Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Efficacy of RG7787, a next-generation mesothelin-targeted immunotoxin, against triple-negative breast and gastric cancers.

ABSTRACT: The RG7787 mesothelin-targeted recombinant immunotoxin (RIT) consists of an antibody fragment targeting mesothelin (MSLN) fused to a 24-kD fragment of Pseudomonas exotoxin A for cell killing. Compared with prior RITs, RG7787 has improved properties for clinical development including decreased nonspecific toxicity and immunogenicity and resistance to degradation by lysosomal proteases. MSLN is a cell surface glycoprotein highly expressed by many solid tumor malignancies. New reports have demonstrated that MSLN is expressed by a significant percentage of triple-negative breast and gastric cancer clinical specimens. Here, panels of triple-negative breast and gastric cancer cell lines were tested for surface MSLN expression, and for sensitivity to RG7787 in vitro and in animal models. RG7787 produced >95% cell killing of the HCC70 and SUM149 breast cancer cell lines in vitro with IC50 < 100 pmol/L. RG7787 was also effective against gastric cancer cell lines MKN28, MKN45, and MKN74 in vitro, with subnanomolar IC50s. In a nude mouse model, RG7787 treatment (2.5 mg/kg i.v. qod ×3-4) resulted in a statistically significant 41% decrease in volumes of HCC70 xenograft tumors (P < 0.0001) and an 18% decrease in MKN28 tumors (P < 0.0001). Pretreatment with paclitaxel (50 mg/kg i.p.) enhanced efficacy, producing 88% and 70% reduction in tumor volumes for HCC70 and MKN28, respectively, a statistically significant improvement over paclitaxel alone (P < 0.0001 for both). RG7787 merits clinical testing for triple-negative breast and gastric cancers.

SUBMITTER: Alewine C

PROVIDER: S-EPMC4221527 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Mesothelin-targeted immunotoxin RG7787 has synergistic anti-tumor activity when combined with taxanes.

Project description:Recombinant immunotoxins (RITs) are antibody-based therapeutics that carry a toxin payload. The RG7787 RIT targets the cancer antigen mesothelin to deliver a recombinantly-engineered, reduced immunogenicity variant of Pseudomonas exotoxin A (PE) to the cytosol where it inhibits protein synthesis. Here we demonstrate that maximal doses of RG7787 temporarily halt growth of pancreatic cancer tumor xenografts, similar to the approved drugs gemcitabine and nab-paclitaxel, however, combination of the RIT with nab-paclitaxel produces durable complete regressions in most mice. Synergy between taxane and anti-MSLN RITs has been previously demonstrated in mouse models, but direct interaction of the combination in cell culture was not observed. Here, we show that this favorable interaction occurs in cell culture, is dependent on the dose and duration of RG7787 exposure, requires the catalytically active PE, and still occurs with RIT targeting a non-MSLN surface antigen. Unexpectedly, the combination does not increase RG7787-mediated protein synthesis inhibition nor perturb downstream apoptotic markers of RIT-mediated killing, but does augment levels of acetylated tubulin, a marker of taxane activity. Taken together, these data suggest that PE increases cell sensitivity to taxane-mediated killing by increasing taxane-mediated microtubule stability and priming cells for apoptosis by decreasing levels of the pro-survival factor Mcl-1.

| S-EPMC5354724 | biostudies-literature

Efficacy of Anti-mesothelin Immunotoxin RG7787 plus Nab-Paclitaxel against Mesothelioma Patient-Derived Xenografts and Mesothelin as a Biomarker of Tumor Response.

Project description:Purpose: The purpose of this study was to evaluate the antitumor efficacy of the reduced immunogenicity anti-mesothelin immunotoxin RG7787 plus nab-paclitaxel against primary mesothelioma cell lines and tumor xenografts and the utility of mesothelin as a biomarker of tumor response.Experimental Design: Early-passage human malignant mesothelioma cell lines NCI-Meso16, NCI-Meso19, NCI-Meso21, and NCI-Meso29 were evaluated for sensitivity to RG7787 or nab-paclitaxel alone or in combination. In addition, the antitumor activity of RG7787 plus nab-paclitaxel was evaluated using NCI-Meso16, NCI-Meso21, and NCI-Meso29 tumor xenografts in immunodeficient mice. Serum mesothelin was measured at different time points to determine whether its levels correlated with tumor response.Results: All four primary mesothelioma cell lines highly expressed mesothelin with 41 × 103 to 346 × 103 mesothelin sites per cell and were sensitive to RG7787, with IC50 ranging from 0.3 to 10 ng/mL. Except for NCI-Meso19, these cells were also sensitive to nab-paclitaxel, with IC50 of 10 to 25 ng/mL. In vitro, RG7787 plus nab-paclitaxel led to decreased cell viability compared with either agent alone. In NCI-Meso16 tumor xenografts, treatment with RG7787 plus nab-paclitaxel led to sustained complete tumor regressions. Similar antitumor efficacy was observed against NCI-Meso21 and NCI-Meso29 tumor xenografts. In all three tumor xenograft models, changes in human serum mesothelin correlated with response to therapy and were undetectable in mice with complete tumor regression with RG7787 and nab-paclitaxel.Conclusions: RG7787 plus nab-paclitaxel is very active against primary human mesothelioma cells in vitro as well as in vivo, with serum mesothelin levels correlating with tumor response. These results indicate that this combination could be useful for treating patients with mesothelioma. Clin Cancer Res; 23(6); 1564-74. ©2016 AACR.

| S-EPMC5352557 | biostudies-literature

Genetic alterations of triple negative breast cancer by targeted next-generation sequencing and correlation with tumor morphology.

Project description:Triple negative breast cancer represents a heterogeneous group of breast carcinomas, both at the histologic and genetic level. Although recent molecular studies have comprehensively characterized the genetic landscape of these tumors, few have integrated a detailed histologic examination into the analysis. In this study, we defined the genetic alterations in 39 triple negative breast cancers using a high-depth targeted massively parallel sequencing assay and correlated the findings with a detailed morphologic analysis. We obtained representative frozen tissue of primary triple negative breast cancers from patients treated at our institution between 2002 and 2010. We characterized tumors according to their histologic subtype and morphologic features. DNA was extracted from paired frozen primary tumor and normal tissue samples and was subjected to a targeted massively parallel sequencing platform comprising 229 cancer-associated genes common across all experiments. The average number of non-synonymous mutations was 3 (range 0-10) per case. The most frequent somatic alterations were mutations in TP53 (74%) and PIK3CA (10%) and MYC amplifications (26%). Triple negative breast cancers with apocrine differentiation less frequently harbored TP53 mutations (25%) and MYC gains (0%), and displayed a high mutation frequency in PIK3CA and other PI3K signaling pathway-related genes (75%). Using a targeted massively parallel sequencing platform, we identified the key somatic genetic alterations previously reported in triple negative breast cancers. Furthermore, our findings show that triple negative breast cancers with apocrine differentiation constitute a distinct subset, characterized by a high frequency of PI3K pathway alterations similar to luminal subtypes of breast cancer.

| S-EPMC4848211 | biostudies-literature

Anticancer Effects of Mesothelin-Targeted Immunotoxin Therapy Are Regulated by Tyrosine Kinase DDR1.

Project description:Recombinant immunotoxins (RIT) have been highly successful in cancer therapy due, in part, to the high cancer-specific expression of cell surface antigens such as mesothelin, which is overexpressed in mesothelioma, ovarian, lung, breast, and pancreatic cancers, but is limited in normal cells. RG7787 is a clinically optimized RIT consisting of a humanized anti-mesothelin Fab fused to domain III of Pseudomonas exotoxin A, in which immunogenic B-cell epitopes are silenced. To enhance the therapeutic efficacy of RITs, we conducted a kinome RNAi sensitization screen, which identified discoidin domain receptor 1 (DDR1), a collagen-activated tyrosine kinase, as a potential target. The collagen/DDR1 axis is implicated in tumor-stromal interactions and potentially affects tumor response to therapy. Therefore, we investigated the effects of DDR1 on RIT. Knockdown of DDR1 by siRNA or treatment with inhibitor, 7rh, greatly enhanced the cytotoxic activity of RG7787 in several cancer cell lines. Investigation into the mechanism of action showed DDR1 silencing was associated with decreased expression of several ribosomal proteins and enhanced inhibition of protein synthesis. Conversely, induction of DDR1 expression or collagen-stimulated DDR1 activity protected cancer cells from RG7787 killing. Moreover, the combination of RG7787 and DDR1 inhibitor caused greater shrinkage of tumor xenografts than either agent alone. These data demonstrate that DDR1 is a key modulator of RIT activity and represents a novel therapeutic strategy to improve targeting of mesothelin-expressing cancers.

| S-EPMC4794364 | biostudies-literature

Using next-generation sequencing to redefine BRCAness in triple-negative breast cancer.

Project description:BRCAness is considered a predictive biomarker to platinum and poly(ADP-ribose) polymerase (PARP) inhibitors. However, recent trials showed that its predictive value was limited in triple-negative breast cancer (TNBC) treated with platinum. Moreover, tumors with mutations of DNA damage response (DDR) genes, such as homologous recombination (HR) genes, could be sensitive to platinum and PARP inhibitors. Thus, we aim to explore the relationship between mutation status of DDR genes and BRCAness in TNBC. We sequenced 56 DDR genes in 120 TNBC and identified BRCAness by array comparative genomic hybridization. The sequencing results showed that 13, 14, and 14 patients had BRCA, non-BRCA HR, and non-HR DDR gene mutations, respectively. Array comparative genomic hybridization revealed that BRCA-mutated and HR gene-mutated TNBC shared similar BRCAness features, both having higher numbers and longer length of large-scale structural aberration (LSA, >10 Mb) and similar altered chromosomal regions of LSA. These suggested non-BRCA HR gene-mutated TNBC shared similar characteristics with BRCA-mutated TNBC, indicating non-BRCA HR gene-mutated TNBC sensitive to platinum and PARP inhibitors. Among tumors with mutation of non-HR DDR genes, 3 PTEN and 1 MSH6 mutation also contained significant LSAs (BRCAness); however, they had different regions of genomic alteration to BRCA and HR gene-mutated tumors, might explain prior findings that PTEN- and MSH6-mutated cancer cells not sensitive to PARP inhibitors. Therefore, we hypothesize that the heterogeneous genomic background of BRCAness indicates different responsiveness to platinum and PARP inhibitors. Direct sequencing DDR genes in TNBC should be applied to predict their sensitivity toward platinum and PARP inhibitors.

| S-EPMC7156820 | biostudies-literature

Clinical Validation of Targeted Next Generation Sequencing for Colon and Lung Cancers.

Project description:Recently, Next Generation Sequencing (NGS) has begun to supplant other technologies for gene mutation testing that is now required for targeted therapies. However, transfer of NGS technology to clinical daily practice requires validation.We validated the Ion Torrent AmpliSeq Colon and Lung cancer panel interrogating 1850 hotspots in 22 genes using the Ion Torrent Personal Genome Machine. First, we used commercial reference standards that carry mutations at defined allelic frequency (AF). Then, 51 colorectal adenocarcinomas (CRC) and 39 non small cell lung carcinomas (NSCLC) were retrospectively analyzed.Sensitivity and accuracy for detecting variants at an AF >4% was 100% for commercial reference standards. Among the 90 cases, 89 (98.9%) were successfully sequenced. Among the 86 samples for which NGS and the reference test were both informative, 83 showed concordant results between NGS and the reference test; i.e. KRAS and BRAF for CRC and EGFR for NSCLC, with the 3 discordant cases each characterized by an AF <10%.Overall, the AmpliSeq colon/lung cancer panel was specific and sensitive for mutation analysis of gene panels and can be incorporated into clinical daily practice.

| S-EPMC4569137 | biostudies-literature

Next-Generation Sequencing Targeted Panel in Routine Care for Metastatic Colon Cancers.

Project description:In digestive oncology, the clinical impact of targeted next-generation sequencing (NGS) in routine practice should be addressed. In this work, we studied the impact of a 22-gene NGS amplicon-based panel with Ion Torrent Proton Sequencing, prospectively performed in routine practice. We analyzed the results of extended molecular testing, beyond RAS and BRAF, in metastatic colorectal cancer (mCRC) patients in a single-center, retrospective, observational study of consecutive mCRC patients followed up at the Georges Pompidou European Hospital between January 2016 and December 2018. Overall, 210 patients with mCRC were included. Median follow-up was 25.4 months (IQR: 14.9-39.5). The three most frequently mutated genes were: TP53 (63%), KRAS (41%) and PIK3CA (19%). A positive association was found between overall survival and performance status (PS) ≥ 2 (HR: 4.91 (1.84-13.1); p = 0.001) and differentiation (HR: 4.70 (1.51-14.6); p = 0.007) in multivariate analysis. The NGS panel enabled five patients to access a targeted therapy not currently registered for CRC. In conclusion, targeted NGS panels in mCRC are feasible in routine practice, but need to be regularly updated and in-depth studies are needed to better analyze the prognostic factors.

| S-EPMC8616114 | biostudies-literature

Revealing targeted therapeutic opportunities in triple-negative breast cancers: a new strategy.

Project description: Not available

| S-EPMC3899176 | biostudies-literature

Next Generation CD44v6-Specific CAR-NK Cells Effective against Triple Negative Breast Cancer.

Project description:There is a medical need to develop new and effective therapies against triple-negative breast cancer (TNBC). Chimeric antigen receptor (CAR) natural killer (NK) cells are a promising alternative to CAR-T cell therapy for cancer. A search for a suitable target in TNBC identified CD44v6, an adhesion molecule expressed in lymphomas, leukemias and solid tumors that is implicated in tumorigenesis and metastases. We have developed a next-generation CAR targeting CD44v6 that incorporates IL-15 superagonist and checkpoint inhibitor molecules. We could show that CD44v6 CAR-NK cells demonstrated effective cytotoxicity against TNBC in 3D spheroid models. The IL-15 superagonist was specifically released upon recognition of CD44v6 on TNBC and contributed to the cytotoxic attack. PD1 ligands are upregulated in TNBC and contribute to the immunosuppressive tumor microenvironment (TME). Competitive inhibition of PD1 neutralized inhibition by PD1 ligands expressed on TNBC. In total, CD44v6 CAR-NK cells are resistant to TME immunosuppression and offer a new therapeutic option for the treatment of BC, including TNBC.

| S-EPMC10218876 | biostudies-literature

Anti-Mesothelin Recombinant Immunotoxin Therapy for Colorectal Cancer.

Project description:BackgroundMesothelin (MSLN) is a cell surface glycoprotein expressed at a high level on many malignancies, including pancreatic adenocarcinoma, serous ovarian cancer, and epithelioid mesothelioma. MSLN-targeted recombinant immunotoxins (RITs) consist of an anti-MSLN Fv fused to the catalytic domain of Pseudomonas exotoxin A. Recent data has also shown that MSLN is expressed at clinically relevant levels on the surface of colorectal cancer (CRC). In this study, CRC cell lines were tested for MSLN expression and susceptibility to MSLN-targeted RITs.Materials and methodsCRC cell lines were tested for membranous MSLN expression via flow cytometry. Cell lines expressing MSLN were tested by WST-8 cell viability assay for sensitivity to various RITs and chemotherapeutic agents. CRC cell line SW-48 was tested in a mouse model for response to RIT as a single agent or in combination with actinomycin D and oxaliplatin.ResultsCRC cell lines were susceptible to anti-MSLN RITs at half maximal inhibitory concentration levels comparable with those previously described in pancreatic cancer cell lines. In a nude mouse model, MSLN-targeted RIT treatment of SW48 CRC tumors resulted in a significant decrease in tumor volume. Although combination therapy with standard of care chemotherapeutic oxaliplatin did not improve tumor regressions, combination therapy with actinomycin D resulted in > 90% tumor volume reduction with 50% complete regressions.ConclusionsThese data support the development of anti-MSLN RITs as well as other MSLN-targeted therapies for CRC.

| S-EPMC8317202 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data