Anti-Mesothelin Recombinant Immunotoxin Therapy for Colorectal Cancer

Cerise, Adam; Bera, Tapan K.; Liu, Xiufen; Jiang, Wei; Pastan, Ira

doi:10.1016/j.clcc.2019.06.006

Cited by 13 publications

(9 citation statements)

References 30 publications

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“…The cytotoxicity and antitumor effects of LMB-100 were verified on different cancer types including breast ( 126 ), gastric ( 126 ), lung ( 127 ), ovarian ( 128 ), and colorectal ( 129 ) cancers, as well as pancreatic ductal adenocarcinoma ( 130 – 133 ). Almost all cell lines corresponding to these malignancies were affected by LMB-100 at concentrations in the picomolar range (as low as 6.8 pmol/lit) ( 130 – 133 ).…”

Section: Pseudomonas Exotoxin Amentioning

confidence: 99%

“…However, although the treatment of xenograft models with LMB-100 alone resulted in some PRs and tumor regression, no cases of CR were reported ( 124 , 126 ). Therefore, LMB-100 was evaluated in combination with other chemotherapeutics, including taxanes (paclitaxel and nano-albumin bound (Nab)-paclitaxel) ( 126 – 128 , 130 , 134 ), platinum-based agents (cisplatin and oxaliplatin) ( 128 , 129 ), actinomycin D ( 129 , 135 ), and gemcitabine ( 134 ). Co-administration of LMB-100 with the taxanes enhanced the antitumor activity in a synergistic manner and even resulted in four CRs in gastric cancer (received paclitaxel) ( 126 ), as well as pancreatic cancer (received nab-paclitaxel) ( 134 ) xenografts.…”

Section: Pseudomonas Exotoxin Amentioning

confidence: 99%

“…Co-administration of LMB-100 with the taxanes enhanced the antitumor activity in a synergistic manner and even resulted in four CRs in gastric cancer (received paclitaxel) ( 126 ), as well as pancreatic cancer (received nab-paclitaxel) ( 134 ) xenografts. Likewise, actinomycin D co-administration synergistically potentiated the antitumor activity of LMB-100 in pancreatic ( 135 ) and colorectal ( 129 ) carcinoma xenografts and resulted in some CRs. Cisplatin co-administration in an ovarian xenograft model also enhanced antitumor activity of LMB-100, though in an additive manner and without any CRs ( 128 ).…”

Section: Pseudomonas Exotoxin Amentioning

confidence: 99%

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Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

2021

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Cancer is one of the prominent causes of death worldwide. Despite the existence of various modalities for cancer treatment, many types of cancer remain uncured or develop resistance to therapeutic strategies. Furthermore, almost all chemotherapeutics cause a range of side effects because they affect normal cells in addition to malignant cells. Therefore, the development of novel therapeutic agents that are targeted specifically toward cancer cells is indispensable. Immunotoxins (ITs) are a class of tumor cell-targeted fusion proteins consisting of both a targeting moiety and a toxic moiety. The targeting moiety is usually an antibody/antibody fragment or a ligand of the immune system that can bind an antigen or receptor that is only expressed or overexpressed by cancer cells but not normal cells. The toxic moiety is usually a protein toxin (or derivative) of animal, plant, insect, or bacterial origin. To date, three ITs have gained Food and Drug Administration (FDA) approval for human use, including denileukin diftitox (FDA approval: 1999), tagraxofusp (FDA approval: 2018), and moxetumomab pasudotox (FDA approval: 2018). All of these ITs take advantage of bacterial protein toxins. The toxic moiety of the first two ITs is a truncated form of diphtheria toxin, and the third is a derivative of Pseudomonas exotoxin (PE). There is a growing list of ITs using PE, or its derivatives, being evaluated preclinically or clinically. Here, we will review these ITs to highlight the advances in PE-based anticancer strategies, as well as review the targeting moieties that are used to reduce the non-specific destruction of non-cancerous cells. Although we tried to be as comprehensive as possible, we have limited our review to those ITs that have proceeded to clinical trials and are still under active clinical evaluation.

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Section: Pseudomonas Exotoxin Amentioning

confidence: 99%

Section: Pseudomonas Exotoxin Amentioning

confidence: 99%

Section: Pseudomonas Exotoxin Amentioning

confidence: 99%

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Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

2021

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“…More importantly, six DMPs of four genes may have transcription-affected, prognostic, and platinum-response predictive functions in HNSC and UCEC, including MSLN (cg10398993), PRKAR2B (cg00888463), MSX1 (cg00486340), and PARD6A (cg15426734, cg01573194, and cg16794070). MSLN, a glycoprotein on the cell surface, is overexpressed in many cancers and is relevant to novel anti-cancer treatment by regulating the tumor microenvironment ( Hilliard, 2018 ; Cerise et al, 2019 ). PRKAR2B plays a significant oncogenic and metastasis-promoting role in prostate cancer, especially in castration-resistant prostate cancers ( Sha et al, 2018 ; Xia et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Systematic Investigation of DNA Methylation Associated With Platinum Chemotherapy Resistance Across 13 Cancer Types

Sun

et al. 2021

Front. Pharmacol.

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Background: Platinum resistance poses a significant problem for oncology clinicians. As a result, the role of epigenetics and DNA methylation in platinum-based chemoresistance has gained increasing attention from researchers in recent years. A systematic investigation of aberrant methylation patterns related to platinum resistance across various cancer types is urgently needed.Methods: We analyzed the platinum chemotherapy response-related methylation patterns from different perspectives of 618 patients across 13 cancer types and integrated transcriptional and clinical data. Spearman’s test was used to evaluate the correlation between methylation and gene expression. Cox analysis, the Kaplan-Meier method, and log-rank tests were performed to identify potential risk biomarkers based on differentially methylated positions (DMPs) and compare survival based on DMP values. Support vector machines and receiver operating characteristic curves were used to identify the platinum-response predictive DMPs.Results: A total of 3,703 DMPs (p value < 0.001 and absolute delta beta >0.10) were identified, and the DMP numbers of each cancer type varied. A total of 39.83% of DMPs were hypermethylated and 60.17% were hypomethylated in platinum-resistant patients. Among them, 405 DMPs (Benjamini and Hochberg adjusted p value < 0.05) were found to be associated with prognosis in tumor patients treated with platinum-based regimens, and 664 DMPs displayed the potential to predict platinum chemotherapy response. In addition, we defined six DNA DMPs consisting of four gene members (mesothelin, protein kinase cAMP-dependent type II regulatory subunit beta, msh homeobox 1, and par-6 family cell polarity regulator alpha) that may have favorable prognostic and predictive values for platinum chemotherapy.Conclusion: The methylation-transcription axis exists and participates in the complex biological mechanism of platinum resistance in various cancers. Six DMPs and four associated genes may have the potential to serve as promising epigenetic biomarkers for platinum-based chemotherapy and guide clinical selection of optimal treatment.

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“…LMB-100 is currently in Phase I/II trials in patients with mesothelioma, cholangiocarcinoma and pancreatic adenocarcinoma; however, the potential of mesothelin-targeted ITX in CRC has been overlooked. In a recent study, the sensitivity of CRC lines to LMB-100 in vitro was found to be similar to that of pancreatic adenocarcinoma cells [ 136 ]. Moreover, there was a significant delay in tumor growth in mice bearing CRC xenografts treated with LMB-100 as monotherapy and 50% complete regression in mice receiving combination treatment with Actinomycin D.…”

Section: Antibody Fragment-based Immunotoxins In Crc: Preclinical Developmentsmentioning

confidence: 99%

Antibody-Based Immunotoxins for Colorectal Cancer Therapy

et al. 2021

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Monoclonal antibodies (mAbs) are included among the treatment options for advanced colorectal cancer (CRC). However, while these mAbs effectively target cancer cells, they may have limited clinical activity. A strategy to improve their therapeutic potential is arming them with a toxic payload. Immunotoxins (ITX) combining the cell-killing ability of a toxin with the specificity of a mAb constitute a promising strategy for CRC therapy. However, several important challenges in optimizing ITX remain, including suboptimal pharmacokinetics and especially the immunogenicity of the toxin moiety. Nonetheless, ongoing research is working to solve these limitations and expand CRC patients’ therapeutic armory. In this review, we provide a comprehensive overview of targets and toxins employed in the design of ITX for CRC and highlight a wide selection of ITX tested in CRC patients as well as preclinical candidates.

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Anti-Mesothelin Recombinant Immunotoxin Therapy for Colorectal Cancer

Cited by 13 publications

References 30 publications

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

Systematic Investigation of DNA Methylation Associated With Platinum Chemotherapy Resistance Across 13 Cancer Types

Antibody-Based Immunotoxins for Colorectal Cancer Therapy

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