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| Open AccessInhibition of interleukin-1β reduces myelofibrosis and osteosclerosis in mice with JAK2-V617F driven myeloproliferative neoplasm
Inflammatory cytokines are elevated in patients with myeloproliferative neoplasms (MPN). Here the authors show that the JAK2-V617F mutation is associated with increased expression of IL-1 in MPN patients and that loss of IL-1β in JAK2-V617F mutant hematopoietic cells reduces MPN symptoms and myelofibrosis in a mouse model.
- Shivam Rai
- , Elodie Grockowiak
- & Radek C. Skoda
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Article
| Open AccessCtIP-dependent nascent RNA expression flanking DNA breaks guides the choice of DNA repair pathway
RNA has been implicated in DNA repair. This work shows that the interplay of RNAPII-generated nascent RNA, RNA:DNA hybrids and the resection factor CtIP guide DNA double strand break repair pathway choice towards error-free homologous recombination.
- Daniel Gómez-Cabello
- , George Pappas
- & Jiri Bartek
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Article
| Open AccessIn vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response
Standard assessment of immune infiltration of biopsies is not sufficient to accurately predict response to immunotherapy. Here, the authors show that reflectance confocal microscopy can be used to quantify dynamic vasculature and inflammatory features to better predict treatment response in skin cancers.
- Aditi Sahu
- , Kivanc Kose
- & Milind Rajadhyaksha
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Article
| Open AccessBiomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma
Biomarkers predictive of response to T cell therapy remain to be better defined. This study identifies potential predictive and pharmacodynamic markers of response to NY-ESO-1 T-cell therapy in a solid tumor that may inform lymphodepletion, cell dose, and strategies to enhance anticancer efficacy.
- Alexandra Gyurdieva
- , Stefan Zajic
- & Ioanna Eleftheriadou
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Article
| Open AccessIntegrated cohort of esophageal squamous cell cancer reveals genomic features underlying clinical characteristics
The mutational landscape of esophageal squamous cell cancer (ESCC) remains poorly characterised. Here, the authors integrate multiple published datasets and systematically evaluate the mutational signatures and the related genomic and clinical features in ESCC.
- Minghao Li
- , Zicheng Zhang
- & Baosheng Li
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Article
| Open AccessHigh p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer
CDK4/6 inhibitor resistance is common in breast cancer. Here, the authors show that p16 overexpression may be linked to reduced efficacy of CDK4/6 inhibition, and show that the combination with PI3K inhibitors may increase anti-tumour effects.
- Marta Palafox
- , Laia Monserrat
- & Violeta Serra
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Comment
| Open AccessPotential solutions for manufacture of CAR T cells in cancer immunotherapy
CAR T cell therapy is an effective cancer treatment, but biological and manufacturing hurdles hamper its broad breakthrough. Although the first step towards automated manufacture of CAR cells has been taken, new technologies are needed to enable the treatment of large patient groups.
- Ulrich Blache
- , Georg Popp
- & Stephan Fricke
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Article
| Open AccessOXTRHigh stroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling
Worst pattern of invasion (WPOI) is a parameter used to quantify tumor invasiveness of oral squamous cell carcinoma (OSCC). Here the authors show that a fibroblast subset characterized by the expression of the oxytocin receptor is enriched in highly invasive WPOI 4-5 OSCC tumors and can be targeted to reduce the desmoplastic stroma and tumor metastasis.
- Liang Ding
- , Yong Fu
- & Yanhong Ni
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Article
| Open AccessMulti-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia
The molecular heterogeneity of KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) remains poorly characterised. Here, the authors perform multi-omics analysis for 84 ALL patients and suggest 5 distinct subgroups for risk stratification and personalised treatment.’
- Tomoya Isobe
- , Masatoshi Takagi
- & Junko Takita
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Article
| Open AccessEpithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence
The study of tumour dormancy is limited by suitable in vivo models. Here the authors show that mammary intraductal breast cancer (BC) xenografts model estrogen receptor α-positive (ER+) BC dormancy and rapid metastatic progression characteristic of triple-negative (TN) BC. The dormant disseminated ER+ BC cells display characteristics of epithelial-mesenchymal plasticity and forced expression of E-cadherin allows them to overcome dormancy.
- Patrick Aouad
- , Yueyun Zhang
- & Cathrin Brisken
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Article
| Open AccessSelective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling
Tumor loss of IFN-γ signalling is a major mechanism of resistance to immune checkpoint blockers. Here the authors report that melanoma cells with knockout of IFNγR1 show constitutive JAK1/2 activation and that the JAK1/2 inhibitor ruxolitinib can overcome resistance to anti-CTLA-4 therapy.
- Hongxing Shen
- , Fengyuan Huang
- & Lewis Zhichang Shi
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Article
| Open AccessMultifunctional nanoparticle potentiates the in situ vaccination effect of radiation therapy and enhances response to immune checkpoint blockade
Radiotherapy can activate an in situ vaccine response and promote response to immune checkpoint inhibitors. Here the authors design a multifunctional nanoparticle to enhance tumor antigen presentation and modulate the tumor immune microenvironment following radiotherapy, showing improved anti-tumor immune responses in radiotherapy-treated tumors when combined with immune checkpoint inhibitors.
- Ying Zhang
- , Raghava N. Sriramaneni
- & Zachary S. Morris
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Article
| Open AccessA nanoengineered topical transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer
Cisplatin is the most frequently used chemotherapeutic agent for the treatment of patients with oral cavity squamous cell carcinoma (OCSCC), however, systemic administration is often associated with dose limiting side effects. Here the authors design and test a nano-engineered patch system (PRV111) for the local delivery of cisplatin-loaded chitosan nanoparticles and report the results of a phase 1/2 clinical trial of PRV111 in patients with OCSCC.
- Manijeh Goldberg
- , Aaron Manzi
- & Evgeny Izumchenko
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Article
| Open AccessA lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy
Combination therapies simultaneously inhibiting different therapeutic targets in cancer is challenged by individual pharmacokinetic profiles. Here, the authors generate an orally provided multi-targeted kinase inhibitor that is lymphatic absorbed and increases survival in a murine model of myelofibrosis.
- Brian D. Ross
- , Youngsoon Jang
- & Marcian E. Van Dort
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Article
| Open AccessSingle cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma
The components of the glioma immune microenvironment and their roles in promoting tumourigenesis remain poorly understood. Here, the use of single-cell RNA sequencing and multiplexed tissue-imaging in adult and pediatric high-grade gliomas reveals the activity and spatial organization of the immunomodulatory purinergic signaling pathway.
- Shannon Coy
- , Shu Wang
- & Sandro Santagata
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Article
| Open AccessGeneration of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance
Modelling of aggressive lymphomas, such as double hit lymphoma, has been challenging. Here the authors engineer a CRISPR activation mouse to enable the generation of these aggressive lymphomas and identify the pro-survival BCL-2 protein A1 as a venetoclax resistance factor.
- Yexuan Deng
- , Sarah T. Diepstraten
- & Marco J. Herold
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Article
| Open AccessUltra-deep sequencing validates safety of CRISPR/Cas9 genome editing in human hematopoietic stem and progenitor cells
As CRISPR-based therapies enter the clinic, evaluation of safety remains a critical and active area of study. Here the authors use next generation sequencing to achieve high sequencing depth and demonstrate that clinically relevant delivery of high-fidelity Cas9 to primary HSPCs and ex vivo culture up to 10 days does not introduce or enrich for tumorigenic variants.
- M. Kyle Cromer
- , Valentin V. Barsan
- & Matthew H. Porteus
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Article
| Open AccessBlocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer
Cancer-associated cachexia is characterized by loss of body weight, skeletal muscle and adipose tissue which relates to higher mortality in cancer patients. Here, the authors show in a lung cancer murine model that both ActRIIB signalling inhibition and restoring appetite are necessary to revert cachexia and improve survival in female mice.
- Andre Lima Queiroz
- , Ezequiel Dantas
- & Marcus D. Goncalves
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Article
| Open AccessUnified classification and risk-stratification in Acute Myeloid Leukemia
Classification and risk-stratification for Acute Myeloid Leukemia (AML) at diagnosis are primarily based on cytogenetics and only a few gene mutations. Here, the authors study the genomic landscape of 3653 AML patients and characterize 16 non-overlapping molecular subgroups of clinical relevance for disease classification and risk prognostication.
- Yanis Tazi
- , Juan E. Arango-Ossa
- & Elli Papaemmanuil
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Article
| Open AccessReactive oxygen species-responsive and Raman-traceable hydrogel combining photodynamic and immune therapy for postsurgical cancer treatment
Combined immune checkpoint blockade (ICB) and photodynamic therapies have huge potential but suffer from possible damage of the antibodies. Here, the authors create a ROS-responsive hydrogel that protects the ICB antibodies and allows for sustained co-delivery and demonstrate restrained regrowth of tumours in vivo.
- Yiyi Zhang
- , Sidan Tian
- & Liang Luo
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Article
| Open AccessSerine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers
Metabolic reprogramming is associated with cancer development and therapy resistance. Here, the authors show that downregulation of the serine biosynthesis enzyme PHGDH in a fraction of patients is associated with relapse in platinum-treated ovarian cancers and to NAD+ and PARP activity upregulation.
- Tom Van Nyen
- , Mélanie Planque
- & Frédéric Amant
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Article
| Open AccessMolecular characterization of colorectal cancer related peritoneal metastatic disease
Colorectal cancer can lead to the development of peritoneal metastases, which are associated with worse disease outcome. Here, the authors characterize peritoneal metastases from 52 patients using RNA-seq and mutational sequencing and show a distinct molecular subtype.
- Kristiaan J. Lenos
- , Sander Bach
- & Louis Vermeulen
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Article
| Open AccessThe spatio-temporal evolution of multiple myeloma from baseline to relapse-refractory states
Spatially and temporally resolved data can improve our understanding of evolution and treatment resistance in multiple myeloma (MM). Here, the authors analyse spatial and longitudinal heterogeneity in MM patients using multi-region sequencing, and identify subclones associated with relapse and therapy resistance.
- Leo Rasche
- , Carolina Schinke
- & Niels Weinhold
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Article
| Open AccessComprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity
The identification of molecular biomarkers in cancer of unknown primary site (CUP) cases may enable the improvement of prognosis in these patients. Here, the authors integrate whole genome/exome, transcriptome and methylome data in 70 CUP patients, recommend therapies based on their analysis and report clinical outcome data.
- Lino Möhrmann
- , Maximilian Werner
- & Hanno Glimm
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Article
| Open AccessSpatiotemporal control of engineered bacteria to express interferon-γ by focused ultrasound for tumor immunotherapy
Several approaches have been recently proposed to engineer bacteria for cancer immunotherapy. Here the authors design an ultrasound-responsive bacterium for the controlled release of IFNy at the tumor site, promoting anti-tumor immune responses in preclinical models.
- Yuhao Chen
- , Meng Du
- & Fei Yan
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Article
| Open AccessDNA methylation-based epigenetic signatures predict somatic genomic alterations in gliomas
No clinical assay currently exists to classify glioma tumours based on gene expression. Here, the authors develop a DNA methylation-based classifier, Unified Diagnostic Pipeline (UniD) that identifies genomic alterations and gene expression subtypes of gliomas.
- Jie Yang
- , Qianghu Wang
- & Erik P. Sulman
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Article
| Open AccessHSF1 phosphorylation establishes an active chromatin state via the TRRAP–TIP60 complex and promotes tumorigenesis
Here the authors show phosphorylation of heat shock factor 1 (HSF1) at S419 via the chromatin-bound kinase PLK1, promotes HSF1 recruitment of histone acetyltransferases and histone acetylation reader proteins TRIM33 and TRIM24, which actually also execute histone H2BK120 mono-ubiquitination at target genes. Furthermore, HSF1 phosphorylation has an impact on melanoma cell proliferation.
- Mitsuaki Fujimoto
- , Ryosuke Takii
- & Akira Nakai
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Article
| Open AccessDecoding kinase-adverse event associations for small molecule kinase inhibitors
Small molecule kinase inhibitors (SMKIs) are being approved at a fast pace under expedited programs for anticancer treatment. Here, the authors employ a machine-learning model to examine the relationships between kinase targets and adverse events in the trials of 16 FDA-approved SMKIs.
- Xiajing Gong
- , Meng Hu
- & Liang Zhao
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Article
| Open AccessEngineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy
Proteolysis targeting chimeras (PROTACs) have emerged as promising cancer therapy agents but have suffered from systemic toxicity issues. Here, the authors report on the creation of polymeric PROTAC nanoparticles for tumour targeting delivery and demonstrate protein degradation in vivo, in combination with photodynamic therapy.
- Jing Gao
- , Bo Hou
- & Haijun Yu
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Article
| Open AccessPancreatic tumor eradication via selective Pin1 inhibition in cancer-associated fibroblasts and T lymphocytes engagement
Pharmacological inhibition of the prolyl isomerase PIN1, highly expressed in cancer cells and cancer associated fibroblasts (CAF), has been proposed for cancer therapy. Here the authors report the design of a DNA-barcoded micellular system functionalized with antibodies targeting CAFs and a T cell recruiting aptamer to deliver the PIN1 inhibitor AG17724, showing antitumor response in preclinical models of pancreatic cancer.
- Jiaye Liu
- , Yang Wang
- & Yong Liu
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Article
| Open AccessIntratumor graph neural network recovers hidden prognostic value of multi-biomarker spatial heterogeneity
Cancer prognosis using multiregion sampling is costly and not completely reliable due to the required biomarker homogenisation step. Here, the authors develop an intratumor graph neural network for prognosis in multiregion cancer samples based on in situ biomarkers and gene expression that does not need homogenisation.
- Lida Qiu
- , Deyong Kang
- & Haohua Tu
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Article
| Open AccessEngineered biomimetic nanoparticles achieve targeted delivery and efficient metabolism-based synergistic therapy against glioblastoma
Targeting cancer-associated metabolism is evolving as a promising approach for cancer therapy. Here, the authors generate cancer cell-membrane encapsulated nanoparticles to induce cell cycle arrest and cytotoxicity in lactate-high cancer cells, reducing tumourigensis in glioblastoma cell-line and patient-derived models.
- Guihong Lu
- , Xiaojun Wang
- & Wei Wei
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Article
| Open AccessProteomic analysis reveals key differences between squamous cell carcinomas and adenocarcinomas across multiple tissues
Squamous cell carcinomas are an aggressive cancer type which can occur in multiple organ systems. Here, the authors analyse the proteome of SCC cancers from 17 organs and show commonly dysregulated proteins independent of location.
- Qi Song
- , Ye Yang
- & Yingyong Hou
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Article
| Open AccessHypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy
Hypoxia can promote tumor escape from immune surveillance and immunotherapy. Here, the authors show that hypoxia induces T and NK cell dysfunction through HIF1α-mediated epigenetic suppression of effector gene expression, conferring resistance to anti-PD1 blockade in triple negative breast cancer models.
- Shijun Ma
- , Yue Zhao
- & Qiang Yu
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Article
| Open AccessQualitative differences in disease-associated MEK mutants reveal molecular signatures and aberrant signaling-crosstalk in cancer
MEK1 mutations are found in cancer and RASopathies, but their effects remain unclear. Here, the authors reveal a mutant MEK1 structure and qualitative differences in biological properties between the cancer- and RASopathy-associated mutants, providing insights into the pathophysiology, diagnosis, and treatment of these diseases.
- Yuji Kubota
- , Yuko Fujioka
- & Mutsuhiro Takekawa
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Article
| Open AccessIntegration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer
Some cancer patients with impaired HLA-I still respond to immunotherapy. Here the authors combine a cytotoxic gene signature from CD4+ and CD8+ T cells with tumor mutational burden to predict immunotherapy response in NSCLC patients, including those with HLA-LOH.
- Denise Lau
- , Sonal Khare
- & Aly A. Khan
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Article
| Open AccessThe HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors
Long non-coding RNAs (lncRNAs) can contribute to cancers that are driven by Sonic hedgehog (SHH) signaling. Here the authors report that lncRNA HHIP-AS1 stabilises the mRNA of dynein complex 1, thereby, promoting the pro-mitotic effects of SHH-driven tumors.
- Jasmin Bartl
- , Marco Zanini
- & Marc Remke
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Article
| Open AccessA randomized phase 3 trial of Gemcitabine or Nab-paclitaxel combined with cisPlatin as first-line treatment in patients with metastatic triple-negative breast cancer
Platinum agents, such as carboplatin and cisplatin, have been recommended in combination with gemcitabine for the treatment of metastatic triple negative breast cancer (TNBC). Here the authors report the results of a randomized phase 3 trial to compare the efficacy of first-line nab-paclitaxel/cisplatin to gemcitabine/cisplatin in patients with TNBC.
- Biyun Wang
- , Tao Sun
- & Xichun Hu
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Article
| Open AccessMulti-modal molecular programs regulate melanoma cell state
The regulation of the distinct intrinsic phenotypic states in melanoma remain poorly characterised. Here, multi-omics analysis for a panel of 68 early passage melanoma cell lines reveals that cancer cell intrinsic transcriptomic programs are associated with distinct immune features.
- Miles C. Andrews
- , Junna Oba
- & Scott E. Woodman
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Matters Arising
| Open AccessLimitations of molecular testing in combination with computerized tomographic for lung cancer screening
- Frederic W. Grannis Jr
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Article
| Open AccessThe cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer
Looking for metabolic-associated vulnerabilities is a promising approach for therapeutic intervention in KRAS-mutant colorectal cancer. Here, the authors show that the cholesterol-uptake regulator PCSK9 drives tumourigenesis and is a therapeutic target in KRASmutant colorectal cancer.
- Chi Chun Wong
- , Jian-Lin Wu
- & Jun Yu
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Article
| Open AccessRecurrent somatic mutations as predictors of immunotherapy response
Few genetic biomarkers are known for cancer immunotherapy. Here the authors identify recurrently-mutated genes and pathways associated with treatment response and develop a classifier using tumour whole exome sequencing and clinical features.
- Zoran Z. Gajic
- , Aditya Deshpande
- & Neville E. Sanjana
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Article
| Open AccessClinical relevance of molecular characteristics in Burkitt lymphoma differs according to age
Survival outcomes in Burkitt lymphoma differ between adult and paediatric patients. Here, the authors show differences in mutational frequencies between age groups, and a transition between mutational profiles which occurs between 25 and 40 years.
- Birgit Burkhardt
- , Ulf Michgehl
- & Georg Lenz
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Article
| Open AccessMonomethyl auristatin antibody and peptide drug conjugates for trimodal cancer chemo-radio-immunotherapy
Monomethyl auristatin (MMAE), also known for its radiosensitizer properties, is a common antibody drug conjugate used for cancer therapy. Here the authors show that, in combination with radiotherapy, tumor-directed antibodies or peptides conjugated to MMAE promote anti-tumor immune responses, improving response to checkpoint inhibitors in preclinical cancer models.
- Dina V. Hingorani
- , Michael M. Allevato
- & Sunil J. Advani
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Article
| Open AccessAn in situ hydrogel-mediated chemo-immunometabolic cancer therapy
Tryptophan metabolism, leading to the accumulation of kynurenine (Kyn) in the tumor microenvironment, restricts anti-tumor immunity. Here the authors report the design of a hydrogel loaded with doxorubicin and Kyn-degrading kynureninase to relieve immunosuppression, showing anti-tumor responses in preclinical models.
- Bo Wang
- , Jing Chen
- & Minglin Ma
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Article
| Open AccessThe genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma
The genetic factors involved in disease progression and drug resistance in multiple myeloma (MM) are varied and complex. Here, genomic and transcriptomic profiling of 511 relapsed and refractory MM patients reveals genetic alterations in several oncogenic pathways contributing to progression and resistance to MM therapies.
- Josh N. Vo
- , Yi-Mi Wu
- & Arul M. Chinnaiyan
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Article
| Open AccessGlutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors
Small molecules that target RNA Polymerase I inhibit ribosome biogenesis to activate p53 through the nucleolar surveillance response pathway. Here, the authors show that p53 induction by ribosome stress is dependent on extracellular glutamine availability.
- Melvin Pan
- , Christiane Zorbas
- & Tsuyoshi Osawa
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Article
| Open AccessCombinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer
The oncoprotein c-Myc is often overexpressed in triple negative breast cancer and has a role in tumor progression and resistance to therapy. Here the authors show that elevated MYC expression is correlated with low immune infiltration, diminished MHC-I pathway expression and that CpG/aOX40 treatment could overcome resistance to PD-L1 blockade in MYC-high breast tumors.
- Joyce V. Lee
- , Filomena Housley
- & Andrei Goga
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Article
| Open AccessRu(II) photocages enable precise control over enzyme activity with red light
The cytochrome P450 enzyme CYP1B1 is overexpressed in a variety of tumors, and is correlated with poor treatment outcomes; thus, it is desirable to develop CYP1B1 inhibitors to restore chemotherapy efficacy. Here the authors describe the creation of light-triggered CYP1B1 inhibitors as “prodrugs”, and achieve >6000-fold improvement in potency upon activation with low-energy (660 nm) light.
- Dmytro Havrylyuk
- , Austin C. Hachey
- & Edith C. Glazer