Therapeutic Targeting of the Cancer-Specific Cell Surface Biomarker nfP2X7

Barden, Julian A.; Gidley-Baird, A. A.; Teh, Liew Cheng; Rajasekariah, G-Halli; Pedersen, John; Christensen, Neil; Spielman, Derek; Ashley, David M.

doi:10.4172/2155-9899.1000432

Cited by 5 publications

(7 citation statements)

References 50 publications

(75 reference statements)

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“…This was confirmed using a mouse monoclonal antibody (BPM09, supplied by Biosceptre) (Maianski et al, 2007). In another study, increased expression of nfP2X7 was observed as prostate disease progressed (Barden et al, 2016). P2X7 expression by IHC also was compared with the levels of prostate-specific antigen (PSA) in 174 prostate cancer biopsies .…”

Section: Prostate Cancermentioning

confidence: 84%

“…Prostate (Slater et al, 2004a;Maianski et al, 2007;Adinolfi et al, 2009;Barden et al, 2009;Ravenna et al, 2009;Adinolfi et al, 2010;Barden et al, 2014;Ghalali et al, 2014;Qiu et al, 2014;Solini et al, 2015;Barden et al, 2016;Gilbert et al, 2019) Lung (Barden et al, 2009;Takai et al, 2012;Jelassi et al, 2013;Barden et al, 2014;Takai et al, 2014;Schmid et al, 2015;Gilbert et al, 2019) Kidney (Liu et al, 2015;Gilbert et al, 2019) Colorectal (Coutinho-Silva et al, 2005;Barden et al, 2009;Li et al, 2009;Kunzli et al, 2011;Bian et al, 2013;Barden et al, 2014;Barden et al, 2016;Qian et al, 2017;Gilbert et al, 2019;) Gastric (Barden et al, 2009;Barden et al, 2014;Calik et al, 2020) Breast (Slater et al, 2004b;Barden et al, 2009;Li et al, 2009;Tafani et al, 2010;Jelassi et al, 2011;Huang et al, 2013;Jelassi et al, 2013;Barden et al, 2014;Chadet et al, 2014;<...>…”

Section: Cancer Typeunclassified

“…nfP2X7 protein also was upregulated in 25 SCC compared to 20 keratoacanthomas (KA) . Using an affinity purified sheep polyclonal antibody to nfP2X7, systemic treatment of advanced cat SCC showed decreased lesion size (Barden et al, 2016). In a more recent study, the presence of nfP2X7 was shown in BCC and antibodies specific for nfP2X7 rather than fully functional P2X7 were shown to be a safe treatment for BCC with 65% of patients showing reduced lesion area, 20% showing stable tumor size and 15% with increased lesion area (Gilbert et al, 2017).…”

Section: Breast Cancermentioning

confidence: 99%

“…In healthy tissues, P2X7 is expressed mainly in the central nervous system (CNS), peripheral nervous system (PNS), and in immune cells, which supports its emergence as a target for chronic pain and chronic inflammatory diseases . P2X7 is also overexpressed in a number of cancer types, potentially driving tumor development and survival (Adinolfi et al, 2002;Adinolfi et al, 2009;Adinolfi et al, 2012;Barden et al, 2014;Amoroso et al, 2015;Barden et al, 2016;Gilbert et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

et al. 2020

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P2X7 is a transmembrane receptor expressed in multiple cell types including neurons, dendritic cells, macrophages, monocytes, B and T cells where it can drive a wide range of physiological responses from pain transduction to immune response. Upon activation by its main ligand, extracellular ATP, P2X7 can form a nonselective channel for cations to enter the cell. Prolonged activation of P2X7, via high levels of extracellular ATP over an extended time period can lead to the formation of a macropore, leading to depolarization of the plasma membrane and ultimately to cell death. Thus, dependent on its activation state, P2X7 can either drive cell survival and proliferation, or induce cell death. In cancer, P2X7 has been shown to have a broad range of functions, including playing key roles in the development and spread of tumor cells. It is therefore unsurprising that P2X7 has been reported to be upregulated in several malignancies. Critically, ATP is present at high extracellular concentrations in the tumor microenvironment (TME) compared to levels observed in normal tissues. These high levels of ATP should present a survival challenge for cancer cells, potentially leading to constitutive receptor activation, prolonged macropore formation and ultimately to cell death. Therefore, to deliver the proven advantages for P2X7 in driving tumor survival and metastatic potential, the P2X7 macropore must be tightly controlled while retaining other functions. Studies have shown that commonly expressed P2X7 splice variants, distinct SNPs and posttranslational receptor modifications can impair the capacity of P2X7 to open the macropore. These receptor modifications and potentially others may ultimately protect cancer cells from the negative consequences associated with constitutive activation of P2X7. Significantly, the effects of both P2X7 agonists and antagonists in preclinical tumor models of cancer demonstrate the potential for agents modifying P2X7 function, to provide innovative cancer therapies. This review summarizes recent advances in understanding of the structure and functions of P2X7 and how these impact P2X7 roles in cancer progression. We also review potential therapeutic approaches directed against P2X7.

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Section: Prostate Cancermentioning

confidence: 84%

Section: Cancer Typeunclassified

Section: Breast Cancermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

et al. 2020

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“…Growth of experimental tumours is strongly inhibited by P2X7R antagonism of both cancer and immune cells (see [ 57 ]). A non-functional P2X7R, nfP2X7R, is expressed on cancer cells and has been proposed as a novel therapeutic target for human cancer [ 58 , 59 ]. A phase I clinical trial has recently demonstrated that nfP2X7R-targeted antibodies were a novel, safe and tolerable topical therapy for basal cell carcinoma [ 60 ].…”

Section: P2x7r and Tumour Progressionmentioning

confidence: 99%

The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression

Burnstock

Knight

2017

Purinergic Signalling

195

166

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Seven P2X ion channel nucleotide receptor subtypes have been cloned and characterised. P2X7 receptors (P2X7R) are unusual in that there are extra amino acids in the intracellular C terminus. Low concentrations of ATP open cation channels sometimes leading to cell proliferation, whereas high concentrations of ATP open large pores that release inflammatory cytokines and can lead to apoptotic cell death. Since many diseases involve inflammation and immune responses, and the P2X7R regulates inflammation, there has been recent interest in the pathophysiological roles of P2X7R and the potential of P2X7R antagonists to treat a variety of diseases. These include neurodegenerative diseases, psychiatric disorders, epilepsy and a number of diseases of peripheral organs, including the cardiovascular, airways, kidney, liver, bladder, skin and musculoskeletal. The potential of P2X7R drugs to treat tumour progression is discussed.

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Pre-clinical validation of a pan-cancer CAR-T cell immunotherapy targeting nfP2X7

Bandara,

Foeng,

Gundsambuu

et al. 2023

Nat Commun

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Chimeric antigen receptor (CAR)-T cell immunotherapy is a novel treatment that genetically modifies the patients’ own T cells to target and kill malignant cells. However, identification of tumour-specific antigens expressed on multiple solid cancer types, remains a major challenge. P2X purinoceptor 7 (P2X7) is a cell surface expressed ATP gated cation channel, and a dysfunctional version of P2X7, named nfP2X7, has been identified on cancer cells from multiple tissues, while being undetectable on healthy cells. We present a prototype -human CAR-T construct targeting nfP2X7 showing potential antigen-specific cytotoxicity against twelve solid cancer types (breast, prostate, lung, colorectal, brain and skin). In xenograft mouse models of breast and prostate cancer, CAR-T cells targeting nfP2X7 exhibit robust anti-tumour efficacy. These data indicate that nfP2X7 is a suitable immunotherapy target because of its broad expression on human tumours. CAR-T cells targeting nfP2X7 have potential as a wide-spectrum cancer immunotherapy for solid tumours in humans.

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Therapeutic Targeting of the Cancer-Specific Cell Surface Biomarker nfP2X7

Cited by 5 publications

References 50 publications

P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression

Pre-clinical validation of a pan-cancer CAR-T cell immunotherapy targeting nfP2X7

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