Molecular Profiling Provides Clinical Insights into Targeted and Immunotherapies as well as Prognosis for Colorectal Cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE222300 | GEO | 2023/01/09
REPOSITORIES: GEO
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Project description:Background and aims Tumor genetic testing is indispensable in the management of primary and advanced colorectal cancer, with one-third of patients progressing despite standard care. We aimed to refine the indications for genomics-guided precision therapy. Methods We prospectively sequenced 869 tumors from Chinese patients with colorectal cancer and performed a comprehensive analysis of clinical and genomic profiles. The clinical significance of single mutation and co-occurring events was assessed in metastatic colorectal cancer (mCRC). The tumor immune microenvironment was evaluated by Immunoscore assay and single-cell sequencing. Results Single gene somatic mutations in BRAF and RBM10 were associated with shorter progression-free survival (PFS) in treatment-naive mCRC patients (BRAF: hazard ratio [HR] = 2.2 [95% CI, 1.1-4.4]; RBM10: HR= 6.8 [95% CI, 2.6-17.3]), and RBM10 remained a risk factor irrespective of the addition of bevacizumab to the chemotherapy regimens. KRAS mutations coexisting with those in AMER1 or APC were enriched in the metastatic cohort (26.23%), which had poor PFS and did not benefit from bevacizumab. 40 patients (4.6%) carried pathogenic or likely pathogenic germline alterations in the DNA damage repair pathway and 30% of them had double-hit events in the tumor with higher MSI scores. High tumor indel burden with MSI-high suggested a large number of tumor-infiltrating lymphocytes, whereas POLE-mutant with TMB-ultrahigh indicated a relatively quiescent immunophenotype. The heterogeneous genomic-immunological ecosystem was reflected in the divergent antigen presentation, immune checkpoint protein expression and responses of T cells to pembrolizumab treatment. Conclusion Integrated analysis of the clinical, genomic, and immunological profiles of colorectal cancer provides insights into prognostic stratification, drug response and potential clinical trials.
2023-01-10 | GSE222202 | GEO
Project description:Precision medicine in oncology promises the matching of genomic, molecular, and clinical data with underlying mechanisms of a range of novel anticancer therapeutics to develop more rational and effective antitumor strategies in a timely manner. However, despite the remarkable progress made in the understanding of novel drivers of different oncogenic processes, success rates for the approval of oncology drugs remain low with substantial fiscal consequences. In this article, we focus on how recent rapid innovations in technology have brought greater clarity to the biological and clinical complexities of different cancers and advanced the development of molecularly targeted agents and immunotherapies in clinical trials. We discuss the key challenges of identifying and validating predictive biomarkers of response and resistance using both tumor and surrogate tissues, as well as the hurdles associated with intratumor heterogeneity. Finally, we outline evolving strategies employed in early-phase trial designs that incorporate omics-based technologies.
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Project description:Pulmonary sarcomatoid carcinomas (PSCs) are rare and aggressive histological types of non-small cell lung cancer (NSCLC) with a median overall survival of about 9-12 months. In detail, PSCs comprise five different histological subtypes: pleomorphic carcinoma (PLC), giant cell carcinoma (GCC), spindle cell carcinoma (SCC), carcinosarcoma (CS) and pulmonary blastoma (PB). Preoperative pathological diagnosis may fail to identify these tumors and therapeutic options are still limited. PSCs have been scarcely characterized from a molecular point of view because of their rarity, and to date no specific markers have been found for PSCs in comparison with other NSCLC types. In this study a highly sensitive amplicon based whole transcriptome quantification analysis was performed, using the Ion AmpliSeq Transcriptome Human Gene Expression Kit (Life Technologies) on a selected series of 14 PSCs (1 PB, 4 CS, 2 SCC, 2 GCC, 5 PLC) and 3 samples of normal lung parenchyma. PSCs expression data were then compared with transcriptome data of lung adenocarcinoma and squamous cell carcinoma available on The Cancer Genome Atlas database. Thirty-eight genes specifically deregulated in PSC samples were identified. Among these, IGJ and SLMAP were validated by immunohistochemistry on an independent cohort (30 PSCs, 31 lung adenocarcinoma and 31 squamous cell carcinoma cases). Furthermore, a pathway enrichment analysis, performed on differentially expressed genes, revealed that FOXO signalling and Fanconi Anemia pathways, playing a pivotal role in cancer development and progression, are enriched in PSC tumors. The description of peculiar molecular profiles besides increasing our knowledge on PSCs biology may suggest new diagnostic and therapeutic strategies.
2019-03-12 | GSE110205 | GEO
Project description:The continuous improvements of our understanding of the pathophysiological changes that occur in multiple sclerosis (MS) have translated into many novel therapeutic agents at different stages of development. These agents target more specifically the innate or the adaptive immune response. We will review agents available or under development that target the humoral pathways of the adaptive immune response. As such, humoral targeted immunotherapies that are being developed for MS are discussed herein: rituximab, ocrelizumab, and ofatumumab show promise as B-cell depleting agents. Other agents, such as atacicept were suspended during development in MS due to increased inflammatory activity versus the placebo. Although most agents were tested in relapsing-remitting forms of MS, rituximab and ocrelizumab have both been studied in progressive MS, whereas ocrelizumab only is currently moving forward in primary progressive MS trials. We provide an overview of agents available and under development that target the humoral response and include their mechanisms of action, safety profiles, and results of clinical trials.
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Project description:Immunotherapies that harness the immune system to kill cancer cells have showed significant therapeutic efficacy in many human malignancies. A growing number of studies have highlighted the relevance of neoantigens in recognizing cancer cells by intrinsic T cells. Cancer neoantigens are a direct consequence of somatic mutations presenting on the surface of individual cancer cells. Neoantigens are fully cancer-specific and exempt from central tolerance. In addition, neoantigens are important targets for checkpoint blockade therapy. Recently, technological innovations have made neoantigen discovery possible in a variety of malignancies, thus providing an impetus to develop novel immunotherapies that selectively enhance T cell reactivity for the destruction of cancer cells while leaving normal tissues unharmed. In this review, we aim to introduce the methods of the identification of neoantigens, the mutational patterns of human cancers, related clinical trials, neoantigen burden and sensitivity to immune checkpoint blockade. Moreover, we focus on relevant challenges of targeting neoantigens for cancer treatment.
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Project description:Uveal melanoma (UM) has well-characterised somatic copy number alterations (SCNA) in chromosomes 1, 3, 6 and 8, in addition to mutations in GNAQ, GNA11, CYSLTR2, PLCB4, BAP1, SF3B1 and EIF1AX, most being linked to metastatic-risk. To gain further insight into the molecular landscape of UM, we designed a targeted next-generation sequencing (NGS) panel to detect SCNA and mutations in routine clinical UM samples. We compared hybrid-capture and amplicon-based target enrichment methods and tested a larger cohort of primary UM samples on the best performing panel. UM clinical samples processed either as fresh-frozen, formalin-fixed paraffin embedded (FFPE), small intraocular biopsies or following irradiation were successfully profiled using NGS, with hybrid capture outperforming the PCR-based enrichment methodology. We identified monosomy 3 (M3)-UM that were wild-type for BAP1 but harbored SF3B1 mutations, novel frameshift deletions in SF3B1 and EIF1AX, as well as a PLCB4 mutation outside of the hotspot on exon 20 coinciding with a GNAQ mutation in some UM. We observed samples that harboured mutations in both BAP1 and SF3B1, and SF3B1 and EIF1AX, respectively. Novel mutations were also identified in TTC28, KTN1, CSMD1 and TP53BP1. NGS can simultaneously assess SCNA and mutation data in UM, in a reliable and reproducible way, irrespective of sample type or previous processing. BAP1 and SF3B1 mutations, in addition to 8q copy number, are of added importance when determining UM patient outcome.
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Project description:Pulmonary sarcomatoid carcinomas (PSC) are a rare group of lung cancer with a median overall survival of 9-12 months. PSC are divided into five histotypes, challenging to diagnose and treat. The identification of PSC biomarkers is warranted, but PSC molecular profile remains to be defined. Herein, a targeted whole transcriptome analysis was performed on 14 PSC samples, evaluated also for the presence of the main oncogene mutations and rearrangements. PSC expression data were compared with transcriptome data of lung adenocarcinomas (LUAD) and squamous cell carcinomas (LUSC) from The Cancer Genome Atlas. Deregulated genes were used for pathway enrichment analysis; the most representative genes were tested by immunohistochemistry (IHC) in an independent cohort (30 PSC, 31 LUAD, 31 LUSC). All PSC cases were investigated for PD-L1 expression. Thirty-eight genes deregulated in PSC were identified, among these IGJ and SLMAP were confirmed by IHC. Moreover, Forkhead box signaling and Fanconi anemia pathways were specifically enriched in PSC. Finally, some PSC harboured alterations in genes targetable by tyrosine kinase inhibitors, as EGFR and MET. We provide a deep molecular characterization of PSC; the identification of specific molecular profiles, besides increasing our knowledge on PSC biology, might suggest new strategies to improve patients management.
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Project description:Gold glyconanoparticles loaded with the listeriolysin O peptide 91-99 (GNP-LLO91-99), a bacterial peptide with anti-metastatic properties, are vaccine delivery platforms facilitating immune cell targeting and increasing antigen loading. Here, we present proof of concept analyses for the consideration of GNP-LLO91-99 nanovaccines as a novel immunotherapy for cutaneous melanoma. Studies using mouse models of subcutaneous melanoma indicated that GNP-LLO91-99 nanovaccines recruite and modulate dendritic cell (DC) function within the tumour, alter tumour immunotolerance inducing melanoma-specific cytotoxic T cells, cause complete remission and improve survival. GNP-LLO91-99 nanovaccines showed superior tumour regression and survival benefits, when combined with anti-PD-1 or anti-CTLA-4 checkpoint inhibitors, resulting in an improvement in the efficacy of these immunotherapies. Studies on monocyte-derived DCs from patients with stage IA, IB or IIIB melanoma confirmed the ability of GNP-LLO91-99 nanovaccines to complement the action of checkpoint inhibitors, by not only reducing the expression of cell-death markers on DCs, but also potentiating DC antigen-presentation. We propose that GNP-LLO91-99 nanovaccines function as immune stimulators and immune effectors and serve as safe cancer therapies, alone or in combination with other immunotherapies.
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Project description:There are encouraging signs in our collective progress to leverage the immune system to treat pediatric cancers. Here, we summarize interim successes in cancer immunotherapy and opportunities to translate from the adult world to pediatrics, and highlight challenges that could benefit from additional development, focusing on solid tumors. Just a decade ago, other than antibodies targeting disialoganglioside (GD2) in neuroblastoma, pediatric cancer immunotherapy was mostly relegated to obscure preclinical studies in a few academic labs. Today there are numerous clinical trials of a variety of antibody, cellular, gene, and viral therapies and vaccines designed to either promote antitumor immunity or specifically attack validated immunotherapy targets. Understanding those targets and their pediatric relevance is paramount. While much work is underway to evaluate the utility of numerous immunologic targets, the lack of regulatory approvals is emblematic of the challenges that remain. Herein we focus our review on the most promising targeted immunotherapies in clinical trials for children.
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