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PDF file - 180K, Table S1. Genes in the VDV signature, ordered by anti-VEGF response in human IBC trial. Table S2. Gene Ontology terms over-represented in VDV signature. Table S3. Summary of tumors models tested.

PDF file - 233K, Fig S4A. Validation and application of a compacted 22-gene VDV subset in human clinical samples. Fig S4B and C. Stratification of NO16966 patients by VEGF and CD31 expression levels.

Supplementary Fig. S1 from Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake

PDF file - 154K, Fig S5. Most proxVDV genes are not obviously up-regulated by rVEGF in vitro.

Supplementary Table S1 from Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake

Supplementary Table S3 from Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake

PDF file - 83K, Fig S6. Effect of VDV gene expression and bevacizumab treatment in OS.

The insulin-like growth factor (IGF) system consists of two ligands (IGF-I and IGF-II), which both signal through IGF-I receptor (IGF-IR) to stimulate proliferation and inhibit apoptosis, with activity contributing to malignant growth of many types of human cancers. We have developed a humanized, affinity-matured anti-human IGF-IR monoclonal antibody (h10H5), which binds with high affinity and specificity to the extracellular domain. h10H5 inhibits IGF-IR-mediated signaling by blocking IGF-I and IGF-II binding and by inducing cell surface receptor down-regulation via internalization and degradation, with the extracellular and intracellular domains of IGF-IR being differentially affected by the proteasomal and lysosomal inhibitors. In vitro, h10H5 exhibits antiproliferative effects on cancer cell lines. In vivo, h10H5 shows single-agent antitumor efficacy in human SK-N-AS neuroblastoma and SW527 breast cancer xenograft models and even greater efficacy in combination with the chemotherapeutic agent docetaxel or an anti–vascular endothelial growth factor antibody. Antitumor activity of h10H5 is associated with decreased AKT activation and glucose uptake and a 316-gene transcription profile with significant changes involving DNA metabolic and cell cycle machineries. These data support the clinical testing of h10H5 as a biotherapeutic for IGF-IR-dependent human tumors and furthermore illustrate a new method of monitoring its activity noninvasively in vivo via 2-fluoro-2-deoxy-d-glucose-positron emission tomography imaging. [Mol Cancer Ther 2008;7(9):2599–608]

PDF file - 113K, Fig S1. Kinetics of anti-VEGF effects on proliferation (ki67) and tumor burden in the RIP-TβAg model.

Supplementary Fig. S2 from Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake

Purpose: The aim of this study was to identify conserved pharmacodynamic and potential predictive biomarkers of response to anti-VEGF therapy using gene expression profiling in preclinical tumor models and in patients.Experimental Design: Surrogate markers of VEGF inhibition [VEGF-dependent genes or VEGF-dependent vasculature (VDV)] were identified by profiling gene expression changes induced in response to VEGF blockade in preclinical tumor models and in human biopsies from patients treated with anti-VEGF monoclonal antibodies. The potential value of VDV genes as candidate predictive biomarkers was tested by correlating high or low VDV gene expression levels in pretreatment clinical samples with the subsequent clinical efficacy of bevacizumab (anti-VEGF)-containing therapy.Results: We show that VDV genes, including direct and more distal VEGF downstream endothelial targets, enable detection of VEGF signaling inhibition in mouse tumor models and human tumor biopsies. Retrospective analyses of clinical trial data indicate that patients with higher VDV expression in pretreatment tumor samples exhibited improved clinical outcome when treated with bevacizumab-containing therapies.Conclusions: In this work, we identified surrogate markers (VDV genes) for in vivo VEGF signaling in tumors and showed clinical data supporting a correlation between pretreatment VEGF bioactivity and the subsequent efficacy of anti-VEGF therapy. We propose that VDV genes are candidate biomarkers with the potential to aid the selection of novel indications as well as patients likely to respond to anti-VEGF therapy. The data presented here define a diagnostic biomarker hypothesis based on translational research that warrants further evaluation in additional retrospective and prospective trials. Clin Cancer Res; 19(13); 3681–92. ©2013 AACR.

PDF file - 63K, Fig S3. Enrichment of VDV markers Tumor-Associated Endothelial Cells.

PDF file - 708K, Fig S2A. Histological evidence for the in vivo activity of VEGF pathway inhibitors in MDA-MB-231 tumors. Fig S2B. In vivo VEGF blockade or VEGFR-2 downstream signaling inhibition induces consistent downregulation of proxVDV genes. Fig S2C. The proxVDV gene ESM1 is an in vivo VEGF target specifically expressed in tumor-associated vasculature

Supplementary Fig. S3 from Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake

Supplementary Figure 1 from Antibody-Drug Conjugates for the Treatment of Non–Hodgkin's Lymphoma: Target and Linker-Drug Selection

PDF file - 95K

Antibody-drug conjugates (ADC), potent cytotoxic drugs covalently linked to antibodies via chemical linkers, provide a means to increase the effectiveness of chemotherapy by targeting the drug to neoplastic cells while reducing side effects. Here, we systematically examine the potential targets and linker-drug combinations that could provide an optimal ADC for the treatment for non–Hodgkin's lymphoma. We identified seven antigens (CD19, CD20, CD21, CD22, CD72, CD79b, and CD180) for potential treatment of non–Hodgkin's lymphoma with ADCs. ADCs with cleavable linkers mediated in vivo efficacy via all these targets; ADCs with uncleavable linkers were only effective when targeted to CD22 and CD79b. In target-independent safety studies in rats, the uncleavable linker ADCs showed reduced toxicity, presumably due to the reduced release of free drug or other toxic metabolites into the circulation. Thus, our data suggest that ADCs with cleavable linkers work on a broad range of targets, and for specific targets, ADCs with uncleavable linkers provide a promising opportunity to improve the therapeutic window for ADCs in humans. [Cancer Res 2009;69(6):2358–64]

Supplementary Table 1 from Antibody-Drug Conjugates for the Treatment of Non–Hodgkin's Lymphoma: Target and Linker-Drug Selection

PDF file - 6626K, Validation of IHC antibody specificity for LDHB, LDHA, MCT1, and MCT4

PDF file - 963K, Additional top targets from RNAi screen that are specifically required for triple negative breast cancer

Supplementary Figure Legend from Antibody-Drug Conjugates for the Treatment of Non–Hodgkin's Lymphoma: Target and Linker-Drug Selection

XLSX file - 25K, RNAi optimization and screening conditions

XLSX file - 59K, Genes that comprise the glycolysis and oxidative phosphorylation gene signatures

PDF file - 663K, Glycolysis signature genes that correlate to LDHB expression in basal-like tumors

PDF file - 257K, Animal weight change and tumor volume of individual xenograft tumors

PDF file - 791K, mRNA expression profiles of lactate dehydrogenase enzymes in breast cancer subtypes

XLSX file - 31K, Results from the RNAi screen and identification of hits

Purpose: The aim of this study was to identify conserved pharmacodynamic and potential predictive biomarkers of response to anti-VEGF therapy using gene expression profiling in preclinical tumor models and in patients. Experimental Design: Surrogate markers of VEGF inhibition [VEGF-dependent genes or VEGF-dependent vasculature (VDV)] were identified by profiling gene expression changes induced in response to VEGF blockade in preclinical tumor models and in human biopsies from patients treated with anti-VEGF monoclonal antibodies. The potential value of VDV genes as candidate predictive biomarkers was tested by correlating high or low VDV gene expression levels in pretreatment clinical samples with the subsequent clinical efficacy of bevacizumab (anti-VEGF)-containing therapy. Results: We show that VDV genes, including direct and more distal VEGF downstream endothelial targets, enable detection of VEGF signaling inhibition in mouse tumor models and human tumor biopsies. Retrospective analyses of clinical trial data indicate that patients with higher VDV expression in pretreatment tumor samples exhibited improved clinical outcome when treated with bevacizumab-containing therapies. Conclusions: In this work, we identified surrogate markers (VDV genes) for in vivo VEGF signaling in tumors and showed clinical data supporting a correlation between pretreatment VEGF bioactivity and the subsequent efficacy of anti-VEGF therapy. We propose that VDV genes are candidate biomarkers with the potential to aid the selection of novel indications as well as patients likely to respond to anti-VEGF therapy. The data presented here define a diagnostic biomarker hypothesis based on translational research that warrants further evaluation in additional retrospective and prospective trials. Clin Cancer Res; 19(13); 3681–92. ©2013 AACR.

Among Breast Cancer (BC) classification, Triple-Negative (TN) form is the most aggressive, lacking efficient and specific treatment. Our project aims at investigating the possibility to convert TNBC tumor cell lines in Estrogen Receptor (ER), Progesterone Receptor (PR) and/or Human Epidermal growth factor Receptor 2 (HER2)-positive cells using various modalities (siRNA, CRISPR-Cas9, small molecules). Our approach consists in optimizing a multi-parametric High-Content Screening (HCS) relying on phenotypic read-outs such as expression of TNBC positive and negative markers, cell behavior and viability. This poster will present our initial results, validation and future plans. This thesis project fits within a context of drug discovery, innovation, comparison of technologies and understanding of key biological processes and pathways, carried out in partnership between Servier Research Institute and Institut Curie. Citation Format: Albane Gaudeau, Véronique Lamamy, Anne-Laure Jaskowiak, Xavier Scerri, Benjamin Chanrion, Thierry Dorval, Elaine Del Nery, Franck Perez, Jacques Camonis, Jean-Philippe Stéphan. Investigation of triple-negative breast cancer tumor conversion through high-content screening approaches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1487.

Spliceosome coordinated RNA splicing is an essential cellular process that can generate an immensely diverse repertoire of RNA. While cancer cells have been known to hijack this process to generate splice forms with oncogenic function, the specific role of spliceosome components in this process is not well understood. In this study, we use an integrative genomic approach to identify PRPF6, a member of the tri-snRNP spliceosome complex as essential for colon cancer growth. We show that, in addition to PRPF6, other tri-snRNP components are coordinately overexpressed or amplified in cancer cells. Inhibition of the tri-snRNP complex, but not other spliceosome components, abrogated cancer cell growth only in dependent cancer cell lines in vitro and in vivo. High resolution transcriptome analysis reveals that the tri-snRNP complex binds and regulates the splicing of a relatively small number of genes, many of which are transcriptional targets of the c-MYC oncogene. Intriguingly, many components of the tri-snRNP complex are mutated in a genetic form of Retinitis Pigmentosa. This genetic corollary suggests that the tri-snRNP complex is necessary in specific cellular contexts that may depend on the proper transcription and splicing of a tri-snRNP regulated set of genes. Citation Format: Adam Adler, Zhaoshi Jiang, Mark McCleland, Elizabeth Blackwood, Sharon Yee, Benjamin Haley, Jean-Philippe Stephan, Sofia Hussain, Vivek Chopra, Ron Firestein. The tri-snRNP spliceosome complex is required for MYC-dependent cancer growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3203. doi:10.1158/1538-7445.AM2013-3203 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.