Intracellular Cargo Delivery by an Octaarginine Transporter Adapted to Target Prostate Cancer Cells through Cell Surface Protease Activation

2006 ◽  
Vol 17 (3) ◽  
pp. 787-796 ◽  
Author(s):  
Elena A. Goun ◽  
Rajesh Shinde ◽  
Karen W. Dehnert ◽  
Angie Adams-Bond ◽  
Paul A. Wender ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Surface ◽  
Cancer Cells ◽  
Prostate Cancer Cells ◽  
Cargo Delivery ◽  
Protease Activation ◽  
Cell Surface Protease

Abstract 1213: Thymidine kinase 1 is on the cell surface of prostate cancer cells

2016 ◽  
Author(s):  
Evita G. Weagel ◽  
Roger P. Chu ◽  
Wei Meng ◽  
Rachel A. Brog ◽  
Michelle H. Townsend ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Surface ◽  
Cancer Cells ◽  
Thymidine Kinase ◽  
Prostate Cancer Cells ◽  
Thymidine Kinase 1

scholarly journals PTEN inhibits cell proliferation and induces apoptosis by downregulating cell surface IGF-IR expression in prostate cancer cells

Oncogene ◽  
2004 ◽  
Vol 23 (3) ◽  
pp. 786-794 ◽  
Author(s):  
Hong Zhao ◽  
Joelle Dupont ◽  
Shoshana Yakar ◽  
Michael Karas ◽  
Derek LeRoith
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Cell Surface ◽  
Cancer Cells ◽  
Prostate Cancer Cells

scholarly journals A Comprehensive Analysis of FUT8 Overexpressing Prostate Cancer Cells Reveals the Role of EGFR in Castration Resistance

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 468 ◽  
Author(s):  
Naseruddin Höti ◽  
Tung-Shing Lih ◽  
Jianbo Pan ◽  
Yangying Zhou ◽  
Ganglong Yang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Surface ◽  
Cancer Cells ◽  
Growth Factor Receptor ◽  
Androgen Deprivation ◽  
Cell Surface Receptor ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Prostate Cancer Cells

The emergence of castration-resistance is one of the major challenges in the management of patients with advanced prostate cancer. Although the spectrum of systemic therapies that are available for use alongside androgen deprivation for treatment of castration-resistant prostate cancer (CRPC) is expanding, none of these regimens are curative. Therefore, it is imperative to apply systems approaches to identify and understand the mechanisms that contribute to the development of CRPC. Using comprehensive proteomic approaches, we show that a glycosylation-related enzyme, alpha (1,6) fucosyltransferase (FUT8), which is upregulated in CRPC, might be responsible for resistance to androgen deprivation. Mechanistically, we demonstrated that overexpression of FUT8 resulted in upregulation of the cell surface epidermal growth factor receptor (EGFR) and corresponding downstream signaling, leading to increased cell survival in androgen-depleted conditions. We studied the coregulatory mechanisms of EGFR and FUT8 expression in CRPC xenograft models and found that castration induced FUT8 overexpression associated with increased expression of EGFR. Taken together, our findings suggest a crucial role played by FUT8 as a mediator in switching prostate cancer cells from nuclear receptor signaling (androgen receptor) to the cell surface receptor (EGFR) mechanisms in escaping castration-induced cell death. These findings have clinical implication in understanding the role of FUT8 as a master regulator of cell surface receptors in cancer-resistant phenotypes.

718 AMG 509, a STEAP1 x CD3 bispecific XmAb® 2+1 immune therapy, exhibits avidity-driven binding and preferential killing of high STEAP1-expressing prostate and Ewing sarcoma cancer cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A760-A760
Author(s):  
Cong Li ◽  
Madeline Fort ◽  
Lingming Liang ◽  
Gregory Moore ◽  
Matthew Bernett ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Cell Surface ◽  
Cancer Cells ◽  
Ewing Sarcoma ◽  
Half Life ◽  
Laboratory Animal ◽  
Prostate Cancer Cells ◽  
Animal Care

BackgroundMetastatic castration-resistant prostate cancer (mCRPC) and Ewing sarcoma (EWS) are diseases for which immune therapies could potentially provide benefit. STEAP1 (Six Transmembrane Epithelial Antigen of the Prostate 1) is a cell surface protein with elevated expression in mCRPC 1 and EWS.2MethodsWe designed AMG 509, a novel, half-life extended, STEAP1 x CD3 XmAb® 2+1 bispecific antibody to induce T cell-mediated cytotoxicity against STEAP1-expressing cancer cells. AMG 509 contains two identical anti-STEAP1 Fab domains, an anti-CD3 scFv domain, and an effectorless Fc domain that extends serum half-life. We characterized STEAP1 expression in normal and tumor tissues by immunohistochemistry, and we assessed the pharmacological properties of AMG 509 including binding, T cell-mediated redirected lysis, and in vivo antitumor activity.ResultsWe detected high STEAP1 surface expression on 80% of primary prostate tumors (n=88), 89% of mCRPC lesions (n=114), including 84% of mCRPC bone metastases (n=31), and 63% of EWS samples (n=35). In contrast, in normal tissues (n=72), low STEAP1 expression was detected in only six other tissues, including the normal prostate. AMG 509 bound to recombinant human CD3ε with a KD of 27.6 nM, and it bound specifically to 293T cells transfected with human STEAP1 with an EC50 of 3.8 nM. AMG 509 triggered potent T cell-redirected lysis of STEAP1-positive cancer cells, with a median EC50 of 37 pM across 19 cancer cell lines that endogenously express various levels of STEAP1. AMG 509-mediated cytotoxicity was specific, as it showed no activity against prostate cancer cells in which STEAP1 was knocked out. AMG 509 was 65-fold more potent in inducing the redirected lysis of prostate cancer cells in vitro than an XmAb® molecule with a single anti-STEAP1 Fab domain. AMG 509 had greater cytotoxic activity against high STEAP1-expressing cancer cells than against low STEAP1-expressing cancer cells, and it had minimal activity against normal cells. This preferential killing of high STEAP1-expressing cells is likely driven by the avidity conferred by the dual STEAP1-binding domains, a feature that may help reduce off-target effects in the clinic. In vivo, AMG 509 induced robust anti-tumor activity in prostate cancer and EWS mouse xenograft models, with concomitant CD8+ T-cell activation and expansion in tumors.ConclusionsAMG 509 is a specific, first-in-class T cell-recruiting antibody with avidity-driven activity against STEAP1-positive malignancies. AMG 509 is currently being evaluated for safety, pharmacokinetics, and efficacy in a phase 1, first-in-human study in patients with mCRPC (NCT04221542).AcknowledgementsThe authors acknowledge Micah Robinson, PhD of Amgen Inc. for medical writing support.Trial RegistrationClinicalTrials. gov Identifier: NCT04221542Ethics ApprovalAll animal experimental protocols were approved by an Institutional Animal Care and Use Committee (IACUC protocol number 2015-01243) and were conducted in accordance with the guidelines of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) (Amgen) or the standards of the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals (IACUC protocol number 15015x) in a facility certified with an Office of Laboratory Animal Welfare (OLAW) (UTHSA).ReferencesGrunewald TGP, Ranft A, Esposito I, Silva-Buttkus P da, Aichler M, Baumhoer D, Schaefer KL, Ottaviano L, Poremba C, Jundt G, Jurgens H, Dirksen U, Richter GHS, Burdach S. High STEAP1 expression is associated with improved outcome of Ewing’s sarcoma patients. Ann Oncol 2012; 23:2185–2190.Hubert RS, Vivanco I, Chen E, Rastegar S, Leong K, Mitchell SC, Madraswala R, Zhou Y, Kuo J, Raitano AB, Jakobvits A, Saffran SC, Afar DE. STEAP: a prostate-specific cell-surface antigen highly expressed in human prostate tumors. Proc Natl Acad Sci USA 1999;96:14523–14528.

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