Anti-glypican-1 antibody–drug conjugate is a potential therapy against pancreatic cancer

Nishigaki, Takahiko; Takahashi, Tsuyoshi; Serada, Satoshi; Fujimoto, Minoru; Ohkawara, Tomoharu; Hara, Hisashi; Sugase, Takahito; Otsuru, Toru; Saito, Yuya; Tsujii, Shigehiro; Nomura, Taisei; Miyazaki, Yasuhiro; Makino, Tomoki; Kurokawa, Yukinori; Nakajima, Kiyokazu; Eguchi, Hidetoshi; Yamasaki, Makoto; Mori, Masaki; Doki, Yuichiro; Naka, Tetsuji

doi:10.1038/s41416-020-0781-2

Cited by 31 publications

(34 citation statements)

References 32 publications

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“…MLN0624 conjugates anti-guanylyl cyclase C to MMAE, and it is reported to have a limited benefit for patients with PDAC [ 183 ]. A glypican-1 antibody has been conjugated to monomethyl auristatin F (MMAF) and significantly inhibits the growth of xenografts derived from patients with PDAC [ 184 ]. Anetumab ravtansine conjugates an anti-mesothelin antibody to the tubulin inhibitor DM4, and it exhibited great tolerance in a phase I trial and warrants future investigation [ 185 ].…”

Section: The Immunosuppressive Microenvironment and Immunotherapy In mentioning

confidence: 99%

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is a malignancy characterized by a poor prognosis and high mortality rate. Genetic mutations and altered molecular pathways serve as targets in precise therapy. Using next-generation sequencing (NGS), these aberrant alterations can be identified and used to develop strategies that will selectively kill cancerous cells in patients with PDAC. The realization of targeted therapies in patients with PDAC may be summarized by three approaches. First, because oncogenes play a pivotal role in tumorigenesis, inhibition of dysregulated oncogenes is a promising method (Table 3). Numerous researchers are developing strategies to target oncogenes, such as KRAS, NRG1, and NTRK and related molecules, although most of the results are unsatisfactory. Accordingly, emerging strategies are being developed to target these oncogenes, including simultaneously inhibiting multiple molecules or pathways, modification of mutant residues by small molecules, and RNA interference. Second, researchers have attempted to reactivate inactivated tumour suppressors or modulate related molecules. TP53, CDKN2A and SMAD4 are three major tumour suppressors involved in PDAC. Advances have been achieved in clinical and preclinical trials of therapies targeting these three genes, and further investigations are warranted. The TGF-β-SMAD4 signalling pathway plays a dual role in PDAC tumorigenesis and participates in mediating tumour-stroma crosstalk and modulating the tumour microenvironment (TME); thus, molecular subtyping of pancreatic cancer according to the SMAD4 mutation status may be a promising precision oncology technique. Finally, genes such as KDM6A and BRCA have vital roles in maintaining the structural stability and physiological functions of normal chromosomes and are deficient in some patients with PDAC, thus serving as potential targets for correcting these deficiencies and precisely killing these aberrant tumour cells. Recent clinical trials, such as the POLO (Pancreas Cancer Olaparib Ongoing) trial, have reported encouraging outcomes. In addition to genetic event-guided treatment, immunotherapies such as chimeric antigen receptor T cells (CAR-T), antibody-drug conjugates, and immune checkpoint inhibitors also exhibit the potential to target tumours precisely, although the clinical value of immunotherapies as treatments for PDAC is still limited. In this review, we focus on recent preclinical and clinical advances in therapies targeting aberrant genes and pathways and predict the future trend of precision oncology for PDAC.

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Section: The Immunosuppressive Microenvironment and Immunotherapy In mentioning

confidence: 99%

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

et al. 2020

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“…The same group developed a different GPC1-ADC, also conjugated to MMAF, which showed tumor growth inhibition in patient-derived tumor models of pancreatic cancer. 154 …”

Section: Part B: the Role Of The Glycocalyx In Vascular Related Diseamentioning

confidence: 99%

The Glycocalyx and Its Role in Vascular Physiology and Vascular Related Diseases

Weinbaum

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et al. 2020

Cardiovasc Eng Tech

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Purpose In 2007 the two senior authors wrote a review on the structure and function of the endothelial glycocalyx layer (Weinbaum in Annu Rev Biomed Eng 9:121–167, 2007). Since then there has been an explosion of interest in this hydrated gel-like structure that coats the luminal surface of endothelial cells that line our vasculature due to its important functions in (A) basic vascular physiology and (B) vascular related diseases. This review will highlight the major advances that have occurred since our 2007 paper. Methods A literature search mainly focusing on the role of the glycocalyx in the two major areas described above was performed using electronic databases. Results In part (A) of this review, the new formulation of the century old Starling principle, now referred to as the Michel–Weinbaum glycoclayx model or revised Starling hypothesis, is described including new subtleties and physiological ramifications. New insights into mechanotransduction and release of nitric oxide due to fluid shear stress sensed by the glycocalyx are elaborated. Major advances in understanding the organization and function of glycocalyx components, and new techniques for measuring both its thickness and spatio-chemical organization based on super resolution, stochastic optical reconstruction microscopy (STORM) are presented. As discussed in part (B) of this review, it is now recognized that artery wall stiffness associated with hypertension and aging induces glycocalyx degradation, endothelial dysfunction and vascular disease. In addition to atherosclerosis and cardiovascular diseases, the glycocalyx plays an important role in lifestyle related diseases (e.g., diabetes) and cancer. Infectious diseases including sepsis, Dengue, Zika and Corona viruses, and malaria also involve the glycocalyx. Because of increasing recognition of the role of the glycocalyx in a wide range of diseases, there has been a vigorous search for methods to protect the glycocalyx from degradation or to enhance its synthesis in disease environments. Conclusion As we have seen in this review, many important developments in our basic understanding of GCX structure, function and role in diseases have been described since the 2007 paper. The future is wide open for continued GCX research.

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“…Moreover, in vivo, naked and conjugated versions of anti-tissue factor mAbs have shown significant antitumour activity in mouse models [ 33 , 34 , 35 , 36 ]. Similarly, treatment with mAbs targeting podocalyxin [ 37 ], HER2 [ 38 ], glypican-1 [ 39 ], cell surface plectin 1 [ 40 ], galectin-9 [ 41 ], RON [ 42 ], BAG3 [ 43 ], CLDN18.2 [ 44 ], mesothelin [ 45 ], vimentin [ 46 ] and doublecortin-like kinase 1 [ 47 ] inhibited the growth of pancreatic tumours in xenograft models. On the other hand, mAbs have also been studied as platforms for cancer theranostics (i.e., a combination of diagnostics and therapeutic) in several animal models [ 48 ].…”

Section: Preclinical Studiesmentioning

confidence: 99%

Therapeutic Application of Monoclonal Antibodies in Pancreatic Cancer: Advances, Challenges and Future Opportunities

Arias-Pinilla

Modjtahedi

2021

Cancers

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Pancreatic cancer remains as one of the most aggressive cancer types. In the absence of reliable biomarkers for its early detection and more effective therapeutic interventions, pancreatic cancer is projected to become the second leading cause of cancer death in the Western world in the next decade. Therefore, it is essential to discover novel therapeutic targets and to develop more effective and pancreatic cancer-specific therapeutic agents. To date, 45 monoclonal antibodies (mAbs) have been approved for the treatment of patients with a wide range of cancers; however, none has yet been approved for pancreatic cancer. In this comprehensive review, we discuss the FDA approved anticancer mAb-based drugs, the results of preclinical studies and clinical trials with mAbs in pancreatic cancer and the factors contributing to the poor response to antibody therapy (e.g. tumour heterogeneity, desmoplastic stroma). MAb technology is an excellent tool for studying the complex biology of pancreatic cancer, to discover novel therapeutic targets and to develop various forms of antibody-based therapeutic agents and companion diagnostic tests for the selection of patients who are more likely to benefit from such therapy. These should result in the approval and routine use of antibody-based agents for the treatment of pancreatic cancer patients in the future.

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Anti-glypican-1 antibody–drug conjugate is a potential therapy against pancreatic cancer

Cited by 31 publications

References 32 publications

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

The Glycocalyx and Its Role in Vascular Physiology and Vascular Related Diseases

Therapeutic Application of Monoclonal Antibodies in Pancreatic Cancer: Advances, Challenges and Future Opportunities

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