Reply to: Reconciling differences in impact of molecular subtyping on response to cisplatin-based chemotherapy.
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SUBMITTER: Taber A
PROVIDER: S-EPMC8355314 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic. Here we perform a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converge on genomic instability driven by a high number of chromosomal alterations, indels, signature 5 mutations and/or BRCA2 mutations. Expression data identifies the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression are associated with treatment response. Through integration of genomic and transcriptomic data, we demonstrate patient stratification to groups of low and high likelihood of cisplatin-based response. This could pave the way for future patient selection following validation in prospective clinical trials.
| S-EPMC7519650 | biostudies-literature
Project description:The primary goal of this study is to identify molecular subtypes of breast cancer through gene expression profiles of 327 breast cancer samples and determine molecular and clinical characteristics of different breast cancer subtypes. We studied expression signatures of different cellular functions (e.g., cell proliferation/cell cycle, wound response, tumor stromal response, vascular endothelial normalization, drug esponse genes, etc.) in different breast cancer molecular subtypes and investigated how microarray-based breast cancer molecular subtypes may be used to guide treatment. Gene expression profiles of 327 breast cancer samples were determined using total RNA and Affymetrix U133 plus 2.0 arrays.
2011-04-24 | E-GEOD-20685 | biostudies-arrayexpress
Project description:The primary goal of this study is to identify molecular subtypes of breast cancer through gene expression profiles of 327 breast cancer samples and determine molecular and clinical characteristics of different breast cancer subtypes. We studied expression signatures of different cellular functions (e.g., cell proliferation/cell cycle, wound response, tumor stromal response, vascular endothelial normalization, drug esponse genes, etc.) in different breast cancer molecular subtypes and investigated how microarray-based breast cancer molecular subtypes may be used to guide treatment.
2011-04-24 | GSE20685 | GEO
Project description:Platinum-based drugs that induce DNA damage are commonly used first-line chemotherapy agents for testicular, bladder, head and neck, lung, esophageal, stomach, and ovarian cancers. The inherent resistance of tumors to DNA damage often limits the therapeutic efficacy of these agents, such as cisplatin. An enhanced DNA repair and telomere maintenance response by the Mre11/Rad50/Nbs1 (MRN) complex is critical in driving this chemoresistance. We hypothesized therefore that the targeted impairment of native cellular MRN function could sensitize tumor cells to cisplatin. To test this, we designed what we believe to be a novel dominant-negative adenoviral vector containing a mutant RAD50 gene that significantly downregulated MRN expression and markedly disrupted MRN function in human squamous cell carcinoma cells. A combination of cisplatin and mutant RAD50 therapy produced significant tumor cytotoxicity in vitro, with a corresponding increase in DNA damage and telomere shortening. In cisplatin-resistant human squamous cell cancer xenografts in nude mice, this combination therapy caused dramatic tumor regression with increased apoptosis. Our findings suggest the use of targeted RAD50 disruption as what we believe to be a novel chemosensitizing approach for cancer therapy in the context of chemoresistance. This strategy is potentially applicable to several types of malignant tumors that demonstrate chemoresistance and may positively impact the treatment of these patients.
| S-EPMC2701852 | biostudies-other
Project description:The primary goal of this study is to identify molecular subtypes of breast cancer through gene expression profiles of 327 breast cancer samples and determine molecular and clinical characteristics of different breast cancer subtypes. We studied expression signatures of different cellular functions (e.g., cell proliferation/cell cycle, wound response, tumor stromal response, vascular endothelial normalization, drug esponse genes, etc.) in different breast cancer molecular subtypes and investigated how microarray-based breast cancer molecular subtypes may be used to guide treatment. Gene expression profiles of 327 breast cancer samples were determined using total RNA and Affymetrix U133 plus 2.0 arrays.
| S-ECPF-GEOD-20685 | biostudies-other
Project description: Not available
| S-EPMC8979984 | biostudies-literature
Project description:BackgroundFor over 150 years, pathologists have relied on histomorphology to classify and diagnose neoplasms. Their success has been stunning, permitting the accurate diagnosis of thousands of different types of neoplasms using only a microscope and a trained eye. In the past two decades, cancer genomics has challenged the supremacy of histomorphology by identifying genetic alterations shared by morphologically diverse tumors and by finding genetic features that distinguish subgroups of morphologically homogeneous tumors.DiscussionThe Developmental Lineage Classification and Taxonomy of Neoplasms groups neoplasms by their embryologic origin. The putative value of this classification is based on the expectation that tumors of a common developmental lineage will share common metabolic pathways and common responses to drugs that target these pathways. The purpose of this manuscript is to show that grouping tumors according to their developmental lineage can reconcile certain fundamental discrepancies resulting from morphologic and molecular approaches to neoplasm classification. In this study, six issues in tumor classification are described that exemplify the growing rift between morphologic and molecular approaches to tumor classification: 1) the morphologic separation between epithelial and non-epithelial tumors; 2) the grouping of tumors based on shared cellular functions; 3) the distinction between germ cell tumors and pluripotent tumors of non-germ cell origin; 4) the distinction between tumors that have lost their differentiation and tumors that arise from uncommitted stem cells; 5) the molecular properties shared by morphologically disparate tumors that have a common developmental lineage, and 6) the problem of re-classifying morphologically identical but clinically distinct subsets of tumors. The discussion of these issues in the context of describing different methods of tumor classification is intended to underscore the clinical value of a robust tumor classification.SummaryA classification of neoplasms should guide the rational design and selection of a new generation of cancer medications targeted to metabolic pathways. Without a scientifically sound neoplasm classification, biological measurements on individual tumor samples cannot be generalized to class-related tumors, and constitutive properties common to a class of tumors cannot be distinguished from uninformative data in complex and chaotic biological systems. This paper discusses the importance of biological classification and examines several different approaches to the specific problem of tumor classification.
| S-EPMC1208861 | biostudies-literature
Project description:Purpose: Neoadjuvant cisplatin-based Chemotherapy (NAC) followed by cystectomy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Unfortunately, only a third of patients achieve pathologic complete response (pCR). The aim of this study is to deeply investigate the role played by peripheral immunogenicity and the Tumor and Immune Microenvironment (TIME) in patients undergoing NAC to identify predictive and pharmacodynamic biomarkers associated with treatment response or treatment resistance. Experimental design: N= 19 patients with MIBC received NAC and were classified as pCR (n=10) or non-pCR (n=9). Bulk RNA-seq was performed on 13 formalin-fixed paraffin-embedded (FFPE) tumor biopsies collected before treatment with NAC and immune protein evaluations using GeoMx Digital Spatial Profiling (DSP) technology were performed on matched FFPE tumor biopsies collected before and after treatment with NAC. Matching Peripheral blood collected prior treatment initiation and during cystectomy was assessed for lymphocytes and neutrophils counts. Kaplan–Meier analyses and Cox PH regression models were used for survival analyses (OS). Results: Genes associated with immune signaling and DNA repair signaling correlated with treatment outcome of patients with MIBC undergoing NAC. At baseline, gene expression analysis and digital special profile highlighted an abundance of B cells and a reduced neuroendocrine phenotype in the TME of pCR vs. no-pCR. Increased protein expression of immune checkpoints molecules (e.g. LAG3, ICOS, PD-L1) was also observed in the TME of patients with no-pCR. In peripheral blood, a significant increase of lymphocytes and decrease of neutrophils counts, respectively, was observed in pCR vs no-pCR following NAC. Conclusions: When confirmed on a larger cohort, our results might lead to novel therapeutic strategies and to novel biomarkers predicting patients likely to respond to NAC.
2024-08-16 | GSE247185 | GEO
Project description:Pancreatic ductal adenocarcinoma is a highly lethal malignancy, which has now become the seventh most common cause of cancer death in the world, with the highest mortality rates in Europe and North America. In the past 30 years, there has been some progress in 5-year survival (rates increasing from 2.5 to 10%), but this is still extremely poor compared to all other common cancer types. Targeted therapies for advanced pancreatic cancer based on actionable mutations have been disappointing, with only 3-5% showing even a short clinical benefit. There is, however, a molecular diversity beyond mutations in genes responsible for producing classical canonical signaling pathways. Pancreatic cancer is almost unique in promoting an excess production of other components of the stroma, resulting in a complex tumor microenvironment that contributes to tumor development, progression, and response to treatment. Various transcriptional subtypes have also been described. Most notably, there is a strong alignment between the Classical/Pancreatic progenitor and Quasi-mesenchymal/Basal-like/Squamous subtype signatures of Moffit, Collinson, Bailey, Puleo, and Chan-Seng-Yue, which have potential clinical impact. Sequencing of epithelial cell populations enriched by laser capture microscopy combined with single-cell RNA sequencing has revealed the potential genomic evolution of pancreatic cancer as being a consequence of a gene expression continuum from mixed Basal-like and Classical cell populations within the same tumor, linked to allelic imbalances in mutant KRAS, with metastatic tumors being more copy number-unstable compared to primary tumors. The Basal-like subtype appears more chemoresistant with reduced survival compared to the Classical subtype. Chemotherapy and/or chemoradiation will also enrich the Basal-like subtype. Squamous/Basal-like programs facilitate immune infiltration compared with the Classical-like programs. The immune infiltrates associated with Basal and Classical type cells are distinct, potentially opening the door to differential strategies. Single-cell and spatial transcriptomics will now allow single cell profiling of tumor and resident immune cell populations that may further advance subtyping. Multiple clinical trials have been launched based on transcriptomic response signatures and molecular subtyping including COMPASS, Precision Promise, ESPAC6/7, PREDICT-PACA, and PASS1. We review several approaches to explore the clinical relevance of molecular profiling to provide optimal bench-to-beside translation with clinical impact.
| S-EPMC8603393 | biostudies-literature
Project description:BackgroundNeoadjuvant cisplatin-based chemotherapy (NAC) followed by cystectomy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Pathologic complete response (pCR) is associated with favorable outcomes, but only 30%-40% of patients achieve that response. The aim of this study is to investigate the role played by the Tumor and Immune Microenvironment (TIME) in association with the clinical outcome of patients with MIBC undergoing NAC.MethodsNineteen patients received NAC and were classified as pCR (n = 10) or non-pCR (n = 9). Bulk RNA-seq and immune protein evaluations using Digital Spatial Profiling (DSP) were performed on formalin-fixed paraffin-embedded (FFPE) tumor biopsies collected before NAC (baseline). Immunohistochemistry (IHC) evaluation focused on CD3 and CD20 expression was performed on baseline and end-of-treatment (EOT) FFPEs. Baseline peripheral blood was assessed for lymphocyte and neutrophil counts. Kaplan-Meier analyses and Cox PH regression models were used for survival analyses (OS).ResultsIn the periphery, pCR patients showed lower neutrophil counts, and neutrophil/ lymphocyte ratio (NLR) when compared to non-pCR patients. In the tumor microenvironment (TME), gene expression analysis and protein evaluations highlighted an abundance of B cells and CD3+ T cells in pCR versus non-pCR patients. On the contrary, increased protein expression of ARG1+ cells, and cells expressing immune checkpoints such as LAG3, ICOS, and STING were observed in the TME of patients with non-pCR.ConclusionsIn the current study, we demonstrated that lower NLR levels and increased CD3+ T cells and B cell infiltration are associated with improved response and long-term outcomes in patients with MIBC receiving NAC. These findings suggest that the impact of immune environment should be considered in determining the clinical outcome of MIBC patients treated with NAC.
| S-EPMC11310761 | biostudies-literature