Copanlisib Microarray Data
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE243865 | GEO | 2024/04/26
REPOSITORIES: GEO
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Project description:Both the PI3K/AKT/mTOR and androgen receptor (AR) signaling pathways play essential roles in prostate cancer. We compared the impact of PI3K/AKT/mTOR pathway inhibitors with different selectivity profiles on in vitro cell proliferation and apoptosis induction, and observed the strongest effects in androgen-sensitive prostate cancer models. Combination treatment with the AR inhibitor darolutamide led to enhanced apoptosis in these cell lines, with most pronounced effects of the pan-PI3K inhibitor copanlisib. Transcriptomic analysis performed in the androgen-sensitive VCaP cell line revealed that gene expression was more affected by the co-treatment with darolutamide and copanlisib, compared to single agents. A comprehensive reversal of the androgen response and the mTORC1 transcriptional programs was observed. The combination treatment also markedly induced DNA damage. An in vivo efficacy study performed using LuCaP 35, an androgen-sensitive patient-derived prostate cancer model, indicated superior efficacy after combined treatment with copanlisib and darolutamide. Immunohistochemistry analysis of treated tumors furthermore showed increased apoptosis. Altogether these data demonstrate that blocking the PI3K/AKT/mTOR and AR pathways with potent inhibitors has superior anti-tumor efficacy and induces apoptosis in androgen-sensitive prostate cancer models.
2024-01-22 | GSE245454 | GEO
Project description:Drug tolerant persister (DTP) cells enter into a reversible slow-cycling state after cancer drug treatment. These cells are the living proof of response to a drug, and an interesting experimental subject for biomarker discovery. Here, we performed proteomic characterization of the breast cancer (BC) DTP cell secretome after eribulin treatment. First, we showed that eribulin induces a specific secretome in DTP cells as compared to other microtubule targeting agents. Then, we selected and functionally validated growth differentiation factor 15 (GDF15) as a protein significantly over-secreted upon eribulin treatment. Interestingly, GDF15 expression is low/absent in cells that are sensitive to eribulin, strongly upregulated during the response to the drug, and downregulated when stable resistance is ultimately established. Proteomic results were confirmed in 3D-cell culture models using BC cells lines and PDXs, as well as in a TNBC in vivo model. Unexpectedly, despite its biomarker potential for eribulin response, we found that GDF15 is also paradoxically required for survival of DTP cells, although once full resistance to eribulin is established, GDF15 expression largely disappears. Direct participation of GDF15 and its receptor GFRAL in eribulin-induction of DTPs was established by the enhanced cell killing of DTPs by eribulin seen under GDF15 and GFRAL loss of function conditions. These results pointed to a potential benefit of simultaneous targeting of GDF15/GFRAL and eribulin, and indeed we showed that combination therapy of eribulin plus an anti-GDF15 antibody kills BC-DTP cells. Our results suggest that targeting GDF15 may help eradicate DTP cells and block the onset of acquired eribulin resistance, and possibly other cytotoxic drugs. Overall, the combination of cytotoxic agents with targeted agents aimed specifically at DTP cells could be an effective therapeutic approach for metastatic breast cancer patients.
2023-01-09 | PXD034037 | Pride
Project description:The PI3K pathway is a major driver of cancer progression. However, clinical resistance to PI3K inhibition is common. IBL-302 is a novel highly specific triple PIM, PI3K and mTOR inhibitor. Screening IBL-302 in over 700 cell lines representing 47 tumor types identified neuroblastoma as a strong candidate for PIM/PI3K/mTOR inhibition. IBL-302 was more effective than single PI3K inhibition in vitro and IBL-302 treatment of neuroblastoma patient-derived xenograft (PDX) cells induced apoptosis, differentiated tumor cells, and decreased N-Myc protein levels. IBL-302 further enhanced the effect of the common cytotoxic chemotherapies cisplatin, doxorubicin, and etoposide. Global genome, proteome and phospho-proteome analyses identified crucial biological processes, including cell motility and apoptosis, targeted by IBL-302 treatment. While IBL-302 treatment alone reduced tumor growth in vivo, combination therapy with low-dose cisplatin inhibited neuroblastoma PDX growth. Complementing conventional chemotherapy treatment with PIM/PI3K/mTOR inhibition has the potential to improve clinical outcomes and reduce severe late effects in children with high-risk neuroblastoma.
2019-07-11 | PXD014234 | Pride
Project description:Triple-negative breast cancer (TNBC) is an aggressive disease subtype with limited treatment options. Eribulin is a chemotherapeutic approved for the treatment of advanced breast cancer that has been shown to elicit epigenetic changes. We investigated the effect of eribulin treatment on genome-scale DNA methylation patterns in TNBC cells. Following repeated treatment, The results showed that eribulin-induced changes in DNA methylation patterns evident in persister cells. Eribulin also affected the binding of transcription factors to genomic ZEB1 binding sites and regulated several cellular pathways, including ERBB and VEGF signaling and cell adhesion. Eribulin also altered the expression of epigenetic modifiers including DNMT1, TET1, and DNMT3A/B in persister cells. Data from primary human TNBC tumors supported these findings: DNMT1 and DNMT3A levels were altered by eribulin treatment in human primary TNBC tumors. Our results suggest that eribulin modulates DNA methylation patterns in TNBC cells by altering the expression of epigenetic modifiers. These findings have clinical implications for using eribulin as a therapeutic agent.
2023-12-31 | GSE234881 | GEO
Project description:Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer, with approximately 50% of patients having residual disease after neoadjuvant chemotherapy (NACT) and worse prognosis with higher residual cancer burden (RCB). Patient-derived xenograft (PDX) models of breast cancer are an effective discovery platform and tool for preclinical pharmacologic testing and biomarker identification. There is a need for PDX models encompassing the heterogeneity of TNBC both pre- and post- therapy and for identifying clinical and molecular features of patient’s tumors that are associated with success in establishing these models. Using fine-needle aspirates (FNAs), we established orthotopic PDX models of TNBC from the primary breast tumors of patients prior to and following neoadjuvant systemic therapy while enrolled in the ARTEMIS trial (NCT02276443). ARTEMIS is a prospective neoadjuvant clinical trial for women with primary TNBC who are treated with four cycles of Adriamycin combined with cyclophosphamide (AC) followed by taxane +/- different experimental therapies. Serial biopsies were obtained from patients prior to treatment (pre-therapy), from poorly responsive disease after four cycles of AC (mid-NACT), and in cases of AC-resistance, after a three-month course of different experimental therapies and/or additional chemotherapy (post-NACT). Our study cohort includes a total of 269 FNA biopsies from 217 women, generating a total of 62 successful PDX models (overall success-rate = 23%). This cohort includes five serial pre- and mid-NACT PDX pairs, as well as one serial pre-, mid-, post-NACT triplet. Success of PDX engraftment was generally higher from cancers that proved to be treatment-resistant: whether poor response to AC determined by ultrasound measurements mid-NACT (p=0.063), RCB II/III status after NACT (p=0.046), or metastatic relapse within two years of surgery (p=0.008). TNBC molecular subtype determined from gene expression microarrays of pre-NACT tumor revealed no significant association with PDX engraftment rate (p=0.877). Finally, we developed a statistical model predictive of PDX engraftment using percent Ki67 positive cells in the patient’s diagnostic biopsy, positive lymph node status at diagnosis, and low volumetric reduction of the patient’s tumor following AC treatment. This novel bank of 62 PDX models of TNBC provides a valuable resource for biomarker discovery and preclinical therapeutic trials aimed at improving neoadjuvant response rates for patients with TNBC.
2023-01-12 | GSE216333 | GEO
Project description:The purpose of this study is to examine the efficacy of combined PI3K and CDK4/6 inhibition in lung squamous cell carcinoma (LUSC). LUSC patient-derived xenografts (PDX) are used as preclinical models for this study as they are clinically relevant models and have been shown to recapitulate patient tumor hisology, molecular features and drug response. We have demonstrated using the 1x1x1 drug design that PIK3CA mutation predicts response to PI3K inhibitors. This response can be enhanced by combining CDK4/6 inhibitors with PI3K inhibitors, particularly in PIK3CA mutant PDX. PI3K and CDK4/6 inhibitors may be used in combination in PI3K-activated LUSC.
2019-06-18 | GSE109679 | GEO
Project description:Here we quantified tyrosine phosphorylation (pTyr) mediated signaling networks in chemotherapy sensitive (CS) and resistant (CR) TNBC patient derived xenografts (PDX) to gain novel therapeutic insights. We identified Src Family Kinases (SFKs) as potential therapeutic targets in CR TNBC PDXs. Additionally, we performed pTyr analysis on tumor specimens derived from TNBC patients and observed lower prevalence of SFK driven tumors.
2022-10-13 | PXD034154 | Pride
Project description:An estimated 284,000 Americans will be diagnosed with breast cancer in 2021. Of these individuals, 15-20% will be diagnosed with basal-like triple-negative breast cancer (TNBC), which is known to be highly metastatic. Chemotherapy is standard of care for TNBC patients, but acquired chemoresistance is a common clinical problem. There is currently a lack of alternative, targeted treatment strategies for TNBC; this study sought to identify novel therapeutic combinations to treat basal-like TNBCs. For these studies, a set of four human basal-like TNBC cell lines was utilized to determine the cytotoxicity profile of 1,363 unique clinically-used drugs. Ten promising therapeutic candidates were identified, and synergism studies were performed in vitro. Two drug combinations that included KPT-330, an XPO1 inhibitor, were synergistic in all four cell lines. In vivo testing of four basal-like patient-derived xenografts identified a combination, KPT-330 and GSK2126458 (a PI3K/mTOR inhibitor), that decreased tumor burden in mice significantly more than monotherapy with either single agent. Bulk and single-cell RNA-sequencing, immunohistochemical studies, and analysis of published genomic datasets found that XPO1 was abundantly expressed in human basal-like TNBC cell lines, patient-derived xenografts, and patient tumor samples; within basal-like patients, XPO1 overexpression was associated with greater rates of metastases. These studies identify a promising new combination therapy for patients with basal-like TNBC.
2021-10-20 | GSE174391 | GEO
Project description:Disseminated triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options beyond chemotherapy. Therefore, identification of druggable vulnerabilities is a mind aim. Protein kinases play a central role in cancer and particularly in TNBC. They are involved in many oncogenic functions including migration, proliferation, genetic stability or maintenance of stem-cell like properties. In this article we describe a novel multi-kinase inhibitor with antitumor activity in this cancer subtype. EC-70124 is a hybrid indolocarbazole analog obtained by combinatorial biosynthesis of Rebeccamycin and Staurosporine genes that showed antiproliferative effect and in vivo antitumoral activity. Biochemical experiments demonstrated the inhibition of the PI3K/mTOR and JAK/STAT pathways. EC-70124 mediated DNA damage leading to cell cycle arrest at the G2/M phase. Gene set enrichment analyses identified several deregulated functions including cell proliferation, migration, DNA damage, regulation of stem cell differentiation and reversion of the epithelial-mesenchymal transition (EMT) phenotype, among others. Combination studies showed a synergistic interaction of EC-70124 with docetaxel, and an enhanced activity in vivo. Furthermore, EC-70124 had a good pharmacokinetic profile. In conclusion these experiments demonstrate the antitumor activity of EC-70124 in TNBC paving the way for the future clinical development of this drug alone or in combination with chemotherapy.
2015-12-01 | GSE70115 | GEO
Project description:Aberrant activation of PI3K pathway is frequently observed in triple negative breast cancer (TNBC). However single agent PI3K inhibitors have shown limited anti-tumor activity. To investigate biomarkers of response and resistance mechanisms, we tested 17 TNBC patient-derived xenograft (PDX) models representing diverse genomic backgrounds and varying degrees of PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor BKM120. Baseline and post-treatment PDX tumors harvested following 3 days of BKM120 or vehicle administration were subjected to reverse phase protein array (RPPA) to identify protein markers associated with tumor growth response. While BKM120 consistently reduced PI3K pathway activity, as demonstrated by reduced levels of phosphorylated AKT, percentage tumor growth inhibition (%TGI) ranged from 35% in the least sensitive to 84% in the most sensitive PDX model at the completion of approximately 3-4 weeks of treatment. Several biomarkers showed significant association with resistance, including elevated baseline levels of growth factor receptors (EGFR, pHER3 Y1197), PI3Kp85 regulatory subunit, anti-apoptotic protein BclXL, EMT (Vimentin, MMP9, IntegrinaV), NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4, as well as treatment-induced increase in the levels of phosphorylated forms of Aurora kinases. Sensitivity to BKM120 was associated with higher baseline levels of proapoptotic markers (Bak and Caspase 3) and a greater number of markers differentially changed following BKM120 therapy. Interestingly, markers indicating PI3K pathway signaling activation or PTEN loss at baseline were not significantly correlated to %TGI. These results provide important insights into biomarker development for PI3K inhibitors in TNBC.
2021-01-27 | GSE149720 | GEO