Similar Datasets
Project description:Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients' tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor. SIGNIFICANCE: These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.
| S-EPMC7718387 | biostudies-literature
Project description:Medulloblastoma (MB) is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most MB patients receive similar therapies, including surgery, radiation and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease, and survivors suffer severe long-term side effects from therapy. We hypothesize that each MB patient is sensitive to different therapies, and that tailoring therapy based on the molecular and cellular characteristics of patients’ tumors will improve outcomes. To test this, we have assembled a panel of orthotopic patient-derived xenografts (PDXs) and subjected them to DNA sequencing, gene expression profiling and high-throughput drug screening. Analysis of DNA sequencing suggests that most MBs do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provide valuable information about potential therapies for every tumor. For example, drug screening demonstrates that actinomycin D – which is used for treatment of sarcoma but rarely for MB – is active against PDXs representing Group 3 MB, the most aggressive form of the disease. Finally, we show that functional analysis of tumor cells can be used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their tumor.
2020-10-01 | GSE151343 | GEO
Project description:Medulloblastoma (MB) is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most MB patients receive similar therapies, including surgery, radiation and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease, and survivors suffer severe long-term side effects from therapy. We hypothesize that each MB patient is sensitive to different therapies, and that tailoring therapy based on the molecular and cellular characteristics of patients’ tumors will improve outcomes. To test this, we have assembled a panel of orthotopic patient-derived xenografts (PDXs) and subjected them to DNA sequencing, gene expression profiling and high-throughput drug screening. Analysis of DNA sequencing suggests that most MBs do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provide valuable information about potential therapies for every tumor. For example, drug screening demonstrates that actinomycin D – which is used for treatment of sarcoma but rarely for MB – is active against PDXs representing Group 3 MB, the most aggressive form of the disease. Finally, we show that functional analysis of tumor cells can be used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their tumor.
2020-10-01 | GSE151344 | GEO
Project description:Functional precision medicine identifies new therapeutic candidates for medulloblastoma
| PRJNA635569 | ENA
Project description:Functional precision medicine identifies new therapeutic candidates for medulloblastoma (expression dataset)
| PRJNA635573 | ENA
Project description:Functional precision medicine identifies new therapeutic candidates for medulloblastoma (methylation dataset)
| PRJNA635574 | ENA
Project description:Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with high mortality and a lack of targeted therapies. To identify and prioritize druggable targets, we performed genome analysis together with genome-scale siRNA and oncology drug profiling using low-passage tumor cells derived from a patient with treatment-resistant HPV-negative HNSCC.Experimental Design: A tumor cell culture was established and subjected to whole-exome sequencing, RNA sequencing, comparative genome hybridization, and high-throughput phenotyping with a siRNA library covering the druggable genome and an oncology drug library. Secondary screens of candidate target genes were performed on the primary tumor cells and two nontumorigenic keratinocyte cell cultures for validation and to assess cancer specificity. siRNA screens of the kinome on two isogenic pairs of p53-mutated HNSCC cell lines were used to determine generalizability. Clinical utility was addressed by performing drug screens on two additional HNSCC cell cultures derived from patients enrolled in a clinical trial.Results: Many of the identified copy number aberrations and somatic mutations in the primary tumor were typical of HPV(-) HNSCC, but none pointed to obvious therapeutic choices. In contrast, siRNA profiling identified 391 candidate target genes, 35 of which were preferentially lethal to cancer cells, most of which were not genomically altered. Chemotherapies and targeted agents with strong tumor-specific activities corroborated the siRNA profiling results and included drugs that targeted the mitotic spindle, the proteasome, and G2-M kinases WEE1 and CHK1 We also show the feasibility of ex vivo drug profiling for patients enrolled in a clinical trial.Conclusions: High-throughput phenotyping with siRNA and drug libraries using patient-derived tumor cells prioritizes mutated driver genes and identifies novel drug targets not revealed by genomic profiling. Functional profiling is a promising adjunct to DNA sequencing for precision oncology. Clin Cancer Res; 24(12); 2828-43. ©2018 AACR.
| S-EPMC6004257 | biostudies-literature
Project description:Medulloblastoma (MB) is the most common malignant childhood tumor of the brain. Multimodal treatment consisting of surgery, radiation therapy, and chemotherapy reduced cumulative incidence of late mortality but increased the incidence of subsequent neoplasms and severe, incapacitating chronic health conditions. Present treatment strategies fail to recognize heterogeneity within patients despite wide divergence in individual responses. The persistent mortality rates and serious side effects of non-targeted cytotoxic therapies indicate a need for more refined therapeutic approaches. Advanced genomic research has led to the accumulation of an enormous amount of genetic information and resulted in a consensus distinguishing four molecular subgroups, WNT-activated, SHH-activated, and Group 3 and 4 medulloblastomas. These have distinct origin, demographics, molecular alterations, and clinical outcomes. Although subgroup affiliation does not predict response to therapy, new subgroup-specific markers of prognosis can enable a more layered risk stratification with additional subtypes within each primary subgroup. Here, we summarize subgroup-specific genetic alterations and their utility in current treatment strategies. The transition toward molecularly targeted interventions for newly diagnosed MBs remains slow, and prospective trials are needed to confirm stratifications based on molecular alterations. At the same time, numerous studies focus at fine-tuning the intensity of invasive radio- and chemotherapies to reduce intervention-related long-term morbidity. There are an increasing number of immunotherapy-based treatment strategies including immune checkpoint-inhibitors, oncolytic viruses, CAR-T therapy, and NK cells in recurrent and refractory MBs. Although most trials are in early phase, there is hope for therapeutic breakthroughs for advanced MBs within the next decade.
| S-EPMC7098941 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-10-12 | GSE168418 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-12-02 | GSE275444 | GEO