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Genome wide analysis of L1mAb treated SKOV3ip tumors in vivo

ABSTRACT: Recent work has indentified L1-CAM as a novel marker for human carcinoma progression. Functionally, L1-CAM promotes tumor cell invasion and motility, augments tumor growth in nude mice and facilitates experimental tumor metastasis. These functional features qualify L1 as an interesting target molecule for tumor therapy. Here we generated a series of novel mAbs to the L1-CAM ectodomain. Among the novel mAbs, L1-9.3 was selected and its therapeutic potential was analyzed in various isotype variants in a model of SKOV3ip cells growing intraperitoneally in CD1 nude mice. Therapy with the IgG2a variant efficiently prolonged survival and reduced tumor burden. This was accompanied by an increased infiltration of F4/80 positive monocytic cells. Expression profiling of tumor derived mRNA revealed that L1-9.3-IgG2a therapy induced altered expression of cellular genes associated with apoptosis and tumor growth. Our results establish that L1 mAb therapy acts via immunological and non-immunological effector mechanism to block tumor growth.

ORGANISM(S): Homo sapiens

PROVIDER: GSE19171 | GEO | 2010/01/15

SECONDARY ACCESSION(S): PRJNA120583

REPOSITORIES: GEO

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Project description:This proposal aims to develop narrow-spectrum prodrug-activated protein synthesis inhibitors to treat Mycobacterium abscessus (Mabs) infections. It builds on a recent discovery in our program, which elucidated a unique mechanism for prodrug activation of florfenicol amine (FFA) by hijacking the protective methods Mabs uses to block antibiotic action. Non-tuberculous mycobacteria (NTM) are emerging pathogens with high intrinsic drug resistance. Mabs is the most pathogenic refractory NTM member,1-3 and infections with this pathogen are associated with especially poor clinical outcomes, similar to XDR-TB (extensively drug-resistant tuberculosis)1. Florfenicol (FF) is a broad-spectrum analog of chloramphenicol (CAM), is orally bioavailable, safely used in agriculture as it lacks some of the pharmacological liabilities of CAM, and it mitigates plasmid-borne resistance by blocking the primary-hydroxy site of inactivation. FFA is the primary metabolite found in many host species after FF administration. Through routine MIC screening of synthetic intermediates, we discovered that FFA on its own had appreciable WhiB7 transcription factor-dependent MIC activity against Mabs. Further studies demonstrated that in Mabs FFA acts as a prodrug that is acylated into the active form (FFac) within Mabs by Eis2, a Mabs specific acetyltransferase. eis2 is located in the whiB7 resistome, which results in a feed-forward mechanism of action between FFA, eis2, and whiB7, ultimately increasing the conversion of FFA to FFac, resulting in increased sensitivity. FFA was found to be highly synergistic with other protein synthesis inhibitors and resistance to FFA by inactivation of whiB7 or eis2 results in increased sensitivity to aminoglycosides and macrolides. Since eis2 is only present in Mabs and other closely related species, FFA has a narrow spectrum of activity and avoids the potential for mitochondrial cytotoxicity. Preliminary pharmacological studies demonstrate FFA is noncytotoxic and orally bioavailable.

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Genome wide analysis of L1mAb treated SKOV3ip tumors in vivo

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