Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy

Samuel R Denmeade; Annastasiah M Mhaka; D Marc Rosen; W Nathaniel Brennen; Susan Dalrymple; Ingrid Dach; Claus Olesen; Bora Gurel; Angelo M DeMarzo; George Wilding; Michael A Carducci; Craig A Dionne; Jesper Vuust Møller; Poul Nissen; Søren Brøgger Christensen; John T Isaacs

doi:10.1126/scitranslmed.3003886

Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy

Samuel R Denmeade, Annastasiah M Mhaka, D Marc Rosen, W Nathaniel Brennen, Susan Dalrymple, Ingrid Dach, Claus Olesen, Bora Gurel, Angelo M DeMarzo, George Wilding, Michael A Carducci, Craig A Dionne, Jesper Vuust Møller, Poul Nissen, Søren Brøgger Christensen, John T Isaacs

116 Citationer (Scopus)

Abstract

Heterogeneous expression of drug target proteins within tumor sites is a major mechanism of resistance to anticancer therapies. We describe a strategy to selectively inhibit, within tumor sites, the function of a critical intracellular protein, the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump, whose proper function is required by all cell types for viability. To achieve targeted inhibition, we took advantage of the unique expression of the carboxypeptidase prostate-specific membrane antigen (PSMA) by tumor endothelial cells within the microenvironment of solid tumors. We generated a prodrug, G202, consisting of a PSMA-specific peptide coupled to an analog of the potent SERCA pump inhibitor thapsigargin. G202 produced substantial tumor regression against a panel of human cancer xenografts in vivo at doses that were minimally toxic to the host. On the basis of these data, a phase 1 dose-escalation clinical trial has been initiated with G202 in patients with advanced cancer.

Originalsprog	Engelsk
Tidsskrift	Science Translational Medicine
Vol/bind	4
Udgave nummer	140
Sider (fra-til)	140ra86
ISSN	1946-6234
DOI	https://doi.org/10.1126/scitranslmed.3003886
Status	Udgivet - 27 jun. 2012

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10.1126/scitranslmed.3003886

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Denmeade, S. R., Mhaka, A. M., Rosen, D. M., Brennen, W. N., Dalrymple, S., Dach, I., Olesen, C., Gurel, B., DeMarzo, A. M., Wilding, G., Carducci, M. A., Dionne, C. A., Møller, J. V., Nissen, P., Christensen, S. B., & Isaacs, J. T. (2012). Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy. Science Translational Medicine, 4(140), 140ra86. https://doi.org/10.1126/scitranslmed.3003886

Denmeade, SR, Mhaka, AM, Rosen, DM, Brennen, WN, Dalrymple, S, Dach, I, Olesen, C, Gurel, B, DeMarzo, AM, Wilding, G, Carducci, MA, Dionne, CA, Møller, JV, Nissen, P, Christensen, SB & Isaacs, JT 2012, 'Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy', Science Translational Medicine, bind 4, nr. 140, s. 140ra86. https://doi.org/10.1126/scitranslmed.3003886

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title = "Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy",

abstract = "Heterogeneous expression of drug target proteins within tumor sites is a major mechanism of resistance to anticancer therapies. We describe a strategy to selectively inhibit, within tumor sites, the function of a critical intracellular protein, the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump, whose proper function is required by all cell types for viability. To achieve targeted inhibition, we took advantage of the unique expression of the carboxypeptidase prostate-specific membrane antigen (PSMA) by tumor endothelial cells within the microenvironment of solid tumors. We generated a prodrug, G202, consisting of a PSMA-specific peptide coupled to an analog of the potent SERCA pump inhibitor thapsigargin. G202 produced substantial tumor regression against a panel of human cancer xenografts in vivo at doses that were minimally toxic to the host. On the basis of these data, a phase 1 dose-escalation clinical trial has been initiated with G202 in patients with advanced cancer.",

author = "Denmeade, {Samuel R} and Mhaka, {Annastasiah M} and Rosen, {D Marc} and Brennen, {W Nathaniel} and Susan Dalrymple and Ingrid Dach and Claus Olesen and Bora Gurel and DeMarzo, {Angelo M} and George Wilding and Carducci, {Michael A} and Dionne, {Craig A} and M{\o}ller, {Jesper Vuust} and Poul Nissen and Christensen, {S{\o}ren Br{\o}gger} and Isaacs, {John T}",

year = "2012",

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doi = "10.1126/scitranslmed.3003886",

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T1 - Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy

AU - Denmeade, Samuel R

AU - Mhaka, Annastasiah M

AU - Rosen, D Marc

AU - Brennen, W Nathaniel

AU - Dalrymple, Susan

AU - Dach, Ingrid

AU - Olesen, Claus

AU - Gurel, Bora

AU - DeMarzo, Angelo M

AU - Wilding, George

AU - Carducci, Michael A

AU - Dionne, Craig A

AU - Møller, Jesper Vuust

AU - Nissen, Poul

AU - Christensen, Søren Brøgger

AU - Isaacs, John T

PY - 2012/6/27

Y1 - 2012/6/27

N2 - Heterogeneous expression of drug target proteins within tumor sites is a major mechanism of resistance to anticancer therapies. We describe a strategy to selectively inhibit, within tumor sites, the function of a critical intracellular protein, the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump, whose proper function is required by all cell types for viability. To achieve targeted inhibition, we took advantage of the unique expression of the carboxypeptidase prostate-specific membrane antigen (PSMA) by tumor endothelial cells within the microenvironment of solid tumors. We generated a prodrug, G202, consisting of a PSMA-specific peptide coupled to an analog of the potent SERCA pump inhibitor thapsigargin. G202 produced substantial tumor regression against a panel of human cancer xenografts in vivo at doses that were minimally toxic to the host. On the basis of these data, a phase 1 dose-escalation clinical trial has been initiated with G202 in patients with advanced cancer.

AB - Heterogeneous expression of drug target proteins within tumor sites is a major mechanism of resistance to anticancer therapies. We describe a strategy to selectively inhibit, within tumor sites, the function of a critical intracellular protein, the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump, whose proper function is required by all cell types for viability. To achieve targeted inhibition, we took advantage of the unique expression of the carboxypeptidase prostate-specific membrane antigen (PSMA) by tumor endothelial cells within the microenvironment of solid tumors. We generated a prodrug, G202, consisting of a PSMA-specific peptide coupled to an analog of the potent SERCA pump inhibitor thapsigargin. G202 produced substantial tumor regression against a panel of human cancer xenografts in vivo at doses that were minimally toxic to the host. On the basis of these data, a phase 1 dose-escalation clinical trial has been initiated with G202 in patients with advanced cancer.

U2 - 10.1126/scitranslmed.3003886

DO - 10.1126/scitranslmed.3003886

M3 - Journal article

C2 - 22745436

SN - 1946-6234

VL - 4

SP - 140ra86

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 140

ER -

Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy

Abstract

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