Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model

Eva Tonsing-Carter, Barbara J. Bailey, M. Reza Saadatzadeh, Jixin Ding, Haiyan Wang, Anthony L. Sinn, Kacie M. Peterman, Tiaishia K. Spragins, Jayne M. Silver, Alyssa A. Sprouse, Taxiarchis M. Georgiadis, T. Zachary Gunter, Eric C. Long, Robert E. Minto, Christophe C. Marchal, Christopher N. Batuello, Ahmad Safa, Helmut Hanenberg, Paul Territo, George SanduskyLindsey Mayo, Christine M. Eischen, Harlan E. Shannon, Karen Pollok

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Triple-negative breast cancers (TNBC) are typically resistant to treatment, and strategies that build upon frontline therapy are needed. Targeting the murine double minute 2 (Mdm2) protein is an attractive approach, as Mdm2 levels are elevated in many therapy-refractive breast cancers. The Mdm2 protein-protein interaction inhibitor Nutlin-3a blocks the binding of Mdm2 to key signaling molecules such as p53 and p73α and can result in activation of cell death signaling pathways. In the present study, the therapeutic potential of carboplatin and Nutlin-3a to treat TNBC was investigated, as carboplatin is under evaluation in clinical trials for TNBC. In mutant p53 TMD231 TNBC cells, carboplatin and Nutlin-3a led to increased Mdm2 and was strongly synergistic in promoting cell death in vitro. Furthermore, sensitivity of TNBC cells to combination treatment was dependent on p73α. Following combination treatment, γH2AX increased and Mdm2 localized to a larger degree to chromatin compared with single-agent treatment, consistent with previous observations that Mdm2 binds to the Mre11/Rad50/Nbs1 complex associated with DNA and inhibits the DNA damage response. In vivo efficacy studies were conducted in the TMD231 orthotopic mammary fat pad model in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. Using an intermittent dosing schedule of combined carboplatin and Nutlin-3a, there was a significant reduction in primary tumor growth and lung metastases compared with vehicle and single-agent treatments. In addition, there was minimal toxicity to the bone marrow and normal tissues. These studies demonstrate that Mdm2 holds promise as a therapeutic target in combination with conventional therapy and may lead to new clinical therapies for TNBC.

Original languageEnglish (US)
Pages (from-to)2850-2863
Number of pages14
JournalMolecular Cancer Therapeutics
Volume14
Issue number12
DOIs
StatePublished - Dec 1 2015

Fingerprint

Triple Negative Breast Neoplasms
Carboplatin
DNA Damage
Breast
Lung
Proto-Oncogene Proteins c-mdm2
Cell Death
Therapeutics
Chromatin
nutlin 3
Adipose Tissue
Appointments and Schedules
Bone Marrow
Clinical Trials
Breast Neoplasms
Neoplasm Metastasis
DNA
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model. / Tonsing-Carter, Eva; Bailey, Barbara J.; Saadatzadeh, M. Reza; Ding, Jixin; Wang, Haiyan; Sinn, Anthony L.; Peterman, Kacie M.; Spragins, Tiaishia K.; Silver, Jayne M.; Sprouse, Alyssa A.; Georgiadis, Taxiarchis M.; Gunter, T. Zachary; Long, Eric C.; Minto, Robert E.; Marchal, Christophe C.; Batuello, Christopher N.; Safa, Ahmad; Hanenberg, Helmut; Territo, Paul; Sandusky, George; Mayo, Lindsey; Eischen, Christine M.; Shannon, Harlan E.; Pollok, Karen.

In: Molecular Cancer Therapeutics, Vol. 14, No. 12, 01.12.2015, p. 2850-2863.

Research output: Contribution to journalArticle

Tonsing-Carter, E, Bailey, BJ, Saadatzadeh, MR, Ding, J, Wang, H, Sinn, AL, Peterman, KM, Spragins, TK, Silver, JM, Sprouse, AA, Georgiadis, TM, Gunter, TZ, Long, EC, Minto, RE, Marchal, CC, Batuello, CN, Safa, A, Hanenberg, H, Territo, P, Sandusky, G, Mayo, L, Eischen, CM, Shannon, HE & Pollok, K 2015, 'Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model', Molecular Cancer Therapeutics, vol. 14, no. 12, pp. 2850-2863. https://doi.org/10.1158/1535-7163.MCT-15-0237
Tonsing-Carter, Eva ; Bailey, Barbara J. ; Saadatzadeh, M. Reza ; Ding, Jixin ; Wang, Haiyan ; Sinn, Anthony L. ; Peterman, Kacie M. ; Spragins, Tiaishia K. ; Silver, Jayne M. ; Sprouse, Alyssa A. ; Georgiadis, Taxiarchis M. ; Gunter, T. Zachary ; Long, Eric C. ; Minto, Robert E. ; Marchal, Christophe C. ; Batuello, Christopher N. ; Safa, Ahmad ; Hanenberg, Helmut ; Territo, Paul ; Sandusky, George ; Mayo, Lindsey ; Eischen, Christine M. ; Shannon, Harlan E. ; Pollok, Karen. / Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model. In: Molecular Cancer Therapeutics. 2015 ; Vol. 14, No. 12. pp. 2850-2863.
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abstract = "Triple-negative breast cancers (TNBC) are typically resistant to treatment, and strategies that build upon frontline therapy are needed. Targeting the murine double minute 2 (Mdm2) protein is an attractive approach, as Mdm2 levels are elevated in many therapy-refractive breast cancers. The Mdm2 protein-protein interaction inhibitor Nutlin-3a blocks the binding of Mdm2 to key signaling molecules such as p53 and p73α and can result in activation of cell death signaling pathways. In the present study, the therapeutic potential of carboplatin and Nutlin-3a to treat TNBC was investigated, as carboplatin is under evaluation in clinical trials for TNBC. In mutant p53 TMD231 TNBC cells, carboplatin and Nutlin-3a led to increased Mdm2 and was strongly synergistic in promoting cell death in vitro. Furthermore, sensitivity of TNBC cells to combination treatment was dependent on p73α. Following combination treatment, γH2AX increased and Mdm2 localized to a larger degree to chromatin compared with single-agent treatment, consistent with previous observations that Mdm2 binds to the Mre11/Rad50/Nbs1 complex associated with DNA and inhibits the DNA damage response. In vivo efficacy studies were conducted in the TMD231 orthotopic mammary fat pad model in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. Using an intermittent dosing schedule of combined carboplatin and Nutlin-3a, there was a significant reduction in primary tumor growth and lung metastases compared with vehicle and single-agent treatments. In addition, there was minimal toxicity to the bone marrow and normal tissues. These studies demonstrate that Mdm2 holds promise as a therapeutic target in combination with conventional therapy and may lead to new clinical therapies for TNBC.",
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AU - Tonsing-Carter, Eva

AU - Bailey, Barbara J.

AU - Saadatzadeh, M. Reza

AU - Ding, Jixin

AU - Wang, Haiyan

AU - Sinn, Anthony L.

AU - Peterman, Kacie M.

AU - Spragins, Tiaishia K.

AU - Silver, Jayne M.

AU - Sprouse, Alyssa A.

AU - Georgiadis, Taxiarchis M.

AU - Gunter, T. Zachary

AU - Long, Eric C.

AU - Minto, Robert E.

AU - Marchal, Christophe C.

AU - Batuello, Christopher N.

AU - Safa, Ahmad

AU - Hanenberg, Helmut

AU - Territo, Paul

AU - Sandusky, George

AU - Mayo, Lindsey

AU - Eischen, Christine M.

AU - Shannon, Harlan E.

AU - Pollok, Karen

PY - 2015/12/1

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N2 - Triple-negative breast cancers (TNBC) are typically resistant to treatment, and strategies that build upon frontline therapy are needed. Targeting the murine double minute 2 (Mdm2) protein is an attractive approach, as Mdm2 levels are elevated in many therapy-refractive breast cancers. The Mdm2 protein-protein interaction inhibitor Nutlin-3a blocks the binding of Mdm2 to key signaling molecules such as p53 and p73α and can result in activation of cell death signaling pathways. In the present study, the therapeutic potential of carboplatin and Nutlin-3a to treat TNBC was investigated, as carboplatin is under evaluation in clinical trials for TNBC. In mutant p53 TMD231 TNBC cells, carboplatin and Nutlin-3a led to increased Mdm2 and was strongly synergistic in promoting cell death in vitro. Furthermore, sensitivity of TNBC cells to combination treatment was dependent on p73α. Following combination treatment, γH2AX increased and Mdm2 localized to a larger degree to chromatin compared with single-agent treatment, consistent with previous observations that Mdm2 binds to the Mre11/Rad50/Nbs1 complex associated with DNA and inhibits the DNA damage response. In vivo efficacy studies were conducted in the TMD231 orthotopic mammary fat pad model in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. Using an intermittent dosing schedule of combined carboplatin and Nutlin-3a, there was a significant reduction in primary tumor growth and lung metastases compared with vehicle and single-agent treatments. In addition, there was minimal toxicity to the bone marrow and normal tissues. These studies demonstrate that Mdm2 holds promise as a therapeutic target in combination with conventional therapy and may lead to new clinical therapies for TNBC.

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