From Plant to Patient: Thapsigargin, a Tool for Understanding …
111
208. Mesters JR, Barinka C, Li W, Tsukamoto T, Majer P, Slusher BS, Konvalinka J, Hilgenfeld
R (2006) Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and
prostate cancer. EMBO J 25:1375
209. Janssen S, Jakobsen CM, Rosen DM, Ricklis RM, Reineke U, Christensen SB, Lilja H,
Denmeade SR (2004) Screening a combinatorial peptide library to develop a human glandular
kallikrein 2-activated prodrug as targeted therapy for prostate cancer. Mol Cancer Ther 3:1439
210. Denmeade SR, Isaacs JT (2012) Engineering enzymatically activated “molecular grenades”
for cancer. Oncotarget 3:666
211. Denmeade SR, Isaacs JT, Christensen SB (2010) Methods and compositions for the detection
and treatment of cancer using targeted activation of peptide prodrugs and imaging agents.
WO2010107909A2
212. Denmeade SR, Isaacs JT, Christensen SB (2014) Methods and compositions for the detection
of cancer. US 8,772,226 B2
213. Isaacs JT, Denmeade SR, Christensen SB, Lilja H (2003) Prostate-specific prodrugs. US
6,504,014 B1
214. Vander Griend DJ, Antony L, Dalrymple SL, Xu Y, Christensen SB, Denmeade SR, Isaacs JT
(2009) Amino acid containing thapsigargin analogues deplete androgen receptor protein via
synthesis inhibition and induce the death of prostate cancer cells. Mol Cancer Ther 8:1340
215. Mahalingam D, Tubb B, Neumunaiitis JJ, Cen P, Rowe JH, Sarantopoulos J, Kurman MR,
Allgood V, Campos LT (2015) Clinical activity and correlative DCE-MRI imaging of G-202,
a thapsigargin-based prostate-specific membrane antigen-activated prodrug, in progressive
hepatocellular cancer. J Clin Oncol 33(Suppl 3):301
216. Mahalingam D, Wilding G, Denmeade S, Sarantopoulas J, Cosgrove D, Cetnar J, Azad N,
Bruce J, Kurman M, Allgood VE, Carducci M (2016) Mipsagargin, a novel thapsigarginbased PSMA-activated prodrug: results of a first-in-man phase I clinical trial in patients with
refractory, advanced or metastatic solid tumours. Br J Cancer 114:986
217. Mahalingam D, Mahalingam D, Arora SP, Sarantopoulos J, Peguero J, Campos L, Cen P, Rowe
J, Allgood V, Tubb B (2019) A phase II, multicenter, single-arm study of mipsagargin (G202) as a second-line therapy following sorafenib for adult patients with progressive advanced
hepatocellular carcinoma. Cancers 11:6
218. Zimmermann T, Christensen SB, Franzyk H (2018) Preparation of enzyme-activated
thapsigargin prodrugs by solid-phase synthesis. Molecules 23:1463
219. De Ford C, Heidersdorf B, Haun F, Murillo R, Friedrich T, Borner C, Merfort I (2016) The
clerodane diterpene casearin J induces apoptosis of T-ALL cells through SERCA inhibition,
oxidative stress, and interference with Notch1 signaling. Cell Death Dis 7:e2070
Søren Brøgger Christensen obtained his Ph.D. degree in pharmaceutical sciences at the Royal Danish School of Pharmacy
in 1975, supervised by Professor P. Krogsgaard-Larsen. He
undertook Visiting Scientist positions at UCLA (Professor R.
V. Stevens, 1977) and University College London (Professor
John Foreman 1984). He was appointed as Assistant Professor
(1976), Reader (1991), and Professor 2008 at the Royal Danish
School of Pharmacy, which in 2000 was merged with the
University of Copenhagen. He has focused his research on
natural products with biological activities. Licochalcone A was
isolated from Glycyrrhiza inflata and shown to be a potent lead
compound against malaria parasites. Analogues were prepared
in order to develop an optimized drug, with the intellectual
property rights of the biotech company Lica Pharmaceuticals
Ltd. being based on this work. Thapsigargin was isolated from
111
208. Mesters JR, Barinka C, Li W, Tsukamoto T, Majer P, Slusher BS, Konvalinka J, Hilgenfeld
R (2006) Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and
prostate cancer. EMBO J 25:1375
209. Janssen S, Jakobsen CM, Rosen DM, Ricklis RM, Reineke U, Christensen SB, Lilja H,
Denmeade SR (2004) Screening a combinatorial peptide library to develop a human glandular
kallikrein 2-activated prodrug as targeted therapy for prostate cancer. Mol Cancer Ther 3:1439
210. Denmeade SR, Isaacs JT (2012) Engineering enzymatically activated “molecular grenades”
for cancer. Oncotarget 3:666
211. Denmeade SR, Isaacs JT, Christensen SB (2010) Methods and compositions for the detection
and treatment of cancer using targeted activation of peptide prodrugs and imaging agents.
WO2010107909A2
212. Denmeade SR, Isaacs JT, Christensen SB (2014) Methods and compositions for the detection
of cancer. US 8,772,226 B2
213. Isaacs JT, Denmeade SR, Christensen SB, Lilja H (2003) Prostate-specific prodrugs. US
6,504,014 B1
214. Vander Griend DJ, Antony L, Dalrymple SL, Xu Y, Christensen SB, Denmeade SR, Isaacs JT
(2009) Amino acid containing thapsigargin analogues deplete androgen receptor protein via
synthesis inhibition and induce the death of prostate cancer cells. Mol Cancer Ther 8:1340
215. Mahalingam D, Tubb B, Neumunaiitis JJ, Cen P, Rowe JH, Sarantopoulos J, Kurman MR,
Allgood V, Campos LT (2015) Clinical activity and correlative DCE-MRI imaging of G-202,
a thapsigargin-based prostate-specific membrane antigen-activated prodrug, in progressive
hepatocellular cancer. J Clin Oncol 33(Suppl 3):301
216. Mahalingam D, Wilding G, Denmeade S, Sarantopoulas J, Cosgrove D, Cetnar J, Azad N,
Bruce J, Kurman M, Allgood VE, Carducci M (2016) Mipsagargin, a novel thapsigarginbased PSMA-activated prodrug: results of a first-in-man phase I clinical trial in patients with
refractory, advanced or metastatic solid tumours. Br J Cancer 114:986
217. Mahalingam D, Mahalingam D, Arora SP, Sarantopoulos J, Peguero J, Campos L, Cen P, Rowe
J, Allgood V, Tubb B (2019) A phase II, multicenter, single-arm study of mipsagargin (G202) as a second-line therapy following sorafenib for adult patients with progressive advanced
hepatocellular carcinoma. Cancers 11:6
218. Zimmermann T, Christensen SB, Franzyk H (2018) Preparation of enzyme-activated
thapsigargin prodrugs by solid-phase synthesis. Molecules 23:1463
219. De Ford C, Heidersdorf B, Haun F, Murillo R, Friedrich T, Borner C, Merfort I (2016) The
clerodane diterpene casearin J induces apoptosis of T-ALL cells through SERCA inhibition,
oxidative stress, and interference with Notch1 signaling. Cell Death Dis 7:e2070
Søren Brøgger Christensen obtained his Ph.D. degree in pharmaceutical sciences at the Royal Danish School of Pharmacy
in 1975, supervised by Professor P. Krogsgaard-Larsen. He
undertook Visiting Scientist positions at UCLA (Professor R.
V. Stevens, 1977) and University College London (Professor
John Foreman 1984). He was appointed as Assistant Professor
(1976), Reader (1991), and Professor 2008 at the Royal Danish
School of Pharmacy, which in 2000 was merged with the
University of Copenhagen. He has focused his research on
natural products with biological activities. Licochalcone A was
isolated from Glycyrrhiza inflata and shown to be a potent lead
compound against malaria parasites. Analogues were prepared
in order to develop an optimized drug, with the intellectual
property rights of the biotech company Lica Pharmaceuticals
Ltd. being based on this work. Thapsigargin was isolated from