Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2

Daruka Mahadevan, Carla Morales, Laurence S. Cooke, Ann Manziello, David W. Mount, Daniel O. Persky, Richard I. Fisher, Thomas P Miller, Wenqing Qi

Research output: Contribution to journalArticle

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Abstract

Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL), while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932) mouse model showed tumor growth inhibition (TGI) of ∼10-20% (p = 0.001) for M, VCR and M-VCR respectively, while R alone showed ∼50% TGI (p = 0.001). M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100%. Genes that are modulated by M-VCR-R (CENP-C, Auroras) play a role in centromerekinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 coexpressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy.

Original languageEnglish (US)
Article numbere95184
JournalPLoS One
Volume9
Issue number6
DOIs
StatePublished - Jun 3 2014

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vincristine
Vincristine
lethal genes
mice
Tumors
therapeutics
remission
lymphoma
growth retardation
Neoplasms
Aurora Kinase A
MLN 8237
Rituximab
Mantle-Cell Lymphoma
neoplasms
aneuploidy
relapse
Cell proliferation
Aneuploidy
Therapeutics

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2. / Mahadevan, Daruka; Morales, Carla; Cooke, Laurence S.; Manziello, Ann; Mount, David W.; Persky, Daniel O.; Fisher, Richard I.; Miller, Thomas P; Qi, Wenqing.

In: PLoS One, Vol. 9, No. 6, e95184, 03.06.2014.

Research output: Contribution to journalArticle

Mahadevan, Daruka ; Morales, Carla ; Cooke, Laurence S. ; Manziello, Ann ; Mount, David W. ; Persky, Daniel O. ; Fisher, Richard I. ; Miller, Thomas P ; Qi, Wenqing. / Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2. In: PLoS One. 2014 ; Vol. 9, No. 6.
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abstract = "Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL), while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932) mouse model showed tumor growth inhibition (TGI) of ∼10-20{\%} (p = 0.001) for M, VCR and M-VCR respectively, while R alone showed ∼50{\%} TGI (p = 0.001). M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100{\%}. Genes that are modulated by M-VCR-R (CENP-C, Auroras) play a role in centromerekinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 coexpressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy.",
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T1 - Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2

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AU - Morales, Carla

AU - Cooke, Laurence S.

AU - Manziello, Ann

AU - Mount, David W.

AU - Persky, Daniel O.

AU - Fisher, Richard I.

AU - Miller, Thomas P

AU - Qi, Wenqing

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