In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 5116-5116
Abstract:
The well-established capability of tumors to resist single agent chemotherapies underscores the need to identify novel synergistic drug combinations to treat patients with cancer. Here we use an innovative arrayed needle technology to provide rapid in vivo validation of findings from a genome scale RNAi screen and reveal the potential of an unexpected drug combination to treat patients with melanoma. Our efforts focused on the β-catenin pathway. The β-catenin pathway impacts cancer progression in a context dependent manner. In some malignancies such as colon cancer, increased β-catenin activity drives oncogenesis. In contrast activation of β-catenin has been associated with decreased tumor proliferation and improved prognosis in patients with melanoma. A screen with an arrayed library of 14,000 lentiviral shRNA vectors revealed that silencing of dihydrofolate reductase, the target of the classic chemotherapeutic methotrexate, led to synergistic activation of the β-catenin pathway when combined with an inhibitor of GSK3. We therefore explored whether combination therapy, consisting of a GSK3 inhibitor and methotrexate could represent a potential treatment for melanoma patients. Two distinct small molecule inhibitors of GSK3, 6-bromoindirubin-3αoxime (BIO) and Chiron 99021, demonstrated synergy with methotrexate to activate β-catenin signaling in the melanoma cell line A375. To rapidly assess whether the observed synergy translates to the context of a living tumor, precision multiplexed microinjection using Presage technology was performed on mice harboring flank melanoma tumors. Discreet positions on each tumor were injected with either vehicle control, methotexate as a single agent, Chiron 99021 as a single agent, or the combination of the two agents. Analysis of the activation of beta-catenin and histology for markers of cellular proliferation, death, and differentiation allowed us to rapidly evaluate the efficacy of this drug combination. This rapid in vivo validation approach sets the stage for full preclinical evaluation of combined methotrexate and GSK3 inhibitor therapy using advanced co-clinical models of melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5116. doi:1538-7445.AM2012-5116
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2012-5116
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
