Prostate stem cell antigen – novel biomarker and therapeutic target?

Santos, Pedro Bargão; Patel, Hitendra

doi:10.1586/14737140.2014.870481

Cited by 8 publications

(5 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In prostate cancer, cancer-associated antigens PSA, PSMA, PAP, PSCA, MUC1 and PAGE/GAGE have been used to stimulate T cell-mediated immunity [31]. Lack of consistent success could be partly due to some of these antigens being secreted molecules or not prostate-specific [21, 32]. In contrast, AGR2 expression differs between cancer and normal cells in subcellular localization, eAGR2 vs .…”

Section: Discussionmentioning

confidence: 99%

AGR2, a unique tumor-associated antigen, is a promising candidate for antibody targeting

et al. 2019

View full text Add to dashboard Cite

Anterior gradient 2 (AGR2), a protein disulfide isomerase, shows two subcellular localizations: intracellular (iAGR2) and extracellular (eAGR2). In healthy cells that express AGR2, the predominant form is iAGR2, which resides in the endoplasmic reticulum. In contrast, cancer cells secrete and express eAGR2 on the cell surface. We wanted to test if AGR2 is a cancer-specific tumor-associated antigen. We utilized two AGR2 antibodies, P3A5 and P1G4, for in vivo tumor localization and tumor growth inhibition. The monoclonal antibodies recognized both human AGR2 and mouse Agr2. Biodistribution experiments using a syngeneic mouse model showed high uptake of P3A5 AGR2 antibody in xenografted eAgr2 + pancreatic tumors, with limited uptake in normal tissues. In implanted human patient-derived eAGR2 + pancreatic cancer xenografts, tumor growth inhibition was evaluated with antibodies and Gemcitabine (Gem). Inhibition was more potent by P1G4 + Gem combination than Gem alone or P3A5 + Gem. We converted these two antibodies to human:mouse chimeric forms: the constructed P3A5 and P1G4 chimeric mV L hC κ and mV H hC γ (γ1, γ2, γ4) genes were inserted in a single mammalian expression plasmid vector, and transfected into human 293F cells. Expressed human:mouse chimeric IgG1, IgG2 and IgG4 antibodies retained AGR2 binding. Increase in IgG yield by transfected cells could be obtained with serial transfection of vectors with different drug resistance. These chimeric antibodies, when incubated with human blood, effectively lysed eAGR2 + PC3 prostate cancer cells. We have, thus, produced humanized anti-AGR2 antibodies that, after further testing, might be suitable for treatment against a variety of eAGR2 + solid tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

AGR2, a unique tumor-associated antigen, is a promising candidate for antibody targeting

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Molecular targeted therapy has been applied to chronic myeloid leukemia, non-small cell lung cancer, colorectal cancer, gastrointestinal stromal tumors, breast cancer, and other tumors [ 50 - 58 ]. Currently, molecular targeted therapies for prostate cancer undergoing clinical trials include therapies against prostate-specific membrane antigen (PSMA) [ 59 ] and prostate stem cell antigen (PSCA) [ 60 ], anti-angiogenesis drugs, and anti-tumor cell signaling COX-2 inhibitor drugs [ 61 ]. However, at this time, there is no evidence to support the use of molecular targeted therapy in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

TOPK is highly expressed in circulating tumor cells, enabling metastasis of prostate cancer

et al. 2015

View full text Add to dashboard Cite

Circulating tumor cells (CTCs) are important for metastasis in prostate cancer. T-LAK cell-originated protein kinase (TOPK) is highly expressed in cancer cells. Herein, we established a xenograft animal model, isolated and cultured the CTCs, and found CTCs have significantly greater migratory capacity than parental cells. TOPK is more highly expressed in the CTCs than in parental cells and is also highly expressed in the metastatic nodules caused by CTCs in mice. Knocking down TOPK decreased the migration of CTCs both in vitro and in vivo. TOPK was modulated by the PI3K/PTEN and ERK pathways during the metastasis of prostate cancer. High levels of TOPK in the tumors of patients were correlated with advanced stages of prostate cancer, especially for high-risk patients of Gleason score≥8, PSA>20ng/ml. In summary, TOPK was speculated to be one of a potential marker and therapeutic target in advanced prostate cancer.

show abstract

“…A lack of consistent results could in part be attributed to their expression not being restricted to the prostate. For example, PSCA (prostate stem cell antigen) was found expressed also by the bladder, colon, kidney, and stomach ( 86 ). The trials of PSA (PROSTVAC-VF) and PAP (prostatic acid phosphatase, Provenge) were inconclusive with some small increase in survival ( 85 ).…”

Section: Therapeutic Treatments Against Differentiated and Undifferen...mentioning

confidence: 99%

Prostate cancer research: tools, cell types, and molecular targets

Liu

2024

Front. Oncol.

View full text Add to dashboard Cite

Multiple cancer cell types are found in prostate tumors. They are either luminal-like adenocarcinoma or less luminal-like and more stem-like non-adenocarcinoma and small cell carcinoma. These types are lineage related through differentiation. Loss of cancer differentiation from luminal-like to stem-like is mediated by the activation of stem cell transcription factors (scTF) such as LIN28A, NANOG, POU5F1 and SOX2. scTF expression leads to down-regulation of β2-microglobulin (B2M). Thus, cancer cells can change from the scTF˜B2Mhi phenotype of differentiated to that of scTF˙B2Mlo of dedifferentiated in the disease course. In development, epithelial cell differentiation is induced by stromal signaling and cell contact. One of the stromal factors specific to prostate encodes proenkephalin (PENK). PENK can down-regulate scTF and up-regulate B2M in stem-like small cell carcinoma LuCaP 145.1 cells indicative of exit from the stem state and differentiation. In fact, prostate cancer cells can be made to undergo dedifferentiation or reprogramming by scTF transfection and then to differentiate by PENK transfection. Therapies need to be designed for treating the different cancer cell types. Extracellular anterior gradient 2 (eAGR2) is an adenocarcinoma antigen associated with cancer differentiation that can be targeted by antibodies to lyse tumor cells with immune system components. eAGR2 is specific to cancer as normal cells express only the intracellular form (iAGR2). For AGR2-negative stem-like cancer cells, factors like PENK that can target scTF could be effective in differentiation therapy.

show abstract

Prostate stem cell antigen – novel biomarker and therapeutic target?

Cited by 8 publications

References 16 publications

AGR2, a unique tumor-associated antigen, is a promising candidate for antibody targeting

AGR2, a unique tumor-associated antigen, is a promising candidate for antibody targeting

TOPK is highly expressed in circulating tumor cells, enabling metastasis of prostate cancer

Prostate cancer research: tools, cell types, and molecular targets

Contact Info

Product

Resources

About