Cooperative benefit for the combination of rapamycin and imatinib in tuberous sclerosis complex neoplasia

Baskaran Govindarajan, Laura Willoughby, Hamid Band, Adam S. Curatolo, Emir Veledar, Suephy Chen, Michael Y. Bonner, Martin Garrido Abel, Marsha A. Moses, Jack L. Arbiser

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Tuberous sclerosis (TS) is a common autosomal-dominant disorder characterized by tumors of the skin, lung, brain, and kidneys. Monotherapy with rapamycin however resulted in partial regression of tumors, implying the involvement of additional pathways. We have previously implicated platelet-derived growth factor-BB in TS-related tumorigenesis, thus providing a rationale for a combination of mTOR/PDGF blockade using rapamycin and imatinib. Here, we test this combination using a well-established preclinical model of cutaneous tumorigenesis in TS, tsc2ang1 cells derived from a skin tumor from a mouse heterozygous for tsc2. Treatment of tsc2ang1 cells with a combination of rapamycin and imatinib led to an inhibition of proliferation compared with either vehicle treatment or treatment with rapamycin or imatinib monotherapy. Combination therapy also led to a decrease in Akt activation. Potent in vivo activity in animal experiments by combination therapy was noted, without toxicity to the animals. Our findings provide a rationale for the combined use of rapamycin and imatinib, both FDA approved drugs, for the treatment of TS.

Original languageEnglish (US)
Article number11
JournalVascular Cell
Volume4
DOIs
StatePublished - Sep 17 2012

Fingerprint

Tuberous Sclerosis
Sirolimus
Tumors
Skin
Animals
Neoplasms
Platelets
Carcinogenesis
Toxicity
Brain
Chemical activation
Imatinib Mesylate
Kidney
Experiments
Lung
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience
  • Computer Networks and Communications
  • Cell Biology

Cite this

Govindarajan, B., Willoughby, L., Band, H., Curatolo, A. S., Veledar, E., Chen, S., ... Arbiser, J. L. (2012). Cooperative benefit for the combination of rapamycin and imatinib in tuberous sclerosis complex neoplasia. Vascular Cell, 4, [11]. https://doi.org/10.1186/2045-824X-4-11

Cooperative benefit for the combination of rapamycin and imatinib in tuberous sclerosis complex neoplasia. / Govindarajan, Baskaran; Willoughby, Laura; Band, Hamid; Curatolo, Adam S.; Veledar, Emir; Chen, Suephy; Bonner, Michael Y.; Abel, Martin Garrido; Moses, Marsha A.; Arbiser, Jack L.

In: Vascular Cell, Vol. 4, 11, 17.09.2012.

Research output: Contribution to journalArticle

Govindarajan, B, Willoughby, L, Band, H, Curatolo, AS, Veledar, E, Chen, S, Bonner, MY, Abel, MG, Moses, MA & Arbiser, JL 2012, 'Cooperative benefit for the combination of rapamycin and imatinib in tuberous sclerosis complex neoplasia', Vascular Cell, vol. 4, 11. https://doi.org/10.1186/2045-824X-4-11
Govindarajan, Baskaran ; Willoughby, Laura ; Band, Hamid ; Curatolo, Adam S. ; Veledar, Emir ; Chen, Suephy ; Bonner, Michael Y. ; Abel, Martin Garrido ; Moses, Marsha A. ; Arbiser, Jack L. / Cooperative benefit for the combination of rapamycin and imatinib in tuberous sclerosis complex neoplasia. In: Vascular Cell. 2012 ; Vol. 4.
@article{8c99a034ce754064b2856a1b66800f70,
title = "Cooperative benefit for the combination of rapamycin and imatinib in tuberous sclerosis complex neoplasia",
abstract = "Tuberous sclerosis (TS) is a common autosomal-dominant disorder characterized by tumors of the skin, lung, brain, and kidneys. Monotherapy with rapamycin however resulted in partial regression of tumors, implying the involvement of additional pathways. We have previously implicated platelet-derived growth factor-BB in TS-related tumorigenesis, thus providing a rationale for a combination of mTOR/PDGF blockade using rapamycin and imatinib. Here, we test this combination using a well-established preclinical model of cutaneous tumorigenesis in TS, tsc2ang1 cells derived from a skin tumor from a mouse heterozygous for tsc2. Treatment of tsc2ang1 cells with a combination of rapamycin and imatinib led to an inhibition of proliferation compared with either vehicle treatment or treatment with rapamycin or imatinib monotherapy. Combination therapy also led to a decrease in Akt activation. Potent in vivo activity in animal experiments by combination therapy was noted, without toxicity to the animals. Our findings provide a rationale for the combined use of rapamycin and imatinib, both FDA approved drugs, for the treatment of TS.",
author = "Baskaran Govindarajan and Laura Willoughby and Hamid Band and Curatolo, {Adam S.} and Emir Veledar and Suephy Chen and Bonner, {Michael Y.} and Abel, {Martin Garrido} and Moses, {Marsha A.} and Arbiser, {Jack L.}",
year = "2012",
month = "9",
day = "17",
doi = "10.1186/2045-824X-4-11",
language = "English (US)",
volume = "4",
journal = "Vascular Cell",
issn = "2045-824X",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Cooperative benefit for the combination of rapamycin and imatinib in tuberous sclerosis complex neoplasia

AU - Govindarajan, Baskaran

AU - Willoughby, Laura

AU - Band, Hamid

AU - Curatolo, Adam S.

AU - Veledar, Emir

AU - Chen, Suephy

AU - Bonner, Michael Y.

AU - Abel, Martin Garrido

AU - Moses, Marsha A.

AU - Arbiser, Jack L.

PY - 2012/9/17

Y1 - 2012/9/17

N2 - Tuberous sclerosis (TS) is a common autosomal-dominant disorder characterized by tumors of the skin, lung, brain, and kidneys. Monotherapy with rapamycin however resulted in partial regression of tumors, implying the involvement of additional pathways. We have previously implicated platelet-derived growth factor-BB in TS-related tumorigenesis, thus providing a rationale for a combination of mTOR/PDGF blockade using rapamycin and imatinib. Here, we test this combination using a well-established preclinical model of cutaneous tumorigenesis in TS, tsc2ang1 cells derived from a skin tumor from a mouse heterozygous for tsc2. Treatment of tsc2ang1 cells with a combination of rapamycin and imatinib led to an inhibition of proliferation compared with either vehicle treatment or treatment with rapamycin or imatinib monotherapy. Combination therapy also led to a decrease in Akt activation. Potent in vivo activity in animal experiments by combination therapy was noted, without toxicity to the animals. Our findings provide a rationale for the combined use of rapamycin and imatinib, both FDA approved drugs, for the treatment of TS.

AB - Tuberous sclerosis (TS) is a common autosomal-dominant disorder characterized by tumors of the skin, lung, brain, and kidneys. Monotherapy with rapamycin however resulted in partial regression of tumors, implying the involvement of additional pathways. We have previously implicated platelet-derived growth factor-BB in TS-related tumorigenesis, thus providing a rationale for a combination of mTOR/PDGF blockade using rapamycin and imatinib. Here, we test this combination using a well-established preclinical model of cutaneous tumorigenesis in TS, tsc2ang1 cells derived from a skin tumor from a mouse heterozygous for tsc2. Treatment of tsc2ang1 cells with a combination of rapamycin and imatinib led to an inhibition of proliferation compared with either vehicle treatment or treatment with rapamycin or imatinib monotherapy. Combination therapy also led to a decrease in Akt activation. Potent in vivo activity in animal experiments by combination therapy was noted, without toxicity to the animals. Our findings provide a rationale for the combined use of rapamycin and imatinib, both FDA approved drugs, for the treatment of TS.

UR - http://www.scopus.com/inward/record.url?scp=84866057854&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866057854&partnerID=8YFLogxK

U2 - 10.1186/2045-824X-4-11

DO - 10.1186/2045-824X-4-11

M3 - Article

C2 - 22765013

AN - SCOPUS:84866057854

VL - 4

JO - Vascular Cell

JF - Vascular Cell

SN - 2045-824X

M1 - 11

ER -