41 results on '"Wong, Kwok"'
Search Results
2. Incidence, prevalence and survival in patients with Langerhans cell histiocytosis: A national registry study from England, 2013-2019.
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Liu H, Stiller CA, Crooks CJ, Rous B, Bythell M, Broggio J, Rankin J, Nanduri V, Lanyon P, Card TR, Ban L, Elliss-Brookes L, Broughan JM, Paley L, Wong K, Bacon A, Bishton M, and West J
- Subjects
- Child, Adult, Humans, Incidence, Prevalence, Registries, Histiocytosis, Langerhans-Cell epidemiology, Histiocytosis, Langerhans-Cell therapy, Neoplasms epidemiology
- Abstract
This analysis is the largest population-based study to date to provide contemporary and comprehensive epidemiological estimates of all third edition of the International Classification of Diseases for Oncology (ICD-O-3) coded Langerhans cell histiocytosis (LCH) from England. People of all ages were identified from the National Cancer Registration Dataset using ICD-O-3 morphologies 9751-9754 for neoplasms diagnosed in 2013-2019. A total of 658 patients were identified, of whom 324 (49%) were children aged <15 years. The age-standardised incidence rate was 4.46 (95% confidence interval [CI] 3.99-4.98) per million children and 1.06 (95% CI 0.94-1.18) per million adults aged ≥15 years. Prevalence of LCH was 9.95 (95% CI 9.14-10.81) per million persons at the end of 2019. The 1-year overall survival (OS) was 99% (95% CI 97%-100%) for children and 90% (95% CI 87%-93%) for adults. Those aged ≥60 years had poorer OS than those aged <15 years (hazard ratio [HR] 22.12, 95% CI 7.10-68.94; p < 0.001). People in deprived areas had lower OS than those in the least deprived areas (HR 5.36, 95% CI 1.16-24.87; p = 0.03). There will inevitably be other environmental factors and associations yet to be identified, and the continued standardised data collection will allow further evaluation of data over time. This will be increasingly important with developments in LCH management following the large collaborative international trials such as LCH IV., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2022
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3. The current state of the art and future trends in RAS-targeted cancer therapies.
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Punekar SR, Velcheti V, Neel BG, and Wong KK
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- Humans, Mutation, Signal Transduction genetics, Tumor Microenvironment genetics, Neoplasms drug therapy, Neoplasms genetics, Proto-Oncogene Proteins p21(ras)
- Abstract
Despite being the most frequently altered oncogenic protein in solid tumours, KRAS has historically been considered 'undruggable' owing to a lack of pharmacologically targetable pockets within the mutant isoforms. However, improvements in drug design have culminated in the development of inhibitors that are selective for mutant KRAS in its active or inactive state. Some of these inhibitors have proven efficacy in patients with KRAS
G12C -mutant cancers and have become practice changing. The excitement associated with these advances has been tempered by drug resistance, which limits the depth and/or duration of responses to these agents. Improvements in our understanding of RAS signalling in cancer cells and in the tumour microenvironment suggest the potential for several novel combination therapies, which are now being explored in clinical trials. Herein, we provide an overview of the RAS pathway and review the development and current status of therapeutic strategies for targeting oncogenic RAS, as well as their potential to improve outcomes in patients with RAS-mutant malignancies. We then discuss challenges presented by resistance mechanisms and strategies by which they could potentially be overcome., (© 2022. Springer Nature Limited.)- Published
- 2022
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4. Targeting the Atf7ip-Setdb1 Complex Augments Antitumor Immunity by Boosting Tumor Immunogenicity.
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Hu H, Khodadadi-Jamayran A, Dolgalev I, Cho H, Badri S, Chiriboga LA, Zeck B, Lopez De Rodas Gregorio M, Dowling CM, Labbe K, Deng J, Chen T, Zhang H, Zappile P, Chen Z, Ueberheide B, Karatza A, Han H, Ranieri M, Tang S, Jour G, Osman I, Sucker A, Schadendorf D, Tsirigos A, Schalper KA, Velcheti V, Huang HY, Jin Y, Ji H, Poirier JT, Li F, and Wong KK
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- Animals, Cell Culture Techniques, Cell Line, Cell Proliferation, Humans, Mice, Mice, Nude, Antigens, Neoplasm metabolism, Histone-Lysine N-Methyltransferase metabolism, Neoplasms genetics, Repressor Proteins metabolism
- Abstract
Substantial progress has been made in understanding how tumors escape immune surveillance. However, few measures to counteract tumor immune evasion have been developed. Suppression of tumor antigen expression is a common adaptive mechanism that cancers use to evade detection and destruction by the immune system. Epigenetic modifications play a critical role in various aspects of immune invasion, including the regulation of tumor antigen expression. To identify epigenetic regulators of tumor antigen expression, we established a transplantable syngeneic tumor model of immune escape with silenced antigen expression and used this system as a platform for a CRISPR-Cas9 suppressor screen for genes encoding epigenetic modifiers. We found that disruption of the genes encoding either of the chromatin modifiers activating transcription factor 7-interacting protein (Atf7ip) or its interacting partner SET domain bifurcated histone lysine methyltransferase 1 (Setdb1) in tumor cells restored tumor antigen expression. This resulted in augmented tumor immunogenicity concomitant with elevated endogenous retroviral (ERV) antigens and mRNA intron retention. ERV disinhibition was associated with a robust type I interferon response and increased T-cell infiltration, leading to rejection of cells lacking intact Atf7ip or Setdb1 . ATF7IP or SETDB1 expression inversely correlated with antigen processing and presentation pathways, interferon signaling, and T-cell infiltration and cytotoxicity in human cancers. Our results provide a rationale for targeting Atf7ip or Setdb1 in cancer immunotherapy., (©2021 The Authors; Published by the American Association for Cancer Research.)
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- 2021
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5. Clinical Characteristics and Outcomes of COVID-19-Infected Cancer Patients: A Systematic Review and Meta-Analysis.
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Zhang H, Han H, He T, Labbe KE, Hernandez AV, Chen H, Velcheti V, Stebbing J, and Wong KK
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- Asia epidemiology, COVID-19 mortality, COVID-19 virology, Canada epidemiology, Comorbidity, Europe epidemiology, Female, Humans, Male, Neoplasms mortality, Risk Factors, SARS-CoV-2 physiology, Survival Rate, United Kingdom epidemiology, United States epidemiology, COVID-19 epidemiology, Neoplasms epidemiology
- Abstract
Background: Previous studies have indicated coronavirus disease 2019 (COVID-19) patients with cancer have a high fatality rate., Methods: We conducted a systematic review of studies that reported fatalities in COVID-19 patients with cancer. A comprehensive meta-analysis that assessed the overall case fatality rate and associated risk factors was performed. Using individual patient data, univariate and multivariable logistic regression analyses were used to estimate odds ratios (OR) for each variable with outcomes., Results: We included 15 studies with 3019 patients, of which 1628 were men; 41.0% were from the United Kingdom and Europe, followed by the United States and Canada (35.7%), and Asia (China, 23.3%). The overall case fatality rate of COVID-19 patients with cancer measured 22.4% (95% confidence interval [CI] = 17.3% to 28.0%). Univariate analysis revealed age (OR = 3.57, 95% CI = 1.80 to 7.06), male sex (OR = 2.10, 95% CI = 1.07 to 4.13), and comorbidity (OR = 2.00, 95% CI = 1.04 to 3.85) were associated with increased risk of severe events (defined as the individuals being admitted to the intensive care unit, or requiring invasive ventilation, or death). In multivariable analysis, only age greater than 65 years (OR = 3.16, 95% CI = 1.45 to 6.88) and being male (OR = 2.29, 95% CI = 1.07 to 4.87) were associated with increased risk of severe events., Conclusions: Our analysis demonstrated that COVID-19 patients with cancer have a higher fatality rate compared with that of COVID-19 patients without cancer. Age and sex appear to be risk factors associated with a poorer prognosis., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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6. An Empirical Antigen Selection Method Identifies Neoantigens That Either Elicit Broad Antitumor T-cell Responses or Drive Tumor Growth.
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Lam H, McNeil LK, Starobinets H, DeVault VL, Cohen RB, Twardowski P, Johnson ML, Gillison ML, Stein MN, Vaishampayan UN, DeCillis AP, Foti JJ, Vemulapalli V, Tjon E, Ferber K, DeOliveira DB, Broom W, Agnihotri P, Jaffee EM, Wong KK, Drake CG, Carroll PM, Davis TA, and Flechtner JB
- Subjects
- Animals, Antigens, Neoplasm genetics, Biomarkers, Tumor genetics, Biomarkers, Tumor immunology, Cancer Vaccines administration & dosage, Cancer Vaccines immunology, Cell Line, Tumor, Clinical Trials as Topic, DNA Mutational Analysis, Disease Models, Animal, Disease Progression, Genomics methods, Humans, Immunogenicity, Vaccine, Melanoma, Experimental, Mice, Mutation, Neoplasms genetics, Neoplasms therapy, T-Lymphocytes metabolism, T-Lymphocytes pathology, Treatment Outcome, Vaccination, Antigens, Neoplasm immunology, Immunity, Cellular, Neoplasms immunology, Neoplasms pathology, T-Lymphocytes immunology
- Abstract
Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in Escherichia coli , pulsing autologous dendritic cells in an ordered array, and testing the patient's T cells for recognition in an overnight assay. Profiling of T cells from patients with lung cancer revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well tolerated. In an adjuvant setting, immunized patients generated both CD4
+ and CD8+ T-cell responses, with immune responses to 99% of the vaccinated peptide antigens. SIGNIFICANCE: Predicting neoantigens in silico has progressed, but empirical testing shows that T-cell responses are more nuanced than straightforward MHC antigen recognition. The ATLAS bioassay screens tumor mutations to uncover preexisting, patient-relevant neoantigen T-cell responses and reveals a new class of putatively deleterious responses that could affect cancer immunotherapy design. This article is highlighted in the In This Issue feature, p. 521 ., (©2021 American Association for Cancer Research.)- Published
- 2021
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7. A bioengineered arginine-depleting enzyme as a long-lasting therapeutic agent against cancer.
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Chung SF, Kim CF, Tam SY, Choi MC, So PK, Wong KY, Leung YC, and Lo WH
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- Animals, Cell Line, Tumor, Humans, Ions, Metals, Mice, Mice, Inbred BALB C, Mutation, Protein Structure, Secondary, Arginase genetics, Arginase therapeutic use, Arginine antagonists & inhibitors, Neoplasms drug therapy, Protein Engineering
- Abstract
L-Arginine (L-Arg) depletion has attracted great attention in cancer therapy. Although two types of arginine-depleting enzymes, arginine deiminase (ADI) and human arginase I, are undergoing clinical trials, random site of PEGylation, low efficacy of heavy metal as co-factor, and immunogenicity limit the performance of these drugs and cause difficulty in a homogeneous production. Here we screened ten catalytic metal ions and have successfully produced a site-specific mono-PEGylated human arginase I mutant by conjugating the Cys
45 residue to PEG-maleimide to minimize the decrease in activity and produce a homogeneous product. The catalytic efficiency trend of metal ion-enriched human arginase I mutant (HAI) was Co2+ > Ni2+ ≫ Mn2+ . The overall kcat /KM values of Co-HAI and Ni-HAI were higher than Mn-HAI by ~ 8.7- and ~ 5.2-folds, respectively. Moreover, the results of enzyme kinetics and circular dichroism spectrometry demonstrated that the 20 or 40 kDa linear and branched PEG attached on the HAI surface did not affect the enzyme activity and the protein secondary structures. In vitro studies showed that both Co-HAI-PEG20L and Ni-HAI-PEG20L inhibited the growth of eight types of cancer cell lines. The pharmacodynamic study in mice demonstrated that the i.p. administration of Co-HAI-PEG20L at 13 mg/kg and Ni-HAI-PEG20L at 15 mg/kg was able to maintain a L-Arg level below its detection limit for over 120 h after one injection. The body weights of mice could return to normal levels within 5 days after injection, showing that the doses were well-tolerated. Therefore, both the Ni-HAI-PEG20L and Co-HAI-PEG20L are promising candidates for cancer therapy. KEY POINTS: • Mono-PEGylation applied on human arginase I mutant (HAI) successfully. • The catalytic efficiency of Co- and Ni-enriched HAI was higher than the wild type. • At least eight types of cancer cell lines were inhibited by Co- and Ni-HAI-PEG20L. • Co- and Ni-HAI-PEG20L were able to achieve weekly depletion of L-Arg. Graphical abstract.- Published
- 2020
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8. Conditional crude probabilities of death for English cancer patients.
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Wong KF, Lambert PC, Mozumder SI, Broggio J, and Rutherford MJ
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- Adult, Age Factors, Aged, Aged, 80 and over, Cause of Death, England epidemiology, Female, Humans, Male, Middle Aged, Neoplasms classification, Neoplasms pathology, Registries, Survival Analysis, Neoplasms mortality
- Abstract
Background: Cancer survival statistics are typically reported by using measures discounting the impact of other-cause mortality, such as net survival. This is a hypothetical measure and is interpreted as excluding the possibility of cancer patients dying from other causes. Crude probability of death partitions the all-cause probability of death into deaths from cancer and other causes., Methods: The National Cancer Registration and Analysis Service is the single cancer registry for England. In 2006-2015, 1,590,477 malignant tumours were diagnosed for breast, colorectal, lung, melanoma and prostate cancer in adults. We used a relative survival framework, with a period approach, providing estimates for up to 10-year survival. Mortality was partitioned into deaths due to cancer or other causes. Unconditional and conditional (on surviving 1-years and 5-years) crude probability of death were estimated for the five cancers., Results: Elderly patients who survived for a longer period before dying were more likely to die from other causes of death (except for lung cancer). For younger patients, deaths were almost entirely due to the cancer., Conclusion: There are different measures of survival, each with their own strengths and limitations. Careful choices of survival measures are needed for specific scenarios to maximise the understanding of the data.
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- 2019
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9. Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity.
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Robichaux JP, Elamin YY, Vijayan RSK, Nilsson MB, Hu L, He J, Zhang F, Pisegna M, Poteete A, Sun H, Li S, Chen T, Han H, Negrao MV, Ahnert JR, Diao L, Wang J, Le X, Meric-Bernstam F, Routbort M, Roeck B, Yang Z, Raymond VM, Lanman RB, Frampton GM, Miller VA, Schrock AB, Albacker LA, Wong KK, Cross JB, and Heymach JV
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- Ado-Trastuzumab Emtansine therapeutic use, Adult, Animals, Antineoplastic Agents, Immunological pharmacology, Antineoplastic Agents, Immunological therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, DNA Mutational Analysis, Datasets as Topic, Disease Models, Animal, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Drug Synergism, Female, Humans, Male, Mice, Mice, Transgenic, Mutation, Neoplasms genetics, Neoplasms mortality, Neoplasms pathology, Progression-Free Survival, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Quinazolines therapeutic use, Receptor, ErbB-2 genetics, Ado-Trastuzumab Emtansine pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Neoplasms drug therapy, Quinazolines pharmacology, Receptor, ErbB-2 antagonists & inhibitors
- Abstract
We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2019
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10. The Combined Effect of FGFR Inhibition and PD-1 Blockade Promotes Tumor-Intrinsic Induction of Antitumor Immunity.
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Palakurthi S, Kuraguchi M, Zacharek SJ, Zudaire E, Huang W, Bonal DM, Liu J, Dhaneshwar A, DePeaux K, Gowaski MR, Bailey D, Regan SN, Ivanova E, Ferrante C, English JM, Khosla A, Beck AH, Rytlewski JA, Sanders C, Laquerre S, Bittinger MA, Kirschmeier PT, Packman K, Janne PA, Moy C, Wong KK, Verona RI, and Lorenzi MV
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- Animals, Biomarkers, Cell Line, Tumor, Disease Models, Animal, Drug Synergism, Humans, Immunophenotyping, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Mice, Mice, Transgenic, Mutation, Neoplasms drug therapy, Neoplasms genetics, Neoplasms metabolism, Prognosis, Programmed Cell Death 1 Receptor genetics, Pyrazoles pharmacology, Quinoxalines pharmacology, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell metabolism, Receptors, Fibroblast Growth Factor genetics, Receptors, Fibroblast Growth Factor metabolism, Signal Transduction drug effects, T-Lymphocyte Subsets drug effects, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Treatment Outcome, Tumor Microenvironment, Antineoplastic Agents, Immunological pharmacology, Immunity drug effects, Neoplasms immunology, Programmed Cell Death 1 Receptor antagonists & inhibitors, Receptors, Fibroblast Growth Factor antagonists & inhibitors
- Abstract
The success of targeted or immune therapies is often hampered by the emergence of resistance and/or clinical benefit in only a subset of patients. We hypothesized that combining targeted therapy with immune modulation would show enhanced antitumor responses. Here, we explored the combination potential of erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor under clinical development, with PD-1 blockade in an autochthonous FGFR2
K660N /p53mut lung cancer mouse model. Erdafitinib monotherapy treatment resulted in substantial tumor control but no significant survival benefit. Although anti-PD-1 alone was ineffective, the erdafitinib and anti-PD-1 combination induced significant tumor regression and improved survival. For both erdafitinib monotherapy and combination treatments, tumor control was accompanied by tumor-intrinsic, FGFR pathway inhibition, increased T-cell infiltration, decreased regulatory T cells, and downregulation of PD-L1 expression on tumor cells. These effects were not observed in a KRASG12C -mutant genetically engineered mouse model, which is insensitive to FGFR inhibition, indicating that the immune changes mediated by erdafitinib may be initiated as a consequence of tumor cell killing. A decreased fraction of tumor-associated macrophages also occurred but only in combination-treated tumors. Treatment with erdafitinib decreased T-cell receptor (TCR) clonality, reflecting a broadening of the TCR repertoire induced by tumor cell death, whereas combination with anti-PD-1 led to increased TCR clonality, suggesting a more focused antitumor T-cell response. Our results showed that the combination of erdafitinib and anti-PD-1 drives expansion of T-cell clones and immunologic changes in the tumor microenvironment to support enhanced antitumor immunity and survival., (©2019 American Association for Cancer Research.)- Published
- 2019
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11. pH-dependent and cathepsin B activable CaCO 3 nanoprobe for targeted in vivo tumor imaging.
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Sun N, Wang D, Yao G, Li X, Mei T, Zhou X, Wong KY, Jiang B, and Fang Z
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- Animals, Fluorescent Dyes chemistry, Folic Acid analogs & derivatives, Folic Acid chemistry, Humans, Hydrogen-Ion Concentration, MCF-7 Cells, Mice, Nanoparticles ultrastructure, Neoplasms pathology, Organ Specificity, Polyethylene Glycols chemistry, Calcium Carbonate chemistry, Cathepsin B metabolism, Diagnostic Imaging, Nanoparticles chemistry, Neoplasms diagnostic imaging
- Abstract
Background: The intraoperative visualization of tumor cells is a powerful modality for surgical treatment of solid tumors. Since the completeness of tumor excision is closely correlated with the survival of patients, probes that can assist in distinguishing tumor cells are highly demanded. Purpose: In the present study, a fluorescent probe JF1 was synthesized for imaging of tumor cells by conjugating a substrate of cathepsin B (quenching moiety) to Oregon Green derivative JF2 using a self-immolative linker. Methods: JF1 was then loaded into the folate-PEG modified CaCO
3 nanoparticles. The folate receptor-targeted, pH-dependent, and cathepsin B activable CaCO3 nanoprobe was test in vitro and in vivo for tumor imaging. Results: CaCO3 nanoprobe demonstrated good stability and fast lighting ability in tumors under low pH conditions. It also showed lower fluorescence background than the single cathepsin B dependent fluorescent probe. The pH-dependent and cathepsin B controlled "turn-on" property enables precise and fast indication of tumor in vitro and in vivo. Conclusion: This strategy of controlled drug delivery enables in vivo imaging of tumor nodules with a high signal-to-noise ratio, which has great potential in surgical tumor treatment., Competing Interests: The authors report no conflicts of ineterest in this work.- Published
- 2019
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12. Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop.
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Bedognetti D, Ceccarelli M, Galluzzi L, Lu R, Palucka K, Samayoa J, Spranger S, Warren S, Wong KK, Ziv E, Chowell D, Coussens LM, De Carvalho DD, DeNardo DG, Galon J, Kaufman HL, Kirchhoff T, Lotze MT, Luke JJ, Minn AJ, Politi K, Shultz LD, Simon R, Thórsson V, Weidhaas JB, Ascierto ML, Ascierto PA, Barnes JM, Barsan V, Bommareddy PK, Bot A, Church SE, Ciliberto G, De Maria A, Draganov D, Ho WS, McGee HM, Monette A, Murphy JF, Nisticò P, Park W, Patel M, Quigley M, Radvanyi L, Raftopoulos H, Rudqvist NP, Snyder A, Sweis RF, Valpione S, Zappasodi R, Butterfield LH, Disis ML, Fox BA, Cesano A, and Marincola FM
- Subjects
- Advisory Committees, Animals, Biomarkers, Tumor genetics, Biomarkers, Tumor immunology, Congresses as Topic, Disease Models, Animal, Humans, Medical Oncology organization & administration, Neoplasms genetics, Neoplasms immunology, Societies, Medical organization & administration, Treatment Outcome, Tumor Microenvironment genetics, Immunotherapy, Neoplasms therapy, Tumor Microenvironment immunology
- Abstract
Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host's response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14-15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual's recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4-5, 2019.
- Published
- 2019
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13. Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity.
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Vriens K, Christen S, Parik S, Broekaert D, Yoshinaga K, Talebi A, Dehairs J, Escalona-Noguero C, Schmieder R, Cornfield T, Charlton C, Romero-Pérez L, Rossi M, Rinaldi G, Orth MF, Boon R, Kerstens A, Kwan SY, Faubert B, Méndez-Lucas A, Kopitz CC, Chen T, Fernandez-Garcia J, Duarte JAG, Schmitz AA, Steigemann P, Najimi M, Hägebarth A, Van Ginderachter JA, Sokal E, Gotoh N, Wong KK, Verfaillie C, Derua R, Munck S, Yuneva M, Beretta L, DeBerardinis RJ, Swinnen JV, Hodson L, Cassiman D, Verslype C, Christian S, Grünewald S, Grünewald TGP, and Fendt SM
- Subjects
- Animals, Cell Line, Tumor, Cell Membrane metabolism, Cell Proliferation, Fatty Acid Desaturases metabolism, Female, HEK293 Cells, Humans, Male, Mice, Oleic Acids metabolism, Palmitates metabolism, Palmitic Acids metabolism, Stearoyl-CoA Desaturase metabolism, Fatty Acids chemistry, Fatty Acids metabolism, Metabolic Networks and Pathways, Neoplasms metabolism, Neoplasms pathology
- Abstract
Most tumours have an aberrantly activated lipid metabolism
1,2 that enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive to approaches that target fatty acid metabolism and, in particular, fatty acid desaturation3 . This suggests that many cancer cells contain an unexplored plasticity in their fatty acid metabolism. Here we show that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, mouse hepatocellular carcinomas, and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known fatty acid desaturation pathway that is dependent on stearoyl-CoA desaturase. Thus, only by targeting both desaturation pathways is the in vitro and in vivo proliferation of cancer cells that synthesize sapienate impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers.- Published
- 2019
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14. Intron retention is a source of neoepitopes in cancer.
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Smart AC, Margolis CA, Pimentel H, He MX, Miao D, Adeegbe D, Fugmann T, Wong KK, and Van Allen EM
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- Cancer Vaccines immunology, Cell Line, Tumor, Epitope Mapping, Epitopes metabolism, Humans, Neoplasms immunology, Neoplasms therapy, RNA genetics, Computer Simulation, Epitopes genetics, Introns genetics, Models, Genetic, Neoplasms genetics
- Abstract
We present an in silico approach to identifying neoepitopes derived from intron retention events in tumor transcriptomes. Using mass spectrometry immunopeptidome analysis, we show that retained intron neoepitopes are processed and presented on MHC I on the surface of cancer cell lines. RNA-derived neoepitopes should be considered for prospective personalized cancer vaccine development.
- Published
- 2018
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15. Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors.
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Miao D, Margolis CA, Vokes NI, Liu D, Taylor-Weiner A, Wankowicz SM, Adeegbe D, Keliher D, Schilling B, Tracy A, Manos M, Chau NG, Hanna GJ, Polak P, Rodig SJ, Signoretti S, Sholl LM, Engelman JA, Getz G, Jänne PA, Haddad RI, Choueiri TK, Barbie DA, Haq R, Awad MM, Schadendorf D, Hodi FS, Bellmunt J, Wong KK, Hammerman P, and Van Allen EM
- Subjects
- Cohort Studies, Exome, Genomics methods, Humans, Immunity genetics, Mutation, Microsatellite Repeats, Neoplasms genetics, Neoplasms immunology
- Abstract
Tumor mutational burden correlates with response to immune checkpoint blockade in multiple solid tumors, although in microsatellite-stable tumors this association is of uncertain clinical utility. Here we uniformly analyzed whole-exome sequencing (WES) of 249 tumors and matched normal tissue from patients with clinically annotated outcomes to immune checkpoint therapy, including radiographic response, across multiple cancer types to examine additional tumor genomic features that contribute to selective response. Our analyses identified genomic correlates of response beyond mutational burden, including somatic events in individual driver genes, certain global mutational signatures, and specific HLA-restricted neoantigens. However, these features were often interrelated, highlighting the complexity of identifying genetic driver events that generate an immunoresponsive tumor environment. This study lays a path forward in analyzing large clinical cohorts in an integrated and multifaceted manner to enhance the ability to discover clinically meaningful predictive features of response to immune checkpoint blockade.
- Published
- 2018
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16. Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.
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Cañadas I, Thummalapalli R, Kim JW, Kitajima S, Jenkins RW, Christensen CL, Campisi M, Kuang Y, Zhang Y, Gjini E, Zhang G, Tian T, Sen DR, Miao D, Imamura Y, Thai T, Piel B, Terai H, Aref AR, Hagan T, Koyama S, Watanabe M, Baba H, Adeni AE, Lydon CA, Tamayo P, Wei Z, Herlyn M, Barbie TU, Uppaluri R, Sholl LM, Sicinska E, Sands J, Rodig S, Wong KK, Paweletz CP, Watanabe H, and Barbie DA
- Subjects
- Animals, Cell Line, Tumor, Endogenous Retroviruses drug effects, Gene Expression Regulation, Neoplastic, Humans, Mice, Nude, Neoplasms genetics, RNA, Antisense genetics, Endogenous Retroviruses metabolism, Immunity, Innate drug effects, Interferons pharmacology, Neoplasms immunology, Neoplasms virology
- Abstract
Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance
1-4 . This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8 , but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy.- Published
- 2018
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17. Cohort profile: prescriptions dispensed in the community linked to the national cancer registry in England.
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Henson KE, Brock R, Shand B, Coupland VH, Elliss-Brookes L, Lyratzopoulos G, Godfrey P, Haigh A, Hunter K, McCabe MG, Mitchell G, Monckton N, Robson R, Round T, Wong K, and Rashbass J
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Data Accuracy, Data Anonymization, England, Female, Humans, Infant, Infant, Newborn, Information Storage and Retrieval, Male, Medical Record Linkage, Middle Aged, Young Adult, Drug Prescriptions statistics & numerical data, Neoplasms diagnosis, Neoplasms pathology, Registries
- Abstract
Purpose: The linked prescriptions cancer registry data resource was set up to extend our understanding of the pathway for patients with cancer past secondary care into the community, to ultimately improve patient outcomes., Participants: The linked prescriptions cancer registry data resource is currently available for April to July 2015, for all patients diagnosed with cancer in England with a dispensed prescription in that time frame.The dispensed prescriptions data are collected by National Health Service (NHS) Prescription Services, and the cancer registry data are processed by Public Health England. All data are routine healthcare data, used for secondary purposes, linked using a pseudonymised version of the patient's NHS number and date of birth.Detailed demographic and clinical information on the type of cancer diagnosed and treatment is collected by the cancer registry. The dispensed prescriptions data contain basic demographic information, geography measures of the dispensed prescription, drug information (quantity, strength and presentation), cost of the drug and the date that the dispensed prescription was submitted to NHS Business Services Authority., Findings to Date: Findings include a study of end of life prescribing in the community among patients with cancer, an investigation of repeat prescriptions to derive measures of prior morbidity status in patients with cancer and studies of prescription activity surrounding the date of cancer diagnosis., Future Plans: This English linked resource could be used for cancer epidemiological studies of diagnostic pathways, health outcomes and inequalities; to establish primary care comorbidity indices and for guideline concordance studies of treatment, particularly hormonal therapy, as a major treatment modality for breast and prostate cancer which has been largely delivered in the community setting for a number of years., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
- Published
- 2018
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18. Profound Tissue Specificity in Proliferation Control Underlies Cancer Drivers and Aneuploidy Patterns.
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Sack LM, Davoli T, Li MZ, Li Y, Xu Q, Naxerova K, Wooten EC, Bernardi RJ, Martin TD, Chen T, Leng Y, Liang AC, Scorsone KA, Westbrook TF, Wong KK, and Elledge SJ
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation, Chromosome Mapping, Chromosomes genetics, E2F1 Transcription Factor antagonists & inhibitors, E2F1 Transcription Factor genetics, E2F1 Transcription Factor metabolism, Female, Gene Library, Genomics, Humans, Keratins metabolism, Mice, Mice, Inbred NOD, Mice, SCID, Oncogenes, Open Reading Frames genetics, RNA Interference, RNA, Small Interfering metabolism, Aneuploidy, Neoplasms pathology
- Abstract
Genomics has provided a detailed structural description of the cancer genome. Identifying oncogenic drivers that work primarily through dosage changes is a current challenge. Unrestrained proliferation is a critical hallmark of cancer. We constructed modular, barcoded libraries of human open reading frames (ORFs) and performed screens for proliferation regulators in multiple cell types. Approximately 10% of genes regulate proliferation, with most performing in an unexpectedly highly tissue-specific manner. Proliferation drivers in a given cell type showed specific enrichment in somatic copy number changes (SCNAs) from cognate tumors and helped predict aneuploidy patterns in those tumors, implying that tissue-type-specific genetic network architectures underlie SCNA and driver selection in different cancers. In vivo screening confirmed these results. We report a substantial contribution to the catalog of SCNA-associated cancer drivers, identifying 147 amplified and 107 deleted genes as potential drivers, and derive insights about the genetic network architecture of aneuploidy in tumors., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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19. CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation.
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Deng J, Wang ES, Jenkins RW, Li S, Dries R, Yates K, Chhabra S, Huang W, Liu H, Aref AR, Ivanova E, Paweletz CP, Bowden M, Zhou CW, Herter-Sprie GS, Sorrentino JA, Bisi JE, Lizotte PH, Merlino AA, Quinn MM, Bufe LE, Yang A, Zhang Y, Zhang H, Gao P, Chen T, Cavanaugh ME, Rode AJ, Haines E, Roberts PJ, Strum JC, Richards WG, Lorch JH, Parangi S, Gunda V, Boland GM, Bueno R, Palakurthi S, Freeman GJ, Ritz J, Haining WN, Sharpless NE, Arthanari H, Shapiro GI, Barbie DA, Gray NS, and Wong KK
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents, Immunological pharmacology, Cell Line, Tumor, Humans, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Mice, Neoplasms diagnosis, Neoplasms genetics, Neoplasms metabolism, Protein Kinase Inhibitors pharmacology, T-Lymphocytes metabolism, Xenograft Model Antitumor Assays, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, Neoplasms immunology, T-Lymphocytes drug effects, T-Lymphocytes immunology
- Abstract
Immune checkpoint blockade, exemplified by antibodies targeting the PD-1 receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T-cell activation, contributing to antitumor effects in vivo , due in part to the derepression of NFAT family proteins and their target genes, critical regulators of T-cell function. Although CDK4/6 inhibitors decrease T-cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies. Significance: Our results define previously unrecognized immunomodulatory functions of CDK4/6 and suggest that combining CDK4/6 inhibitors with immune checkpoint blockade may increase treatment efficacy in patients. Furthermore, our study highlights the critical importance of identifying complementary strategies to improve the efficacy of immunotherapy for patients with cancer. Cancer Discov; 8(2); 216-33. ©2017 AACR. See related commentary by Balko and Sosman, p. 143 See related article by Jenkins et al., p. 196 This article is highlighted in the In This Issue feature, p. 127 ., (©2017 American Association for Cancer Research.)
- Published
- 2018
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20. Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression.
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Rusan M, Li K, Li Y, Christensen CL, Abraham BJ, Kwiatkowski N, Buczkowski KA, Bockorny B, Chen T, Li S, Rhee K, Zhang H, Chen W, Terai H, Tavares T, Leggett AL, Li T, Wang Y, Zhang T, Kim TJ, Hong SH, Poudel-Neupane N, Silkes M, Mudianto T, Tan L, Shimamura T, Meyerson M, Bass AJ, Watanabe H, Gray NS, Young RA, Wong KK, and Hammerman PS
- Subjects
- Cell Line, Tumor, Humans, Neoplasms pathology, Signal Transduction, Neoplasms therapy
- Abstract
Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adaptive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and in vivo cancer models. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant, which THZ1 can exploit by blocking dynamic transcriptional responses, promoting remodeling of enhancers and key signaling outputs required for tumor cell survival in the setting of targeted therapy. These findings suggest that the addition of THZ1 to targeted therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations. Significance: CDK7/12 inhibition prevents active enhancer formation at genes, promoting resistance emergence in response to targeted therapy, and impedes the engagement of transcriptional programs required for tumor cell survival. CDK7/12 inhibition in combination with targeted cancer therapies may serve as a therapeutic paradigm for enhancing the effectiveness of targeted therapies. Cancer Discov; 8(1); 59-73. ©2017 AACR. See related commentary by Carugo and Draetta, p. 17 This article is highlighted in the In This Issue feature, p. 1 ., (©2017 American Association for Cancer Research.)
- Published
- 2018
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21. Workshop on challenges, insights, and future directions for mouse and humanized models in cancer immunology and immunotherapy: a report from the associated programs of the 2016 annual meeting for the Society for Immunotherapy of cancer.
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Zloza A, Karolina Palucka A, Coussens LM, Gotwals PJ, Headley MB, Jaffee EM, Lund AW, Sharpe AH, Sznol M, Wainwright DA, Wong KK, and Bosenberg MW
- Subjects
- Animals, Humans, Mice, Molecular Targeted Therapy, Societies, Scientific, Tumor Microenvironment, Disease Models, Animal, Immunotherapy methods, Neoplasms immunology, Neoplasms therapy
- Abstract
Understanding how murine models can elucidate the mechanisms underlying antitumor immune responses and advance immune-based drug development is essential to advancing the field of cancer immunotherapy. The Society for Immunotherapy of Cancer (SITC) convened a workshop titled, "Challenges, Insights, and Future Directions for Mouse and Humanized Models in Cancer Immunology and Immunotherapy" as part of the SITC 31st Annual Meeting and Associated Programs on November 10, 2016 in National Harbor, MD. The workshop focused on key issues in optimizing models for cancer immunotherapy research, with discussions on the strengths and weaknesses of current models, approaches to improve the predictive value of mouse models, and advances in cancer modeling that are anticipated in the near future. This full-day program provided an introduction to the most common immunocompetent and humanized models used in cancer immunology and immunotherapy research, and addressed the use of models to evaluate immune-targeting therapies. Here, we summarize the workshop presentations and subsequent panel discussion.
- Published
- 2017
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22. MUC1-C activates EZH2 expression and function in human cancer cells.
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Rajabi H, Hiraki M, Tagde A, Alam M, Bouillez A, Christensen CL, Samur M, Wong KK, and Kufe D
- Subjects
- A549 Cells, Antigens, CD genetics, BRCA1 Protein genetics, Binding Sites, Cadherins genetics, Cell Line, Tumor, Enhancer of Zeste Homolog 2 Protein chemistry, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Histones metabolism, Humans, Methylation, Neoplasms genetics, Promoter Regions, Genetic, Signal Transduction, Enhancer of Zeste Homolog 2 Protein genetics, Enhancer of Zeste Homolog 2 Protein metabolism, Mucin-1 metabolism, Neoplasms metabolism, Transcriptional Activation
- Abstract
The EZH2 histone methyltransferase is a member of the polycomb repressive complex 2 (PRC2) that is highly expressed in diverse human cancers and is associated with a poor prognosis. MUC1-C is an oncoprotein that is similarly overexpressed in carcinomas and has been linked to epigenetic regulation. A role for MUC1-C in regulating EZH2 and histone methylation is not known. Here, we demonstrate that targeting MUC1-C in diverse human carcinoma cells downregulates EZH2 and other PRC2 components. MUC1-C activates (i) the EZH2 promoter through induction of the pRB→E2F pathway, and (ii) an NF-κB p65 driven enhancer in exon 1. We also show that MUC1-C binds directly to the EZH2 CXC region adjacent to the catalytic SET domain and associates with EZH2 on the CDH1 and BRCA1 promoters. In concert with these results, targeting MUC1-C downregulates EZH2 function as evidenced by (i) global and promoter-specific decreases in H3K27 trimethylation (H3K27me3), and (ii) activation of tumor suppressor genes, including BRCA1. These findings highlight a previously unreported role for MUC1-C in activating EZH2 expression and function in cancer cells.
- Published
- 2017
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23. Cardiac Mortality Among 200 000 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The Teenage and Young Adult Cancer Survivor Study.
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Henson KE, Reulen RC, Winter DL, Bright CJ, Fidler MM, Frobisher C, Guha J, Wong KF, Kelly J, Edgar AB, McCabe MG, Whelan J, Cutter DJ, Darby SC, and Hawkins MM
- Subjects
- Adolescent, Adult, Female, Humans, Male, Risk Factors, Survivors, Time Factors, Young Adult, Neoplasms mortality
- Abstract
Background: Survivors of teenage and young adult cancer are acknowledged as understudied. Little is known about their long-term adverse health risks, particularly of cardiac disease that is increased in other cancer populations where cardiotoxic treatments have been used., Methods: The Teenage and Young Adult Cancer Survivor Study cohort comprises 200 945 5-year survivors of cancer diagnosed at 15 to 39 years of age in England and Wales from 1971 to 2006, and followed to 2014. Standardized mortality ratios, absolute excess risks, and cumulative risks were calculated., Results: Two thousand sixteen survivors died of cardiac disease. For all cancers combined, the standardized mortality ratios for all cardiac diseases combined was greatest for individuals diagnosed at 15 to 19 years of age (4.2; 95% confidence interval, 3.4-5.2) decreasing to 1.2 (95% confidence interval, 1.1-1.3) for individuals aged 35 to 39 years (2P for trend <0.0001). Similar patterns were observed for both standardized mortality ratios and absolute excess risks for ischemic heart disease, valvular heart disease, and cardiomyopathy. Survivors of Hodgkin lymphoma, acute myeloid leukaemia, genitourinary cancers other than bladder cancer, non-Hodgkin lymphoma, lung cancer, leukaemia other than acute myeloid, central nervous system tumour, cervical cancer, and breast cancer experienced 3.8, 2.7, 2.0, 1.7, 1.7, 1.6, 1.4, 1.3 and 1.2 times the number of cardiac deaths expected from the general population, respectively. Among survivors of Hodgkin lymphoma aged over 60 years, almost 30% of the total excess number of deaths observed were due to heart disease., Conclusions: This study of over 200 000 cancer survivors shows that age at cancer diagnosis was critical in determining subsequent cardiac mortality risk. For the first time, risk estimates of cardiac death after each cancer diagnosed between the ages of 15 and 39 years have been derived from a large population-based cohort with prolonged follow-up. The evidence here provides an initial basis for developing evidence-based follow-up guidelines., (© 2016 The Authors.)
- Published
- 2016
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24. Evaluating TBK1 as a therapeutic target in cancers with activated IRF3.
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Muvaffak A, Pan Q, Yan H, Fernandez R, Lim J, Dolinski B, Nguyen TT, Strack P, Wu S, Chung R, Zhang W, Hulton C, Ripley S, Hirsch H, Nagashima K, Wong KK, Jánne PA, Seidel-Dugan C, Zawel L, Kirschmeier PT, Middleton RE, Morris EJ, and Wang Y
- Subjects
- Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Humans, Interferon Regulatory Factor-3 genetics, Interferon Regulatory Factor-3 metabolism, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Molecular Targeted Therapy, Neoplasms metabolism, Phosphorylation, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Signal Transduction, Carcinoma, Non-Small-Cell Lung therapy, Interferon Regulatory Factor-3 antagonists & inhibitors, Lung Neoplasms therapy, Neoplasms genetics, Protein Serine-Threonine Kinases antagonists & inhibitors
- Abstract
Unlabelled: TBK1 (TANK-binding kinase 1) is a noncanonical IκB protein kinase that phosphorylates and activates downstream targets such as IRF3 and c-Rel and, mediates NF-κB activation in cancer. Previous reports demonstrated synthetic lethality of TBK1 with mutant KRAS in non-small cell lung cancer (NSCLC); thus, TBK1 could be a novel target for treatment of KRAS-mutant NSCLC. Here, the effect of TBK1 on proliferation in a panel of cancer cells by both genetic and pharmacologic approaches was evaluated. In KRAS-mutant cancer cells, reduction of TBK1 activity by knockdown or treatment with TBK1 inhibitors did not correlate with reduced proliferation in a two-dimensional viability assay. Verification of target engagement via reduced phosphorylation of S386 of IRF3 (pIRF3(S386)) was difficult to assess in NSCLC cells due to low protein expression. However, several cell lines were identified with high pIRF3(S386) levels after screening a large panel of cell lines, many of which also harbor KRAS mutations. Specifically, a large subset of KRAS-mutant pancreatic cancer cell lines was uncovered with high constitutive pIRF3(S386) levels, which correlated with high levels of phosphorylated S172 of TBK1 (pTBK1(S172)). Finally, TBK1 inhibitors dose-dependently inhibited pIRF3(S386) in these cell lines, but this did not correlate with inhibition of cell growth. Taken together, these data demonstrate that the regulation of pathways important for cell proliferation in some NSCLC, pancreatic, and colorectal cell lines is not solely dependent on TBK1 activity., Implications: TBK1 has therapeutic potential under certain contexts and phosphorylation of its downstream target IRF3 is a biomarker of TBK1 activity., (©2014 American Association for Cancer Research.)
- Published
- 2014
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25. New cast for a new era: preclinical cancer drug development revisited.
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Herter-Sprie GS, Kung AL, and Wong KK
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Clinical Trials as Topic, Disease Models, Animal, Drug Discovery, Humans, Mice, Mice, Transgenic, Drug Screening Assays, Antitumor, Neoplasms drug therapy
- Abstract
Molecularly targeted agents promise to revolutionize therapeutics by reducing morbidity and mortality in patients with cancer. However, despite an urgent need for more effective anticancer compounds, current preclinical drug evaluations largely fail to satisfy the demand. New preclinical strategies, including the improvement of sophisticated mouse models and co-clinical study designs, are being used to augment the predictive value of animal-based translational cancer research. Here, we review the development of successful preclinical antineoplastic agents, their associated limitations, and alternative methods to predict clinical outcomes.
- Published
- 2013
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26. Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models.
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Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM, Greninger P, Brown RD, Godfrey JT, Cohoon TJ, Song Y, Lifshits E, Hung KE, Shioda T, Dias-Santagata D, Singh A, Settleman J, Benes CH, Mino-Kenudson M, Wong KK, and Engelman JA
- Subjects
- Aniline Compounds therapeutic use, Animals, Antineoplastic Agents therapeutic use, Benzimidazoles therapeutic use, Drug Screening Assays, Antitumor, Humans, Mice, Neoplasms genetics, Proto-Oncogene Proteins p21(ras) metabolism, Sulfonamides therapeutic use, Aniline Compounds pharmacology, Antineoplastic Agents pharmacology, Benzimidazoles pharmacology, MAP Kinase Kinase Kinases antagonists & inhibitors, Neoplasms drug therapy, Proto-Oncogene Proteins p21(ras) genetics, Sulfonamides pharmacology, bcl-X Protein antagonists & inhibitors
- Abstract
KRAS is the most commonly mutated oncogene, yet no effective targeted therapies exist for KRAS mutant cancers. We developed a pooled shRNA-drug screen strategy to identify genes that, when inhibited, cooperate with MEK inhibitors to effectively treat KRAS mutant cancer cells. The anti-apoptotic BH3 family gene BCL-XL emerged as a top hit through this approach. ABT-263 (navitoclax), a chemical inhibitor that blocks the ability of BCL-XL to bind and inhibit pro-apoptotic proteins, in combination with a MEK inhibitor led to dramatic apoptosis in many KRAS mutant cell lines from different tissue types. This combination caused marked in vivo tumor regressions in KRAS mutant xenografts and in a genetically engineered KRAS-driven lung cancer mouse model, supporting combined BCL-XL/MEK inhibition as a potential therapeutic approach for KRAS mutant cancers., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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27. Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis.
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Bhalla K, Hwang BJ, Dewi RE, Twaddel W, Goloubeva OG, Wong KK, Saxena NK, Biswal S, and Girnun GD
- Subjects
- Animals, Cell Line, Tumor, Dose-Response Relationship, Drug, Humans, Lipids chemistry, Lipogenesis, Liver Neoplasms metabolism, Male, Mice, Mice, Inbred C57BL, Models, Biological, Rats, Triglycerides metabolism, AMP-Activated Protein Kinases metabolism, Hypoglycemic Agents pharmacology, Liver metabolism, Metformin pharmacology, Neoplasms prevention & control, Sterol Regulatory Element Binding Protein 1 metabolism
- Abstract
A number of factors have been identified that increase the risk of hepatocellular carcinoma (HCC). Recently it has become appreciated that type II diabetes increases the risk of developing HCC. This represents a patient population that can be identified and targeted for cancer prevention. The biguanide metformin is a first-line therapy for the treatment of type II diabetes in which it exerts its effects primarily on the liver. A role of metformin in HCC is suggested by studies linking metformin intake for control of diabetes with a reduced risk of HCC. Although a number of preclinical studies show the anticancer properties of metformin in a number of tissues, no studies have directly examined the effect of metformin on preventing carcinogenesis in the liver, one of its main sites of action. We show in these studies that metformin protected mice against chemically induced liver tumors. Interestingly, metformin did not increase AMPK activation, often shown to be a metformin target. Rather metformin decreased the expression of several lipogenic enzymes and lipogenesis. In addition, restoring lipogenic gene expression by ectopic expression of the lipogenic transcription factor SREBP1c rescues metformin-mediated growth inhibition. This mechanism of action suggests that metformin may also be useful for patients with other disorders associated with HCC in which increased lipid synthesis is observed. As a whole these studies show that metformin prevents HCC and that metformin should be evaluated as a preventive agent for HCC in readily identifiable at-risk patients., (2012 AACR)
- Published
- 2012
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28. Activation of FOXO3a is sufficient to reverse mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor chemoresistance in human cancer.
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Yang JY, Chang CJ, Xia W, Wang Y, Wong KK, Engelman JA, Du Y, Andreeff M, Hortobagyi GN, and Hung MC
- Subjects
- Animals, Apoptosis drug effects, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Cell Growth Processes drug effects, Cell Line, Tumor, Chlorpropamide analogs & derivatives, Chlorpropamide pharmacology, Chromones pharmacology, Colonic Neoplasms drug therapy, Colonic Neoplasms metabolism, Drug Resistance, Neoplasm, Drug Synergism, Forkhead Box Protein O3, HCT116 Cells, HT29 Cells, Humans, MAP Kinase Kinase 1 antagonists & inhibitors, MAP Kinase Kinase 1 metabolism, MAP Kinase Kinase 2 antagonists & inhibitors, MAP Kinase Kinase 2 metabolism, Melanoma drug therapy, Melanoma metabolism, Mice, Morpholines pharmacology, Neoplasms enzymology, Phosphatidylinositol 3-Kinases metabolism, Phosphoinositide-3 Kinase Inhibitors, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt metabolism, Benzimidazoles pharmacology, Forkhead Transcription Factors metabolism, Neoplasms drug therapy, Neoplasms metabolism
- Abstract
Drug resistance is a central challenge of cancer therapy that ultimately leads to treatment failure. In this study, we characterized a mechanism of drug resistance that arises to AZD6244, an established mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1/2 inhibitor currently being evaluated in cancer clinical trials. AZD6244 enhanced the expression of transcription factor FOXO3a, which suppressed cancer cell proliferation. In AZD6244-resistant cancer cells, we observed the impaired nuclear localization of FOXO3a, reduced FOXO3a-mediated transcriptional activity, and decreased the expression of FOXO3a target gene Bim after cell treatment with AZD6244. Resistant cells could be sensitized by phosphoinositide 3-kinase (PI3K)/AKT inhibitors, which are known to enhance FOXO3a nuclear translocation. Our findings define FOXO3a as candidate marker to predict the clinical efficacy of AZD6244. Furthermore, they suggest a mechanism of resistance to MEK inhibitors that may arise in the clinic yet can be overcome by cotreatment with PI3K/AKT inhibitors., (Copyright 2010 AACR.)
- Published
- 2010
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29. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.
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Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, McDermott U, Azizian N, Zou L, Fischbach MA, Wong KK, Brandstetter K, Wittner B, Ramaswamy S, Classon M, and Settleman J
- Subjects
- Cell Line, Tumor, Chromatin metabolism, Chromatin pathology, DNA Damage, Histone Deacetylase Inhibitors pharmacology, Histone Demethylases metabolism, Humans, Jumonji Domain-Containing Histone Demethylases antagonists & inhibitors, Jumonji Domain-Containing Histone Demethylases genetics, Jumonji Domain-Containing Histone Demethylases metabolism, Neoplasms metabolism, Receptor, IGF Type 1 metabolism, Drug Resistance, Neoplasm, Neoplasms drug therapy, Neoplasms pathology
- Abstract
Accumulating evidence implicates heterogeneity within cancer cell populations in the response to stressful exposures, including drug treatments. While modeling the acute response to various anticancer agents in drug-sensitive human tumor cell lines, we consistently detected a small subpopulation of reversibly "drug-tolerant" cells. These cells demonstrate >100-fold reduced drug sensitivity and maintain viability via engagement of IGF-1 receptor signaling and an altered chromatin state that requires the histone demethylase RBP2/KDM5A/Jarid1A. This drug-tolerant phenotype is transiently acquired and relinquished at low frequency by individual cells within the population, implicating the dynamic regulation of phenotypic heterogeneity in drug tolerance. The drug-tolerant subpopulation can be selectively ablated by treatment with IGF-1 receptor inhibitors or chromatin-modifying agents, potentially yielding a therapeutic opportunity. Together, these findings suggest that cancer cell populations employ a dynamic survival strategy in which individual cells transiently assume a reversibly drug-tolerant state to protect the population from eradication by potentially lethal exposures., (Copyright 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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30. An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation.
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Schoeberl B, Faber AC, Li D, Liang MC, Crosby K, Onsum M, Burenkova O, Pace E, Walton Z, Nie L, Fulgham A, Song Y, Nielsen UB, Engelman JA, and Wong KK
- Subjects
- Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal immunology, Antibodies, Monoclonal, Humanized, CHO Cells, Cell Line, Tumor, Cetuximab, Cricetinae, Cricetulus, ErbB Receptors antagonists & inhibitors, Gefitinib, Humans, Ligands, Mice, Neoplasms metabolism, Neuregulin-1 pharmacology, Protein Kinase Inhibitors pharmacology, Quinazolines pharmacology, Receptor, ErbB-3 metabolism, Xenograft Model Antitumor Assays, Antibodies, Monoclonal pharmacology, Neoplasms therapy, Receptor, ErbB-3 antagonists & inhibitors, Receptor, ErbB-3 immunology
- Abstract
ErbB3 is a critical activator of phosphoinositide 3-kinase (PI3K) signaling in epidermal growth factor receptor (EGFR; ErbB1), ErbB2 [human epidermal growth factor receptor 2 (HER2)], and [hepatocyte growth factor receptor (MET)] addicted cancers, and reactivation of ErbB3 is a prominent method for cancers to become resistant to ErbB inhibitors. In this study, we evaluated the in vivo efficacy of a therapeutic anti-ErbB3 antibody, MM-121. We found that MM-121 effectively blocked ligand-dependent activation of ErbB3 induced by either EGFR, HER2, or MET. Assessment of several cancer cell lines revealed that MM-121 reduced basal ErbB3 phosphorylation most effectively in cancers possessing ligand-dependent activation of ErbB3. In those cancers, MM-121 treatment led to decreased ErbB3 phosphorylation and, in some instances, decreased ErbB3 expression. The efficacy of single-agent MM-121 was also examined in xenograft models. A machine learning algorithm found that MM-121 was most effective against xenografts with evidence of ligand-dependent activation of ErbB3. We subsequently investigated whether MM-121 treatment could abrogate resistance to anti-EGFR therapies by preventing reactivation of ErbB3. We observed that an EGFR mutant lung cancer cell line (HCC827), made resistant to gefitinib by exogenous heregulin, was resensitized by MM-121. In addition, we found that a de novo lung cancer mouse model induced by EGFR T790M-L858R rapidly became resistant to cetuximab. Resistance was associated with an increase in heregulin expression and ErbB3 activation. However, concomitant cetuximab treatment with MM-121 blocked reactivation of ErbB3 and resulted in a sustained and durable response. Thus, these results suggest that targeting ErbB3 with MM-121 can be an effective therapeutic strategy for cancers with ligand-dependent activation of ErbB3.
- Published
- 2010
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31. Targeting the PI3K signaling pathway in cancer.
- Author
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Wong KK, Engelman JA, and Cantley LC
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Humans, MAP Kinase Kinase Kinases, Phosphatidylinositol 3-Kinases genetics, Receptor, ErbB-2 antagonists & inhibitors, Signal Transduction drug effects, Antineoplastic Agents therapeutic use, Neoplasms drug therapy, Phosphoinositide-3 Kinase Inhibitors
- Abstract
The phosphoinositide 3-kinase (PI3K) pathway is activated in a variety of different human cancers, and inhibitors of this pathway are under active development as anti-cancer therapeutics. In this review, we discuss the data supporting the use of PI3K pathway inhibitors in genetically and clinically defined cancers. This review focuses on their efficacy as single agents and in combination with other targeted therapies, specifically those targeting the MEK-ERK signaling pathway., (Copyright 2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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32. Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer.
- Author
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Sos ML, Fischer S, Ullrich R, Peifer M, Heuckmann JM, Koker M, Heynck S, Stückrath I, Weiss J, Fischer F, Michel K, Goel A, Regales L, Politi KA, Perera S, Getlik M, Heukamp LC, Ansén S, Zander T, Beroukhim R, Kashkar H, Shokat KM, Sellers WR, Rauh D, Orr C, Hoeflich KP, Friedman L, Wong KK, Pao W, and Thomas RK
- Subjects
- Apoptosis drug effects, Cell Line, Tumor, Genotype, Humans, Neoplasms enzymology, Neoplasms pathology, Phosphoinositide-3 Kinase Inhibitors, MAP Kinase Signaling System drug effects, Neoplasms drug therapy, Neoplasms genetics, Phosphatidylinositol 3-Kinases genetics, Protein Kinase Inhibitors pharmacology
- Abstract
In cancer, genetically activated proto-oncogenes often induce "upstream" dependency on the activity of the mutant oncoprotein. Therapeutic inhibition of these activated oncoproteins can induce massive apoptosis of tumor cells, leading to sometimes dramatic tumor regressions in patients. The PI3K and MAPK signaling pathways are central regulators of oncogenic transformation and tumor maintenance. We hypothesized that upstream dependency engages either one of these pathways preferentially to induce "downstream" dependency. Therefore, we analyzed whether downstream pathway dependency segregates by genetic aberrations upstream in lung cancer cell lines. Here, we show by systematically linking drug response to genomic aberrations in non-small-cell lung cancer, as well as in cell lines of other tumor types and in a series of in vivo cancer models, that tumors with genetically activated receptor tyrosine kinases depend on PI3K signaling, whereas tumors with mutations in the RAS/RAF axis depend on MAPK signaling. However, efficacy of downstream pathway inhibition was limited by release of negative feedback loops on the reciprocal pathway. By contrast, combined blockade of both pathways was able to overcome the reciprocal pathway activation induced by inhibitor-mediated release of negative feedback loops and resulted in a significant increase in apoptosis and tumor shrinkage. Thus, by using a systematic chemo-genomics approach, we identify genetic lesions connected to PI3K and MAPK pathway activation and provide a rationale for combined inhibition of both pathways. Our findings may have implications for patient stratification in clinical trials.
- Published
- 2009
- Full Text
- View/download PDF
33. GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer.
- Author
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Scott KL, Kabbarah O, Liang MC, Ivanova E, Anagnostou V, Wu J, Dhakal S, Wu M, Chen S, Feinberg T, Huang J, Saci A, Widlund HR, Fisher DE, Xiao Y, Rimm DL, Protopopov A, Wong KK, and Chin L
- Subjects
- Animals, Cell Line, Tumor drug effects, DNA-Binding Proteins genetics, Female, Gene Knockdown Techniques, Humans, Membrane Proteins genetics, Mice, Mice, Nude, Protein Kinases genetics, Saccharomyces cerevisiae genetics, TOR Serine-Threonine Kinases, Transcription Factors genetics, Antibiotics, Antineoplastic pharmacology, Membrane Proteins metabolism, Neoplasms physiopathology, Protein Kinases metabolism, Signal Transduction, Sirolimus pharmacology
- Abstract
Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in several solid tumour types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma (32%). Here, using integrative analysis of a genomic profile of the region, we identify a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the trans-Golgi network and interacts with components of the retromer complex, which in yeast has been linked to target of rapamycin (TOR) signalling. Mechanistically, GOLPH3 regulates cell size, enhances growth-factor-induced mTOR (also known as FRAP1) signalling in human cancer cells, and alters the response to an mTOR inhibitor in vivo. Thus, genomic and genetic, biological, functional and biochemical data in yeast and humans establishes GOLPH3 as a new oncogene that is commonly targeted for amplification in human cancer, and is capable of modulating the response to rapamycin, a cancer drug in clinical use.
- Published
- 2009
- Full Text
- View/download PDF
34. A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors.
- Author
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Wong KK, Fracasso PM, Bukowski RM, Lynch TJ, Munster PN, Shapiro GI, Jänne PA, Eder JP, Naughton MJ, Ellis MJ, Jones SF, Mekhail T, Zacharchuk C, Vermette J, Abbas R, Quinn S, Powell C, and Burris HA
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents therapeutic use, ErbB Receptors antagonists & inhibitors, Female, Humans, Male, Maximum Tolerated Dose, Middle Aged, Neoplasms diagnosis, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors therapeutic use, Quinolines pharmacokinetics, Quinolines therapeutic use, Receptor, ErbB-2 antagonists & inhibitors, Antineoplastic Agents adverse effects, Neoplasms drug therapy, Protein Kinase Inhibitors adverse effects, Quinolines adverse effects
- Abstract
Purpose: The dose-limiting toxicities, maximum tolerated dose, pharmacokinetic profile, and preliminary antitumor activity of neratinib (HKI-272), an irreversible pan ErbB inhibitor, were determined in patients with advanced solid tumors., Experimental Design: Neratinib was administered orally as a single dose, followed by a 1-week observation period, and then once daily continuously. Planned dose escalation was 40, 80, 120, 180, 240, 320, 400, and 500 mg. For pharmacokinetic analysis, timed blood samples were collected after administration of the single dose and after the first 14 days of continuous daily administration., Results: Dose-limiting toxicity was grade 3 diarrhea, which occurred in one patient treated with 180 mg and in four patients treated with 400 mg neratinib; hence, the maximum tolerated dose was determined to be 320 mg. Other common neratinib-related toxicities included nausea, vomiting, fatigue, and anorexia. Exposure to neratinib was dose dependent, and the pharmacokinetic profile of neratinib supports a once-a-day dosing regimen. Partial response was observed for 8 (32%) of the 25 evaluable patients with breast cancer. Stable disease >or=24 weeks was observed in one evaluable breast cancer patient and 6 (43%) of the 14 evaluable non-small cell lung cancer patients., Conclusion: The maximum tolerated dose of once-daily oral neratinib is 320 mg. The most common neratinib-related toxicity was diarrhea. Antitumor activity was observed in patients with breast cancer who had previous treatment with trastuzumab, anthracyclines, and taxanes, and tumors with a baseline ErbB-2 immunohistochemical staining intensity of 2+ or 3+. The antitumor activity, tolerable toxicity profile, and pharmacokinetic properties of neratinib warrant its further evaluation.
- Published
- 2009
- Full Text
- View/download PDF
35. High-throughput oncogene mutation profiling in human cancer.
- Author
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Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM, Wang M, Feng W, Zander T, MacConaill L, Lee JC, Nicoletti R, Hatton C, Goyette M, Girard L, Majmudar K, Ziaugra L, Wong KK, Gabriel S, Beroukhim R, Peyton M, Barretina J, Dutt A, Emery C, Greulich H, Shah K, Sasaki H, Gazdar A, Minna J, Armstrong SA, Mellinghoff IK, Hodi FS, Dranoff G, Mischel PS, Cloughesy TF, Nelson SF, Liau LM, Mertz K, Rubin MA, Moch H, Loda M, Catalona W, Fletcher J, Signoretti S, Kaye F, Anderson KC, Demetri GD, Dummer R, Wagner S, Herlyn M, Sellers WR, Meyerson M, and Garraway LA
- Subjects
- Gene Expression Profiling, Genome, Human, Genotype, Humans, DNA Mutational Analysis methods, Mutation, Neoplasms genetics, Oncogenes
- Abstract
Systematic efforts are underway to decipher the genetic changes associated with tumor initiation and progression. However, widespread clinical application of this information is hampered by an inability to identify critical genetic events across the spectrum of human tumors with adequate sensitivity and scalability. Here, we have adapted high-throughput genotyping to query 238 known oncogene mutations across 1,000 human tumor samples. This approach established robust mutation distributions spanning 17 cancer types. Of 17 oncogenes analyzed, we found 14 to be mutated at least once, and 298 (30%) samples carried at least one mutation. Moreover, we identified previously unrecognized oncogene mutations in several tumor types and observed an unexpectedly high number of co-occurring mutations. These results offer a new dimension in tumor genetics, where mutations involving multiple cancer genes may be interrogated simultaneously and in 'real time' to guide cancer classification and rational therapeutic intervention.
- Published
- 2007
- Full Text
- View/download PDF
36. Sensitive mutation detection in heterogeneous cancer specimens by massively parallel picoliter reactor sequencing.
- Author
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Thomas RK, Nickerson E, Simons JF, Jänne PA, Tengs T, Yuza Y, Garraway LA, LaFramboise T, Lee JC, Shah K, O'Neill K, Sasaki H, Lindeman N, Wong KK, Borras AM, Gutmann EJ, Dragnev KH, DeBiasi R, Chen TH, Glatt KA, Greulich H, Desany B, Lubeski CK, Brockman W, Alvarez P, Hutchison SK, Leamon JH, Ronan MT, Turenchalk GS, Egholm M, Sellers WR, Rothberg JM, and Meyerson M
- Subjects
- Base Sequence, Humans, Molecular Sequence Data, Neoplasms diagnosis, Sensitivity and Specificity, Chromosome Mapping methods, DNA, Neoplasm genetics, Mutation, Neoplasms genetics
- Abstract
The sensitivity of conventional DNA sequencing in tumor biopsies is limited by stromal contamination and by genetic heterogeneity within the cancer. Here, we show that microreactor-based pyrosequencing can detect rare cancer-associated sequence variations by independent and parallel sampling of multiple representatives of a given DNA fragment. This technology can thereby facilitate accurate molecular diagnosis of heterogeneous cancer specimens and enable patient selection for targeted cancer therapies.
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- 2006
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- View/download PDF
37. Walking the telomere plank into cancer.
- Author
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Wong KK and DePinho RA
- Subjects
- Animals, Cell Transformation, Neoplastic genetics, Genetic Predisposition to Disease, Head and Neck Neoplasms genetics, Humans, Kidney Neoplasms genetics, Lung Neoplasms genetics, Lymphocytes metabolism, Precancerous Conditions genetics, Predictive Value of Tests, Prognosis, Risk Assessment, Risk Factors, Urinary Bladder Neoplasms genetics, Biomarkers, Tumor genetics, Genetic Markers genetics, Neoplasms genetics, Telomere genetics
- Published
- 2003
- Full Text
- View/download PDF
38. The age of cancer: telomeres, checkpoints, and longevity.
- Author
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DePinho RA and Wong KK
- Subjects
- Adolescent, Adult, Animals, Child, Humans, Inflammation, Mice, Middle Aged, Models, Biological, Neoplasms genetics, Neoplasms pathology, Telomere
- Published
- 2003
39. CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC
- Author
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Becker, Jeffrey H, Gao, Yandi, Soucheray, Margaret, Pulido, Ines, Kikuchi, Eiki, Rodríguez, María L, Gandhi, Rutu, Lafuente-Sanchis, Aranzazu, Aupí, Miguel, Alcácer Fernández-Coronado, Javier, Martín-Martorell, Paloma, Cremades, Antonio, Galbis-Caravajal, José M, Alcácer, Javier, Christensen, Camilla L, Simms, Patricia, Hess, Ashley, Asahina, Hajime, Kahle, Michael P, Al-Shahrour, Fatima, Borgia, Jeffrey A, Lahoz, Agustín, Insa, Amelia, Juan, Oscar, Jänne, Pasi A, Wong, Kwok-Kin, Carretero, Julian, and Shimamura, Takeshi
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Lung Cancer ,Cancer ,Lung ,Clinical Research ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Animals ,Carcinoma ,Non-Small-Cell Lung ,Cell Line ,Tumor ,Drug Resistance ,Neoplasm ,Epithelial-Mesenchymal Transition ,ErbB Receptors ,Humans ,Lung Neoplasms ,MAP Kinase Signaling System ,Mice ,Transgenic ,Mutation ,Neoplasms ,Experimental ,Protein Kinase Inhibitors ,Receptors ,CXCR ,beta-Arrestins ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Although EGFR mutant-selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK-ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI-resistant persister cells. Many patients with non-small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutation, who progressed on EGFR inhibitors, demonstrated increased CXCR7 expression. These data suggest that CXCR7 inhibition could considerably delay and prevent the emergence of acquired EGFR TKI resistance in EGFR-mutant NSCLC. SIGNIFICANCE: Increased expression of the chemokine receptor CXCR7 constitutes a mechanism of resistance to EGFR TKI in patients with non-small cell lung cancer through reactivation of ERK signaling.
- Published
- 2019
40. pH-dependent and cathepsin B activable CaCO3 nanoprobe for targeted in vivo tumor imaging
- Author
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Sun, Ning, Wang, Dou, Yao, Guoqiang, Li, Xiaomei, Mei, Ting, Zhou, Xinke, Wong, Kwok-Yin, Jiang, Baishan, and Fang, Zhiyuan
- Subjects
Diagnostic Imaging ,cathepsin B ,tumor imaging ,Hydrogen-Ion Concentration ,Calcium Carbonate ,Polyethylene Glycols ,Mice ,Folic Acid ,activable probe ,Organ Specificity ,fluorescent probe ,Neoplasms ,CaCO3 nanoparticle ,MCF-7 Cells ,Animals ,Humans ,Nanoparticles ,Original Research ,Fluorescent Dyes - Abstract
Background: The intraoperative visualization of tumor cells is a powerful modality for surgical treatment of solid tumors. Since the completeness of tumor excision is closely correlated with the survival of patients, probes that can assist in distinguishing tumor cells are highly demanded. Purpose: In the present study, a fluorescent probe JF1 was synthesized for imaging of tumor cells by conjugating a substrate of cathepsin B (quenching moiety) to Oregon Green derivative JF2 using a self-immolative linker. Methods: JF1 was then loaded into the folate-PEG modified CaCO3 nanoparticles. The folate receptor-targeted, pH-dependent, and cathepsin B activable CaCO3 nanoprobe was test in vitro and in vivo for tumor imaging. Results: CaCO3 nanoprobe demonstrated good stability and fast lighting ability in tumors under low pH conditions. It also showed lower fluorescence background than the single cathepsin B dependent fluorescent probe. The pH-dependent and cathepsin B controlled “turn-on” property enables precise and fast indication of tumor in vitro and in vivo. Conclusion: This strategy of controlled drug delivery enables in vivo imaging of tumor nodules with a high signal-to-noise ratio, which has great potential in surgical tumor treatment.
- Published
- 2019
41. Alterations of LKB1 and KRAS and risk of brain metastasis: Comprehensive characterization by mutation analysis, copy number, and gene expression in non-small-cell lung carcinoma
- Author
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Stinchcombe, Thomas E., Haithcock, Benjamin E., Hayward, Michele C., Roberts, Patrick, Wong, Kwok-Kin, Wang, Anyou, Grilley-Olson, Juneko E., Parsons, Alden M., Lee, Carrie B., Sharpless, Norman E., Thorne, Leigh B., Funkhouser, William K., and Hayes, D. Neil
- Subjects
neoplasms ,respiratory tract diseases - Abstract
Brain metastases are one of the most malignant complications of lung cancer and constitute a significant cause of cancer related morbidity and mortality worldwide. Recent years of investigation suggested a role of LKB1 in NSCLC development and progression, in synergy with KRAS alteration. In this study, we systematically analyzed how LKB1 and KRAS alteration, measured by mutation, gene expression (GE) and copy number (CN), are associated with brain metastasis in NSCLC.
- Published
- 2014
- Full Text
- View/download PDF
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