation ,Combination therapy ,medicine.medical_treatment ,Melanoma ,Cell ,Cancer ,Biology ,medicine.disease ,Bioinformatics ,Targeted therapy ,medicine.anatomical_structure ,Oncology ,Single-cell analysis ,medicine ,Cancer research ,V600E - Abstract
Targeted therapy that inhibits the BRAF (V600E) protein has shown impressive initial responses in metastatic melanoma patients. However, acquired drug resistance, derived from tumor heterogeneity, always limits its efficacy and compromises its treatment outcomes. Melanocyte to neural crest transition (MNT) has been observed to play crucial role in early stage adaptive drug tolerance, and the mathematic modeling indicates the transition is contributed from both stochastic phenotypic transition and non-genetic selection. Whole transcriptomic analysis enriched important signaling proteins that are involved in the resistance development process. Single cell proteomic analysis of those proteins was performed on patient-derived melanoma models to further study the early stage drug tolerance. This resolves how protein signaling network coordination rewires in the process, which cannot be resolved from proteomic analysis of bulk tumor tissue. Signaling network coordination analysis indicates that co-inhibiting the hubs of the network (MEK, NFKB-p65) could keep cells in the drug-susceptible stages. The combination therapy that co-inhibits mutant BRAF, MEK and NFKB-p65 together successfully arrested the MNT transition and induced a sustained tumor growth suppression in multiple patient-derived melanoma cell lines. This study provides us a brand-new way of using single cell proteomic analysis to infer effective combinations by resolving protein signaling network coordination that is inaccessible through traditional bulk-level proteomic measurement. Citation Format: Yapeng Su, Wei Wei, Min Xue, Lidia Robert, Jennifer Tsoi, Thomas Graeber, Antoni Ribas, James Heath. Single cell analysis resolves combinatory targeted therapy for arresting the BRAFi-induced cellular dedifferentiation of metastatic melanomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 879.
- Published
- 2016
48. Risk-adapted treatment in clinical stage I testicular seminoma: the third Spanish Germ Cell Cancer Group study
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Mireia Margeli, Roma Bastus, Lidia Robert, Pablo Maroto, Juan J. Satrústegui, Marta López-Brea, Antonio J. Fernández, Alfonso Sánchez-Muñoz, Javier Sastre, Andrés Meana, José R. Germà, Xavier Garcia del Muro, Regina Gironés, Montserrat Domenech, Purificación Martínez del Prado, J. Terrassa, Jorge Aparicio, and Josep Guma
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Antineoplastic Agents ,Carboplatin ,chemistry.chemical_compound ,Young Adult ,Testicular Neoplasms ,Risk Factors ,medicine ,Humans ,Prospective Studies ,Young adult ,Prospective cohort study ,Survival rate ,Chemotherapy ,business.industry ,Middle Aged ,Neoplasms, Germ Cell and Embryonal ,Surgery ,Seminoma ,Clinical trial ,Oncology ,chemistry ,Chemotherapy, Adjuvant ,Stage I Testicular Seminoma ,business ,Adjuvant ,Orchiectomy - Abstract
Purpose To confirm the efficacy of a risk-adapted treatment approach for patients with clinical stage I seminoma. The aim was to reduce both the risk of relapse and the proportion of patients receiving adjuvant chemotherapy while maintaining a high cure rate. Patients and Methods From 2004 to 2008, 227 patients were included after orchiectomy in a multicenter study. Eighty-four patients (37%) presented no local risk factors, 44 patients (19%) had tumors larger than 4 cm, 25 patients (11%) had rete testis involvement, and 74 patients (33%) had both criteria. Only the latter group received two courses of adjuvant carboplatin, whereas the rest were managed by surveillance. Results After a median follow-up time of 34 months, 16 relapses (7%) have been documented (15 [9.8%] among patients on surveillance and one [1.4%] among those treated with carboplatin). All relapses occurred in retroperitoneal lymph nodes, except for one case in pelvic nodes. Median node size was 25 mm, and median time to recurrence was 14 months. All patients were rendered disease-free with chemotherapy. The actuarial 3-year disease-free survival rate was 88.1% (95% CI, 82.3% to 93.9%) for patients on surveillance and 98.0% (95% CI, 94.0% to 100%) for those treated with adjuvant chemotherapy. Overall 3-year survival was 100%. Conclusion With the limitations of the short follow-up duration, we confirm that a risk-adapted approach is effective for stage I seminoma. Adjuvant carboplatin seems adequate treatment for patients with 2 risk criteria, as is active surveillance for those with 0 to one risk factors. More reliable predictive factors are needed to improve the applicability of this model.
- Published
- 2011
49. Abstract 2682: Melanoma phenotype switching to adapt to BRAF inhibition
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Lidia Robert, Thomas G. Graeber, Blanca Homet Moreno, Jennifer Tsoi, Nhat Truong, Antoni Ribas, and Angel Garica Diaz
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Cancer Research ,Oncology ,Melanoma ,medicine ,Cancer research ,Biology ,medicine.disease ,Phenotype - Abstract
Melanoma can adapt to several stress factors, such as TNF treatment, by changing its phenotype from a highly differentiated (MITF and MART-1 positive) to undifferentiated (neural crest markers) states. We studied this phenomenon as a mechanism of adaptive resistance to BRAF inhibition since melanomas with both MITF high and low have been reported to result in BRAF inhibitor resistance. We treated 17 BRAFV600E mutant melanoma cell lines with the BRAF inhibitor vemurafenib for short term (3 days) or long term (17 days), and compared them to no treatment or TNF treated conditions. We profiled them phenotypically for MART1 antigen (differentiated phenotype) and nerve growth factor receptor (NGFR, neural crest phenotype) expression by flow cytometry. Results comparing median fluorescence intensity (MFI) showed a wide spectrum of adaptive responses to short term BRAF inhibition, followed by solidification or further evolution of these changes upon long term exposure and development of drug tolerance. According to each cell line distribution, we calculated a (x,y) value that organized the cell lines and conditions in four quadrants according to MART1 (x axis) or NGFR (y axis) expression. Two double negative (MART1-/NGFR-) cell lines that were unaffected by treatment and stayed in the same quadrant. Seven MART1-/NGFR+ and four MART1+/NGFR- cell lines slightly changed phenotype with vemurafenib exposure but stayed in the same quadrant. Four cell lines with MART1+/NGFR+ phenotype were greatly influenced by treatment, showing wide plasticity with cells shifting towards NGFR+/MART1- and others towards NGFR-/MART1+. Changes in position between baseline and tolerance to vemurafenib after 17days treatment were numerically quantified as an inferred number from plasticity. Cell lines with double positive (MART1+/NGFR+) phenotype had a significant change in plasticity compared to the rest of cell lines in other quadrants (p = 0.0004). This arranges cells in a four-quadrant pattern that could be likened to a U-turn toward de-differentiation. Cells that de-differentiated with BRAF inhibition mimicked the effect induced by TNF. This effect was driven by a decrease in MITF activity confirmed with a tyrosinase promoter-luciferase assay. In conclusion, baseline melanoma differentiation phenotypes guide the phenotype switch response, with those double positive for differentiation and neural crest markers being at a semi-stable state that can be prone to different plastic changes upon BRAF inhibition. Citation Format: Lidia Robert, Jennifer Tsoi, Angel Garica Diaz, Blanca Homet Moreno, Nhat Truong, Thomas Graeber, Antoni Ribas. Melanoma phenotype switching to adapt to BRAF inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2682. doi:10.1158/1538-7445.AM2015-2682
- Published
- 2015
50. TCR use and cytokine response in PD-1 blockade
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Lidia Robert Faja, Antoni Ribas, Ryan O. Emerson, Steven M Blum, and Jesse M. Zaretsky
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Cancer Research ,Tumor microenvironment ,Oncology ,business.industry ,Effector ,Immunology ,T-cell receptor ,Medicine ,Pd 1 blockade ,business ,Peripheral blood ,Cytokine response ,Blockade - Abstract
3027 Background: PD-1 blockade releases effector T-cells in the tumor microenvironment, but little is known on the effects in peripheral blood. We used T cell receptor (TCR) sequencing and multiple...
- Published
- 2015
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