Resistance to targeted therapies in the brain tumor microenvironment occurs through selection of cells with distinct transcriptomic profiles
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA731910 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14615159.fastq.gz | Fastqsanger.gz | |||
| SRR14615160.fastq.gz | Fastqsanger.gz | |||
| SRR14615161.fastq.gz | Fastqsanger.gz | |||
| SRR14615162.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 4 of 4 |
Similar Datasets
Project description:The brain is a major sanctuary site for metastatic lung cancer cells that evade systemic therapies. We performed pharmacological, biological, and molecular studies to identify the functional link between drug resistance and central nervous system (CNS) relapse in late-stage EGFR mutant non-small cell lung cancer, which frequently progresses in the brain even when treated with the brain penetrant EGFR inhibitor osimertinib. Despite widespread osimertinib distribution in vivo, the brain microvascular tumor microenvironment (TME) is associated with the persistence of malignant cell sub-populations which are poised to further proliferate in the brain as osimertinib-resistant lesions over time. Cellular and molecular features of this poised state are commonly regulated through RhoA signaling, which potentiates the outgrowth of disseminated tumor cells on osimertinib treatment, preferentially in response to extracellular laminin and in the brain. Thus, we identify pre-existing and adaptive features of metastatic and drug resistant cancer cells, which are enhanced by RhoA and the brain TME during the evolution of osimertinib resistant disease.
2022-09-02 | GSE174851 | GEO
Project description:The brain tumor microenvironment primes metastatic cells for resistance to targeted therapies
| PRJNA731909 | ENA
Project description:The brain is a major sanctuary site for metastatic lung cancer cells that evade systemic therapies. We performed pharmacological, biological, and molecular studies to identify the functional link between drug resistance and central nervous system (CNS) relapse in late-stage EGFR mutant non-small cell lung cancer, which frequently progresses in the brain even when treated with the brain penetrant EGFR inhibitor osimertinib. Despite widespread osimertinib distribution in vivo, the brain microvascular tumor microenvironment (TME) is associated with the persistence of malignant cell sub-populations which are poised to further proliferate in the brain as osimertinib-resistant lesions over time. Cellular and molecular features of this poised state are commonly regulated through RhoA signaling, which potentiates the outgrowth of disseminated tumor cells on osimertinib treatment, preferentially in response to extracellular laminin and in the brain. Thus, we identify pre-existing and adaptive features of metastatic and drug resistant cancer cells, which are enhanced by RhoA and the brain TME during the evolution of osimertinib resistant disease.
2022-09-02 | GSE174850 | GEO
Project description:Resistance to targeted therapies in the brain tumor microenvironment is not drive by genetic mutations
| PRJNA731911 | ENA
Project description:The brain is a major sanctuary site for metastatic lung cancer cells that evade systemic therapies. We performed pharmacological, biological, and molecular studies to identify the functional link between drug resistance and central nervous system (CNS) relapse in late-stage EGFR mutant non-small cell lung cancer, which frequently progresses in the brain even when treated with the brain penetrant EGFR inhibitor osimertinib. Despite widespread osimertinib distribution in vivo, the brain microvascular tumor microenvironment (TME) is associated with the persistence of malignant cell sub-populations which are poised to further proliferate in the brain as osimertinib-resistant lesions over time. Cellular and molecular features of this poised state are commonly regulated through RhoA signaling, which potentiates the outgrowth of disseminated tumor cells on osimertinib treatment, preferentially in response to extracellular laminin and in the brain. Thus, we identify pre-existing and adaptive features of metastatic and drug resistant cancer cells, which are enhanced by RhoA and the brain TME during the evolution of osimertinib resistant disease.
2022-09-02 | GSE174852 | GEO
Project description:KMT2A oncoproteins induce epigenetic resistance to targeted therapies.
| PRJNA1060315 | ENA
Project description:Treating unselected cancer patients with new drugs dilutes proof of efficacy when only a fraction of patients respond to therapy. We conducted a meta-analysis on eight primary breast cancer microarray datasets representing diverse breast cancer phenotypes. We present a high-throughput protocol which incorporates drug sensitivity signatures to guide preclinical testing for effective therapeutic agents. Specifically, we focus on drug classes currently undergoing early phase clinical testing. Our genomic and experimental results suggest that the majority of basal-like breast cancers should respond to inhibitors of the phosphatidylinositol-3-kinase pathway, and that a relatively low toxicity histone deacetylase inhibitor, valproic acid, may target aggressive breast cancers. For a subset of drugs, prediction of sensitivity associates with tumor recurrence, suggesting clinical relevance. Preclinical studies using both cell lines and patient tumors grown in 3-dimensional in vitro and orthotopic in vivo preclinical models provide an efficient and highly relevant assessment of drug sensitivity in tumor phenotypes, and validate our genomic analyses. Together, our results show that high-throughput transcriptional profiling can significantly impact drug selection for breast cancer patients. Pre-identification of patient response may not only improve therapeutic response rates, it can also assist in quickly identifying the optimal inclusion criteria for clinical trials. Our model facilitates personalized drug therapy for cancer patients and may be generalized for study of drug efficacy in other diseases. Breast cancer pleural effusion samples from triple negative patients. Compared samples that are computationally predicted to be sensitive to valproic acid and those that are not predicted to be sensitive.
2011-06-01 | E-GEOD-18331 | biostudies-arrayexpress
Project description:In the rapidly advancing field of synthetic biology, there is a critical need for technology to discover targeting moieties for therapeutic biologics. We developed INSPIRE-seq, an approach that utilizes a nanobody library and next-generation sequencing to identify nanobodies selected for complex environments. INSPIRE-seq enables the parallel enrichment of immune cell-binding nanobodies that penetrate the tumor microenvironment. Clone enrichment and specificity varies across immune cell subtypes in the tumor, lymph node, and spleen. INSPIRE-seq identified a dendritic cell binding clone that binds PHB2. Single-cell RNA sequencing revealed a connection with cDC1s, and immunofluorescence confirmed nanobody-PHB2 colocalization along cell membranes. Structural modeling and docking studies assisted binding predictions and will guide nanobody selection. In this work, we demonstrate that INSPIRE-seq offers an unbiased approach to examine complex microenvironments and assist in the development of nanobodies, which could serve as active drugs, modified to become drugs, or used as targeting moieties.
2024-01-26 | PXD046363 | Pride
Project description:In recent years, there has been great progress in the understanding of tumor biology and its surrounding microenvironment. Solid tumors create regions with low oxygen levels, generally termed as hypoxic regions. These hypoxic areas offer a tremendous opportunity to develop targeted therapies. Hypoxia is not a random by-product of the cellular milieu due to uncontrolled tumor growth; rather it is a constantly evolving participant in overall tumor growth and fate. This article reviews current trends and recent advances in drug therapies and delivery systems targeting hypoxia in the tumor microenvironment. In the first part, we give an account of important physicochemical changes and signaling pathways activated in the hypoxic microenvironment. This is then followed by various treatment strategies including hypoxia-sensitive signaling pathways and approaches to develop hypoxia-targeted drug delivery systems.
| S-EPMC4947437 | biostudies-literature
Project description:Treating unselected cancer patients with new drugs dilutes proof of efficacy when only a fraction of patients respond to therapy. We conducted a meta-analysis on eight primary breast cancer microarray datasets representing diverse breast cancer phenotypes. We present a high-throughput protocol which incorporates drug sensitivity signatures to guide preclinical testing for effective therapeutic agents. Specifically, we focus on drug classes currently undergoing early phase clinical testing. Our genomic and experimental results suggest that the majority of basal-like breast cancers should respond to inhibitors of the phosphatidylinositol-3-kinase pathway, and that a relatively low toxicity histone deacetylase inhibitor, valproic acid, may target aggressive breast cancers. For a subset of drugs, prediction of sensitivity associates with tumor recurrence, suggesting clinical relevance. Preclinical studies using both cell lines and patient tumors grown in 3-dimensional in vitro and orthotopic in vivo preclinical models provide an efficient and highly relevant assessment of drug sensitivity in tumor phenotypes, and validate our genomic analyses. Together, our results show that high-throughput transcriptional profiling can significantly impact drug selection for breast cancer patients. Pre-identification of patient response may not only improve therapeutic response rates, it can also assist in quickly identifying the optimal inclusion criteria for clinical trials. Our model facilitates personalized drug therapy for cancer patients and may be generalized for study of drug efficacy in other diseases.
2011-06-01 | GSE18331 | GEO