Inhibition of the Aurora A kinase augments the anti-tumor efficacy of oncolytic measles virotherapy.
Oncolytic measles virus (MV) strains have demonstrated broad spectrum preclinical anti-tumor efficacy, including breast cancer. Aurora A kinase controls mitotic spindle formation and has a critical role in malignant transformation. We hypothesized that the Aurora A kinase inhibitor MLN8237 (alisertib) can increase MV oncolytic effect and efficacy by causing mitotic arrest. Alisertib enhanced MV oncolysis in vitro and significantly improved outcome in vivo against breast cancer xenografts. In a disseminated MDA-231-lu-P4 lung metastatic model, the MV/alisertib combination treatment markedly increased median survival to 82.5 days with 20% of the animals being long-term survivors versus 48 days median survival for the control animals. Similarly, in a pleural effusion model of advanced breast cancer, the MV/alisertib combination significantly improved outcome with a 74.5 day median survival versus the single agent groups (57 and 40 days, respectively). Increased viral gene expression and IL-24 upregulation were demonstrated, representing possible mechanisms for the observed increase in anti-tumor effect. Inhibiting Aurora A kinase with alisertib represents a novel approach to enhance MV-mediated oncolysis and antitumor effect. Both oncolytic MV strains and alisertib are currently tested in clinical trials, this study therefore provides the basis for translational applications of this combinatorial strategy in the treatment of patients with advanced breast cancer.
Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
I D
ID
Iankov
Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
C B
CB
Kurokawa
Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
A B
AB
D'Assoro
Department of Oncology, Mayo Clinic, Rochester, MN, USA.
J N
JN
Ingle
Department of Oncology, Mayo Clinic, Rochester, MN, USA.
E
E
Domingo-Musibay
Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
C
C
Allen
Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
C M
CM
Crosby
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
A A
AA
Nair
Department of Oncology, Mayo Clinic, Rochester, MN, USA.
M C
MC
Liu
Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
I
I
Aderca
Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
M J
MJ
Federspiel
Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.|Department of Oncology, Mayo Clinic, Rochester, MN, USA.
E
E
Galanis
D000230:Adenocarcinoma / Q000556:secondary / Q000628:therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000502:physiology; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000235:genetics; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy*; D002522:Chlorocebus aethiops; D003131:Combined Modality Therapy; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007146:Immunoglobulin lambda-Chains / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy; D008459:Measles virus; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D019076:Transgenes; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays; D000099180:Interleukin-24
D000970:Antineoplastic Agents; D064107:Aurora Kinase B; D001381:Azepines; D001426:Bacterial Proteins; D007146:Immunoglobulin lambda-Chains; D007378:Interleukins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000099180:Interleukin-24; C550258:MLN 8237; C092412:neutrophil-activating protein A, Helicobacter pylori; C576921:AURKB protein, human