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

Samuel R Denmeade, Annastasiah M. Mhaka, D. Marc Rosen, William Brennen, Susan Dalrymple, Ingrid Dach, Claus Olesen, Bora Gurel, Angelo Michael Demarzo, George Wilding, Michael A Carducci, Craig A. Dionne, Jesper V. Møller, Poul Nissen, S. Brøgger Christensen, John Tod Isaacs

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number140ra86
JournalScience Translational Medicine
Volume4
Issue number140
DOIs
StatePublished - Jun 27 2012

Fingerprint

Prodrugs
Endothelial Cells
Neoplasms
Calcium-Transporting ATPases
Sarcoplasmic Reticulum
Endoplasmic Reticulum
Therapeutics
Cellular Microenvironment
Carboxypeptidases
Thapsigargin
Poisons
human glutamate carboxypeptidase II
Heterografts
Cell Survival
Proteins
Clinical Trials
Peptides
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy. / Denmeade, Samuel R; Mhaka, Annastasiah M.; Rosen, D. Marc; Brennen, William; Dalrymple, Susan; Dach, Ingrid; Olesen, Claus; Gurel, Bora; Demarzo, Angelo Michael; Wilding, George; Carducci, Michael A; Dionne, Craig A.; Møller, Jesper V.; Nissen, Poul; Christensen, S. Brøgger; Isaacs, John Tod.

In: Science Translational Medicine, Vol. 4, No. 140, 140ra86, 27.06.2012.

Research output: Contribution to journalArticle

Denmeade, SR, Mhaka, AM, Rosen, DM, Brennen, W, 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, vol. 4, no. 140, 140ra86. https://doi.org/10.1126/scitranslmed.3003886
Denmeade, Samuel R ; Mhaka, Annastasiah M. ; Rosen, D. Marc ; Brennen, William ; Dalrymple, Susan ; Dach, Ingrid ; Olesen, Claus ; Gurel, Bora ; Demarzo, Angelo Michael ; Wilding, George ; Carducci, Michael A ; Dionne, Craig A. ; Møller, Jesper V. ; Nissen, Poul ; Christensen, S. Brøgger ; Isaacs, John Tod. / Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy. In: Science Translational Medicine. 2012 ; Vol. 4, No. 140.
@article{10fbe398fdfb43a2b7f331132c11d2cd,
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 William Brennen and Susan Dalrymple and Ingrid Dach and Claus Olesen and Bora Gurel and Demarzo, {Angelo Michael} and George Wilding and Carducci, {Michael A} and Dionne, {Craig A.} and M{\o}ller, {Jesper V.} and Poul Nissen and Christensen, {S. Br{\o}gger} and Isaacs, {John Tod}",
year = "2012",
month = "6",
day = "27",
doi = "10.1126/scitranslmed.3003886",
language = "English (US)",
volume = "4",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "140",

}

TY - JOUR

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, William

AU - Dalrymple, Susan

AU - Dach, Ingrid

AU - Olesen, Claus

AU - Gurel, Bora

AU - Demarzo, Angelo Michael

AU - Wilding, George

AU - Carducci, Michael A

AU - Dionne, Craig A.

AU - Møller, Jesper V.

AU - Nissen, Poul

AU - Christensen, S. Brøgger

AU - Isaacs, John Tod

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.

UR - http://www.scopus.com/inward/record.url?scp=84863198078&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863198078&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.3003886

DO - 10.1126/scitranslmed.3003886

M3 - Article

VL - 4

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 140

M1 - 140ra86

ER -