Leukemia-specific delivery of mutant NOTCH1 targeted therapy

Publication Date:
2018-01-03
Publisher:
Rockefeller University Press
Print ISSN:
0022-1007
Electronic ISSN:
1540-9538
Topics:
Medicine
Keywords:
Leukemia & Lymphoma
Published by:
http://www.rupress.org/
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autor Roti, G., Qi, J., Kitara, S., Sanchez-Martin, M., Saur Conway, A., Varca, A. C., Su, A., Wu, L., Kung, A. L., Ferrando, A. A., Bradner, J. E., Stegmaier, K.
beschreibung On-target drug delivery remains a challenge in cancer precision medicine; it is difficult to deliver a targeted therapy to cancer cells without incurring toxicity to normal tissues. The SERCA (sarco-endoplasmic reticulum Ca 2+ ATPase) inhibitor thapsigargin inhibits mutant NOTCH1 receptors compared with wild type in T cell acute lymphoblastic leukemia (T-ALL), but its administration is predicted to be toxic in humans. Leveraging the addiction of ALL to folic acid, we conjugated folate to an alcohol derivative of thapsigargin via a cleavable ester linkage. JQ-FT is recognized by folate receptors on the plasma membrane and delivered into leukemia cells as a potent antileukemic agent. In mechanistic and translational models of T-ALL, we demonstrate NOTCH1 inhibition in vitro and in vivo. These proof-of-concept studies support the further optimization of this first-in-class NOTCH1 inhibitor with dual selectivity: leukemia over normal cells and NOTCH1 mutants over wild-type receptors. Furthermore, tumor-specific disruption of Notch signaling may overcome legitimate concerns associated with the tumor suppressor function of nontargeted Notch pathway inhibitors.
citation_standardnr 6127769
datenlieferant ipn_articles
feed_id 96
feed_publisher Rockefeller University Press
feed_publisher_url http://www.rupress.org/
insertion_date 2018-01-03
journaleissn 1540-9538
journalissn 0022-1007
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher Rockefeller University Press
quelle Journal of Experimental Medicine
relation http://jem.rupress.org/cgi/content/short/215/1/197?rss=1
schlagwort Leukemia & Lymphoma
search_space articles
shingle_author_1 Roti, G., Qi, J., Kitara, S., Sanchez-Martin, M., Saur Conway, A., Varca, A. C., Su, A., Wu, L., Kung, A. L., Ferrando, A. A., Bradner, J. E., Stegmaier, K.
shingle_author_2 Roti, G., Qi, J., Kitara, S., Sanchez-Martin, M., Saur Conway, A., Varca, A. C., Su, A., Wu, L., Kung, A. L., Ferrando, A. A., Bradner, J. E., Stegmaier, K.
shingle_author_3 Roti, G., Qi, J., Kitara, S., Sanchez-Martin, M., Saur Conway, A., Varca, A. C., Su, A., Wu, L., Kung, A. L., Ferrando, A. A., Bradner, J. E., Stegmaier, K.
shingle_author_4 Roti, G., Qi, J., Kitara, S., Sanchez-Martin, M., Saur Conway, A., Varca, A. C., Su, A., Wu, L., Kung, A. L., Ferrando, A. A., Bradner, J. E., Stegmaier, K.
shingle_catch_all_1 Leukemia-specific delivery of mutant NOTCH1 targeted therapy
Leukemia & Lymphoma
On-target drug delivery remains a challenge in cancer precision medicine; it is difficult to deliver a targeted therapy to cancer cells without incurring toxicity to normal tissues. The SERCA (sarco-endoplasmic reticulum Ca 2+ ATPase) inhibitor thapsigargin inhibits mutant NOTCH1 receptors compared with wild type in T cell acute lymphoblastic leukemia (T-ALL), but its administration is predicted to be toxic in humans. Leveraging the addiction of ALL to folic acid, we conjugated folate to an alcohol derivative of thapsigargin via a cleavable ester linkage. JQ-FT is recognized by folate receptors on the plasma membrane and delivered into leukemia cells as a potent antileukemic agent. In mechanistic and translational models of T-ALL, we demonstrate NOTCH1 inhibition in vitro and in vivo. These proof-of-concept studies support the further optimization of this first-in-class NOTCH1 inhibitor with dual selectivity: leukemia over normal cells and NOTCH1 mutants over wild-type receptors. Furthermore, tumor-specific disruption of Notch signaling may overcome legitimate concerns associated with the tumor suppressor function of nontargeted Notch pathway inhibitors.
Roti, G., Qi, J., Kitara, S., Sanchez-Martin, M., Saur Conway, A., Varca, A. C., Su, A., Wu, L., Kung, A. L., Ferrando, A. A., Bradner, J. E., Stegmaier, K.
Rockefeller University Press
0022-1007
00221007
1540-9538
15409538
shingle_catch_all_2 Leukemia-specific delivery of mutant NOTCH1 targeted therapy
Leukemia & Lymphoma
On-target drug delivery remains a challenge in cancer precision medicine; it is difficult to deliver a targeted therapy to cancer cells without incurring toxicity to normal tissues. The SERCA (sarco-endoplasmic reticulum Ca 2+ ATPase) inhibitor thapsigargin inhibits mutant NOTCH1 receptors compared with wild type in T cell acute lymphoblastic leukemia (T-ALL), but its administration is predicted to be toxic in humans. Leveraging the addiction of ALL to folic acid, we conjugated folate to an alcohol derivative of thapsigargin via a cleavable ester linkage. JQ-FT is recognized by folate receptors on the plasma membrane and delivered into leukemia cells as a potent antileukemic agent. In mechanistic and translational models of T-ALL, we demonstrate NOTCH1 inhibition in vitro and in vivo. These proof-of-concept studies support the further optimization of this first-in-class NOTCH1 inhibitor with dual selectivity: leukemia over normal cells and NOTCH1 mutants over wild-type receptors. Furthermore, tumor-specific disruption of Notch signaling may overcome legitimate concerns associated with the tumor suppressor function of nontargeted Notch pathway inhibitors.
Roti, G., Qi, J., Kitara, S., Sanchez-Martin, M., Saur Conway, A., Varca, A. C., Su, A., Wu, L., Kung, A. L., Ferrando, A. A., Bradner, J. E., Stegmaier, K.
Rockefeller University Press
0022-1007
00221007
1540-9538
15409538
shingle_catch_all_3 Leukemia-specific delivery of mutant NOTCH1 targeted therapy
Leukemia & Lymphoma
On-target drug delivery remains a challenge in cancer precision medicine; it is difficult to deliver a targeted therapy to cancer cells without incurring toxicity to normal tissues. The SERCA (sarco-endoplasmic reticulum Ca 2+ ATPase) inhibitor thapsigargin inhibits mutant NOTCH1 receptors compared with wild type in T cell acute lymphoblastic leukemia (T-ALL), but its administration is predicted to be toxic in humans. Leveraging the addiction of ALL to folic acid, we conjugated folate to an alcohol derivative of thapsigargin via a cleavable ester linkage. JQ-FT is recognized by folate receptors on the plasma membrane and delivered into leukemia cells as a potent antileukemic agent. In mechanistic and translational models of T-ALL, we demonstrate NOTCH1 inhibition in vitro and in vivo. These proof-of-concept studies support the further optimization of this first-in-class NOTCH1 inhibitor with dual selectivity: leukemia over normal cells and NOTCH1 mutants over wild-type receptors. Furthermore, tumor-specific disruption of Notch signaling may overcome legitimate concerns associated with the tumor suppressor function of nontargeted Notch pathway inhibitors.
Roti, G., Qi, J., Kitara, S., Sanchez-Martin, M., Saur Conway, A., Varca, A. C., Su, A., Wu, L., Kung, A. L., Ferrando, A. A., Bradner, J. E., Stegmaier, K.
Rockefeller University Press
0022-1007
00221007
1540-9538
15409538
shingle_catch_all_4 Leukemia-specific delivery of mutant NOTCH1 targeted therapy
Leukemia & Lymphoma
On-target drug delivery remains a challenge in cancer precision medicine; it is difficult to deliver a targeted therapy to cancer cells without incurring toxicity to normal tissues. The SERCA (sarco-endoplasmic reticulum Ca 2+ ATPase) inhibitor thapsigargin inhibits mutant NOTCH1 receptors compared with wild type in T cell acute lymphoblastic leukemia (T-ALL), but its administration is predicted to be toxic in humans. Leveraging the addiction of ALL to folic acid, we conjugated folate to an alcohol derivative of thapsigargin via a cleavable ester linkage. JQ-FT is recognized by folate receptors on the plasma membrane and delivered into leukemia cells as a potent antileukemic agent. In mechanistic and translational models of T-ALL, we demonstrate NOTCH1 inhibition in vitro and in vivo. These proof-of-concept studies support the further optimization of this first-in-class NOTCH1 inhibitor with dual selectivity: leukemia over normal cells and NOTCH1 mutants over wild-type receptors. Furthermore, tumor-specific disruption of Notch signaling may overcome legitimate concerns associated with the tumor suppressor function of nontargeted Notch pathway inhibitors.
Roti, G., Qi, J., Kitara, S., Sanchez-Martin, M., Saur Conway, A., Varca, A. C., Su, A., Wu, L., Kung, A. L., Ferrando, A. A., Bradner, J. E., Stegmaier, K.
Rockefeller University Press
0022-1007
00221007
1540-9538
15409538
shingle_title_1 Leukemia-specific delivery of mutant NOTCH1 targeted therapy
shingle_title_2 Leukemia-specific delivery of mutant NOTCH1 targeted therapy
shingle_title_3 Leukemia-specific delivery of mutant NOTCH1 targeted therapy
shingle_title_4 Leukemia-specific delivery of mutant NOTCH1 targeted therapy
timestamp 2025-06-30T23:31:42.238Z
titel Leukemia-specific delivery of mutant NOTCH1 targeted therapy
titel_suche Leukemia-specific delivery of mutant NOTCH1 targeted therapy
topic WW-YZ
uid ipn_articles_6127769