In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 14_Supplement ( 2015-07-15), p. B12-B12
Abstract:
Senescence-inducing therapies can block proliferation of malignant cells and promote anti-tumor immune activity. However, the risk of tumor relapse remains high due to the long lifespan of senescence cells with potential to escape senescence. Here our preclinical studies demonstrate that combining a senescent-inducing aurora kinase A (AURKA) inhibitor alisertib (MLN8237) with an MDM2 antagonist [(-)-nutlin 3a] effectively induces robust p53 activation in senescent Tp53WT tumors accompanied by: 1) tumor cell proliferation arrest; 2) mitochondrial depolarization and tumor cell apoptosis; and 3) tumor cell clearance via CCL5-, CCL1- and CCL9-mediated recruitment of anti-tumor leukocytes. This combined therapy shows adequate bioavailability and low toxicity to the host in the mouse model. Moreover, the prominent preclinical response of patient-derived melanoma tumors to the co-targeting of MDM2 and AURKA provides rationale for further investigation of alisertib and MDM2 inhibitors. Citation Format: Anna E. Vilgelm, Jeff S. Pawlikowski, Yan Liu, E. Hawkins Oriana, A. Davis Tyler, Kevin P. Weller, Linda W. Horton, Colt M. McClain, Gregory D. Ayers, David Turner, David C. Essaka, Clinton F. Stewart, Jeffrey A. Sosman, Mark C. Kelley, Jeffrey A. Ecsedy, Jeffrey N. Johnston, Ann Richmond. Synergistic anticancer activity of Aurora A kinase and MDM2 antagonists in melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B12.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.MEL2014-B12
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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