Dual targeting of mTOR and Aurora-A kinase for the treatment of uterine leiomyosarcoma

Kari J. Brewer Savannah, Elizabeth G. Demicco, Kristelle Lusby, Markus P.H. Ghadimi, Roman Belousov, Eric Young, Yiqun Zhang, Kai-Lieh Huang, Alexander J. Lazar, Kelly K. Hunt, Raphael E. Pollock, Chad J. Creighton, Matthew L. Anderson, Dina Lev

Research output: Contribution to journalArticle

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Abstract

Purpose: The significance of mTOR activation in uterine leiomyosarcoma (ULMS) and its potential as a therapeutic target were investigated. Furthermore, given that effective therapies likely require combination mTOR blockade with inhibition of other targets, coupled with recent observations suggesting that Aurora-A kinase (Aurk-A) deregulations commonly occur in ULMS, the preclinical impact of dually targeting both pathways was evaluated. Experimental Design: Immunohistochemical staining was used to evaluate expression of activated mTOR components in a large (>200 samples) ULMS tissue microarray. Effects of mTOR blockade (using rapamycin) and Aurk-A inhibition (using MLN8237) alone and in combination on human ULMS cell growth, cell-cycle progression, and apoptosis were assessed in cellular assays. Drug interactions were determined via combination index analyses. The antitumor effects of inhibitors alone or in combination were evaluated in vivo. Results: Enhanced mTOR activation was seen in human ULMS samples. Increased pS6RP and p4EBP1 expression correlated with disease progression; p4EBP1 was found to be an independent prognosticator of patient outcome. Rapamycin inhibited growth and cell-cycle progression of ULMS cell strains/lines in culture. However, only a cytostatic effect on tumor growth was found in vivo. Combining rapamycin with MLN8237 profoundly (and synergistically) abrogated ULMS cells' growth in culture; interestingly, these effects were seen only when MLN8237 was preadministered. This novel therapeutic combination and scheduling regimen resulted in marked tumor growth inhibition in vivo. Conclusions: mTOR and Aurk-A pathways are commonly deregulated in ULMS. Preclinical data support further exploration of dual mTOR and Aurk-A therapeutic blockade for human ULMS.

Original languageEnglish (US)
Pages (from-to)4633-4645
Number of pages13
JournalClinical Cancer Research
Volume18
Issue number17
DOIs
StatePublished - Sep 1 2012
Externally publishedYes

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Aurora Kinase A
Leiomyosarcoma
Sirolimus
Growth
Therapeutics
Cell Cycle
Cytostatic Agents
Drug Interactions
Disease Progression
Neoplasms
Research Design
Apoptosis
Staining and Labeling

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Brewer Savannah, K. J., Demicco, E. G., Lusby, K., Ghadimi, M. P. H., Belousov, R., Young, E., ... Lev, D. (2012). Dual targeting of mTOR and Aurora-A kinase for the treatment of uterine leiomyosarcoma. Clinical Cancer Research, 18(17), 4633-4645. https://doi.org/10.1158/1078-0432.CCR-12-0436

Dual targeting of mTOR and Aurora-A kinase for the treatment of uterine leiomyosarcoma. / Brewer Savannah, Kari J.; Demicco, Elizabeth G.; Lusby, Kristelle; Ghadimi, Markus P.H.; Belousov, Roman; Young, Eric; Zhang, Yiqun; Huang, Kai-Lieh; Lazar, Alexander J.; Hunt, Kelly K.; Pollock, Raphael E.; Creighton, Chad J.; Anderson, Matthew L.; Lev, Dina.

In: Clinical Cancer Research, Vol. 18, No. 17, 01.09.2012, p. 4633-4645.

Research output: Contribution to journalArticle

Brewer Savannah, KJ, Demicco, EG, Lusby, K, Ghadimi, MPH, Belousov, R, Young, E, Zhang, Y, Huang, K-L, Lazar, AJ, Hunt, KK, Pollock, RE, Creighton, CJ, Anderson, ML & Lev, D 2012, 'Dual targeting of mTOR and Aurora-A kinase for the treatment of uterine leiomyosarcoma', Clinical Cancer Research, vol. 18, no. 17, pp. 4633-4645. https://doi.org/10.1158/1078-0432.CCR-12-0436
Brewer Savannah KJ, Demicco EG, Lusby K, Ghadimi MPH, Belousov R, Young E et al. Dual targeting of mTOR and Aurora-A kinase for the treatment of uterine leiomyosarcoma. Clinical Cancer Research. 2012 Sep 1;18(17):4633-4645. https://doi.org/10.1158/1078-0432.CCR-12-0436
Brewer Savannah, Kari J. ; Demicco, Elizabeth G. ; Lusby, Kristelle ; Ghadimi, Markus P.H. ; Belousov, Roman ; Young, Eric ; Zhang, Yiqun ; Huang, Kai-Lieh ; Lazar, Alexander J. ; Hunt, Kelly K. ; Pollock, Raphael E. ; Creighton, Chad J. ; Anderson, Matthew L. ; Lev, Dina. / Dual targeting of mTOR and Aurora-A kinase for the treatment of uterine leiomyosarcoma. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 17. pp. 4633-4645.
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T1 - Dual targeting of mTOR and Aurora-A kinase for the treatment of uterine leiomyosarcoma

AU - Brewer Savannah, Kari J.

AU - Demicco, Elizabeth G.

AU - Lusby, Kristelle

AU - Ghadimi, Markus P.H.

AU - Belousov, Roman

AU - Young, Eric

AU - Zhang, Yiqun

AU - Huang, Kai-Lieh

AU - Lazar, Alexander J.

AU - Hunt, Kelly K.

AU - Pollock, Raphael E.

AU - Creighton, Chad J.

AU - Anderson, Matthew L.

AU - Lev, Dina

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N2 - Purpose: The significance of mTOR activation in uterine leiomyosarcoma (ULMS) and its potential as a therapeutic target were investigated. Furthermore, given that effective therapies likely require combination mTOR blockade with inhibition of other targets, coupled with recent observations suggesting that Aurora-A kinase (Aurk-A) deregulations commonly occur in ULMS, the preclinical impact of dually targeting both pathways was evaluated. Experimental Design: Immunohistochemical staining was used to evaluate expression of activated mTOR components in a large (>200 samples) ULMS tissue microarray. Effects of mTOR blockade (using rapamycin) and Aurk-A inhibition (using MLN8237) alone and in combination on human ULMS cell growth, cell-cycle progression, and apoptosis were assessed in cellular assays. Drug interactions were determined via combination index analyses. The antitumor effects of inhibitors alone or in combination were evaluated in vivo. Results: Enhanced mTOR activation was seen in human ULMS samples. Increased pS6RP and p4EBP1 expression correlated with disease progression; p4EBP1 was found to be an independent prognosticator of patient outcome. Rapamycin inhibited growth and cell-cycle progression of ULMS cell strains/lines in culture. However, only a cytostatic effect on tumor growth was found in vivo. Combining rapamycin with MLN8237 profoundly (and synergistically) abrogated ULMS cells' growth in culture; interestingly, these effects were seen only when MLN8237 was preadministered. This novel therapeutic combination and scheduling regimen resulted in marked tumor growth inhibition in vivo. Conclusions: mTOR and Aurk-A pathways are commonly deregulated in ULMS. Preclinical data support further exploration of dual mTOR and Aurk-A therapeutic blockade for human ULMS.

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