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Cell Jan 2020Proteins are essential agents of biological processes. To date, large-scale profiling of cell line collections including the Cancer Cell Line Encyclopedia (CCLE) has...
Proteins are essential agents of biological processes. To date, large-scale profiling of cell line collections including the Cancer Cell Line Encyclopedia (CCLE) has focused primarily on genetic information whereas deep interrogation of the proteome has remained out of reach. Here, we expand the CCLE through quantitative profiling of thousands of proteins by mass spectrometry across 375 cell lines from diverse lineages to reveal information undiscovered by DNA and RNA methods. We observe unexpected correlations within and between pathways that are largely absent from RNA. An analysis of microsatellite instable (MSI) cell lines reveals the dysregulation of specific protein complexes associated with surveillance of mutation and translation. These and other protein complexes were associated with sensitivity to knockdown of several different genes. These data in conjunction with the wider CCLE are a broad resource to explore cellular behavior and facilitate cancer research.
Topics: Cell Line, Tumor; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Mass Spectrometry; Microsatellite Instability; Mutation; Neoplasms; Proteome; Proteomics
PubMed: 31978347
DOI: 10.1016/j.cell.2019.12.023 -
Journal of Hematology & Oncology Jul 2022Chemotherapy combined with or without targeted therapy is the fundamental treatment for metastatic colorectal cancer (mCRC). Due to the adverse effects of... (Review)
Review
Chemotherapy combined with or without targeted therapy is the fundamental treatment for metastatic colorectal cancer (mCRC). Due to the adverse effects of chemotherapeutic drugs and the biological characteristics of the tumor cells, it is difficult to make breakthroughs in traditional strategies. The immune checkpoint blockades (ICB) therapy has made significant progress in the treatment of advanced malignant tumors, and patients who benefit from this therapy may obtain a long-lasting response. Unfortunately, immunotherapy is only effective in a limited number of patients with microsatellite instability-high (MSI-H), and segment initial responders can subsequently develop acquired resistance. From September 4, 2014, the first anti-PD-1/PD-L1 drug Pembrolizumab was approved by the FDA for the second-line treatment of advanced malignant melanoma. Subsequently, it was approved for mCRC second-line treatment in 2017. Immunotherapy has rapidly developed in the past 7 years. The in-depth research of the ICB treatment indicated that the mechanism of colorectal cancer immune-resistance has become gradually clear, and new predictive biomarkers are constantly emerging. Clinical trials examining the effect of immune checkpoints are actively carried out, in order to produce long-lasting effects for mCRC patients. This review summarizes the treatment strategies for mCRC patients, discusses the mechanism and application of ICB in mCRC treatment, outlines the potential markers of the ICB efficacy, lists the key results of the clinical trials, and collects the recent basic research results, in order to provide a theoretical basis and practical direction for immunotherapy strategies.
Topics: Colorectal Neoplasms; Humans; Immunologic Factors; Immunotherapy; Microsatellite Instability
PubMed: 35842707
DOI: 10.1186/s13045-022-01294-4 -
Genes, Chromosomes & Cancer Jun 2022The mismatch repair system is a major pathway that functions in the maintenance of genomic integrity. It is involved in mitotic and meiotic recombination, apoptosis,... (Review)
Review
The mismatch repair system is a major pathway that functions in the maintenance of genomic integrity. It is involved in mitotic and meiotic recombination, apoptosis, immunoglobulin gene rearrangement, somatic hypermutation, and other processes. Deficiencies in mismatch repair give rise to hypermutability and the phenomenon called microsatellite instability. Detection of deficient mismatch repair function or microsatellite instability is used diagnostically, predictively, and prognostically. Specifically, deficient mismatch repair function is used for screening of Lynch syndrome, determining patients who are likely to respond to immune checkpoint inhibition, and to contributes to an understanding of which cancer patients may pursue a more aggressive clinical course. Microsatellite instability can be evaluated directly by polymerase chain reaction (PCR) or indirectly by assessment of mismatch repair protein expression using immunohistochemistry (IHC), and mismatch repair function using next-generation sequencing assays which evaluates homopolymer indels. In this article, we provide a concise practical review on mismatch repair deficiency (MMR-d)/microsatellite instability (MSI), focusing on clinical testing, different testing methods, interpretation of findings, the predictive, and prognostic utility of MSI.
Topics: Brain Neoplasms; Colorectal Neoplasms; DNA Mismatch Repair; Humans; Microsatellite Instability; Neoplastic Syndromes, Hereditary
PubMed: 34837268
DOI: 10.1002/gcc.23015 -
International Journal of Gynecological... Mar 2023The Cancer Genome Atlas (TCGA) endometrial cancer data expanded our knowledge about the role of different immunotherapeutic approaches based on molecular subtypes.... (Review)
Review
The Cancer Genome Atlas (TCGA) endometrial cancer data expanded our knowledge about the role of different immunotherapeutic approaches based on molecular subtypes. Immune checkpoint inhibitors demonstrated distinct antitumor activities as monotherapy or in combination. In microsatellite unstable (microsatellite instability-high) endometrial cancer, immunotherapy with immune checkpoint inhibitors showed promising single agent activity in recurrent settings. Different strategies are needed to enhance the response or reverse resistance to immune checkpoint inhibitors, or both, in microsatellite instability-high endometrial cancer. On the other hand, single immune checkpoint inhibitors showed underwhelming efficacy in microsatellite stable endometrial cancer but this was significantly improved using a combination approach. Furthermore, studies are also needed to improve response along with ensuring safety and tolerability in microsatellite stable endometrial cancer. This review summarizes the current indications of immunotherapy for the treatment of advanced and recurrent endometrial cancer. We also outline potential future strategies for an immunotherapy based combination approach in endometrial cancer to combat resistance or enhance response to immune checkpoint inhibitors, or both.
Topics: Humans; Female; Immune Checkpoint Inhibitors; Microsatellite Instability; Endometrial Neoplasms; Immunotherapy; Microsatellite Repeats
PubMed: 36878570
DOI: 10.1136/ijgc-2022-003675 -
Cancer Treatment Reviews Apr 2021Gastric cancer (GC) represents an important contributor to the global burden of cancer, being one of the most common and deadly malignancies worldwide. According to TCGA... (Review)
Review
Gastric cancer (GC) represents an important contributor to the global burden of cancer, being one of the most common and deadly malignancies worldwide. According to TCGA and ACRG classifications, the microsatellite instable (MSI) group represents a significant subset of GCs and is currently in the limelight of many researches due to its favorable survival outcome in resectable stages compared to microsatellite stable tumors. MSI GCs hypermutated phenotype triggers immunosurveillance, making this molecular subgroup a promising candidate for immune checkpoint inhibitors treatment. Conversely, conflicting outcomes have been reported in chemotherapy settings. Due to the clinical relevance of these observations, in this review we report and discuss the molecular, pathological, prognostic, and predictive features of MSI gastric tumors.
Topics: Animals; Antineoplastic Agents; Humans; Microsatellite Instability; Stomach Neoplasms
PubMed: 33721595
DOI: 10.1016/j.ctrv.2021.102175 -
Cells Mar 2020Colorectal cancer (CRC) is the third most common cancer type, and third highest in mortality rates among cancer-related deaths in the United States. Originating from... (Review)
Review
Colorectal cancer (CRC) is the third most common cancer type, and third highest in mortality rates among cancer-related deaths in the United States. Originating from intestinal epithelial cells in the colon and rectum, that are impacted by numerous factors including genetics, environment and chronic, lingering inflammation, CRC can be a problematic malignancy to treat when detected at advanced stages. Chemotherapeutic agents serve as the historical first line of defense in the treatment of metastatic CRC. In recent years, however, combinational treatment with targeted therapies, such as vascular endothelial growth factor, or epidermal growth factor receptor inhibitors, has proven to be quite effective in patients with specific CRC subtypes. While scientific and clinical advances have uncovered promising new treatment options, the five-year survival rate for metastatic CRC is still low at about 14%. Current research into the efficacy of immunotherapy, particularly immune checkpoint inhibitor therapy (ICI) in mismatch repair deficient and microsatellite instability high (dMMR-MSI-H) CRC tumors have shown promising results, but its use in other CRC subtypes has been either unsuccessful, or not extensively explored. This Review will focus on the current status of immunotherapies, including ICI, vaccination and adoptive T cell therapy (ATC) in the treatment of CRC and its potential use, not only in dMMR-MSI-H CRC, but also in mismatch repair proficient and microsatellite instability low (pMMR-MSI-L).
Topics: Animals; Brain Neoplasms; Colonic Neoplasms; Colorectal Neoplasms; Humans; Immunologic Factors; Immunotherapy; Microsatellite Instability; Neoplastic Syndromes, Hereditary
PubMed: 32143413
DOI: 10.3390/cells9030618 -
Journal For Immunotherapy of Cancer Jan 2022Dostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from...
Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study.
BACKGROUND
Dostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with endometrial cancer (EC) participating in a phase I trial of single-agent dostarlimab.
METHODS
GARNET, an ongoing, single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumors, is being undertaken at 123 sites. Two cohorts of patients with EC were recruited: those with dMMR/MSI-H disease (cohort A1) and those with proficient/stable (MMRp/MSS) disease (cohort A2). Patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression. The primary endpoints were objective response rate (ORR) and duration of response (DOR) per RECIST V.1.1, as assessed by blinded independent central review.
RESULTS
Screening began on April 10, 2017, and 129 and 161 patients with advanced EC were enrolled in cohorts A1 and A2, respectively. The median follow-up duration was 16.3 months (IQR 9.5-22.1) for cohort A1 and 11.5 months (IQR 11.0-25.1) for cohort A2. In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. In cohort A2, ORR was 14.1% (95% CI 9.1% to 20.6%) with three complete responses and 19 partial responses. Median DOR was not reached in either cohort. In the combined cohorts, the majority of treatment-related adverse events (TRAEs) were grade 1-2 (75.5%), most commonly fatigue (17.6%), diarrhea (13.8%), and nausea (13.8%). Grade≥3 TRAEs occurred in 16.6% of patients, and 5.5% discontinued dostarlimab because of TRAEs. No deaths were attributable to dostarlimab.
CONCLUSION
Dostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H (ORR 43.5%) and MMRp/MSS EC (ORR 14.1%) with a manageable safety profile.
TRIAL REGISTRATION NUMBER
NCT02715284.
Topics: Antibodies, Monoclonal, Humanized; Biomarkers, Tumor; DNA Mismatch Repair; Endometrial Neoplasms; Female; Humans; Microsatellite Instability; Middle Aged
PubMed: 35064011
DOI: 10.1136/jitc-2021-003777 -
Frontiers in Immunology 2022Colorectal cancers (CRCs) with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) show molecular and clinicopathological characteristics that... (Review)
Review
Colorectal cancers (CRCs) with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) show molecular and clinicopathological characteristics that differ from those of proficient mismatch repair/microsatellite stable CRCs. Despite the importance of MSI-H/dMMR status in clinical decision making, the testing rates for MSI and MMR in clinical practice remain low, even in high-risk populations. Additionally, the real-world prevalence of MSI-H/dMMR CRC may be lower than that reported in the literature. Insufficient MSI and MMR testing fails to identify patients with MSI-H/dMMR CRC, who could benefit from immunotherapy. In this article, we describe the current knowledge of the clinicopathological features, molecular landscape, and radiomic characteristics of MSI-H/dMMR CRCs. A better understanding of the importance of MMR/MSI status in the clinical characteristics and prognosis of CRC may help increase the rates of MMR/MSI testing and guide the development of more effective therapies based on the unique features of these tumors.
Topics: Humans; Microsatellite Instability; DNA Mismatch Repair; Colonic Neoplasms; Colorectal Neoplasms; Prognosis
PubMed: 36618386
DOI: 10.3389/fimmu.2022.1019582 -
Surgical Pathology Clinics Dec 2022Prostate cancer (PCa) is characterized by profound genomic heterogeneity. Recent advances in personalized treatment entail an increasing need of genomic profiling. For... (Review)
Review
Prostate cancer (PCa) is characterized by profound genomic heterogeneity. Recent advances in personalized treatment entail an increasing need of genomic profiling. For localized PCa, gene expression assays can support clinical decisions regarding active surveillance and adjuvant treatment. In metastatic PCa, homologous recombination deficiency, microsatellite instability-high (MSI-H), and CDK12 deficiency constitute main actionable alterations. Alterations in DNA repair genes confer variable sensitivities to poly(ADP-ribose)polymerase inhibitors, and the use of genomic instability assays as predictive biomarker is still incipient. MSI can be assessed by immunohistochemistry To date there is a lack of consensus as to testing standards.
Topics: Male; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Microsatellite Instability; Prostatic Neoplasms; Genetic Testing; Molecular Biology
PubMed: 36344179
DOI: 10.1016/j.path.2022.08.002 -
Nature Medicine Jul 2019Microsatellite instability determines whether patients with gastrointestinal cancer respond exceptionally well to immunotherapy. However, in clinical practice, not every...
Microsatellite instability determines whether patients with gastrointestinal cancer respond exceptionally well to immunotherapy. However, in clinical practice, not every patient is tested for MSI, because this requires additional genetic or immunohistochemical tests. Here we show that deep residual learning can predict MSI directly from H&E histology, which is ubiquitously available. This approach has the potential to provide immunotherapy to a much broader subset of patients with gastrointestinal cancer.
Topics: Deep Learning; Gastrointestinal Neoplasms; Humans; Immunotherapy; Microsatellite Instability
PubMed: 31160815
DOI: 10.1038/s41591-019-0462-y