Discovery of new therapeutic strategies for rare cancers with defined genetic lesions

Abstract Rare cancers are defined as those with an incidence of less than 0.05% in a given population, yet collectively make up ∼20% of all cancers. A proportion of these are characterized by a primary, driving genetic lesion which disrupts normal cell regulation, resulting in malignancy. Patients of rare cancer could potentially benefit from clinically approved targeted therapies developed for other cancers; however their rarity makes recruitment for clinical trials extremely difficult. Cell lines derived from these patients often maintain the genetic lesions present in the parent tumor, and therefore can serve as a platform to evaluate the efficacy of novel therapeutic strategies. Here we describe in vitro strategies for identifying novel treatment regimens for the rare, simple karyotype cancer Myxoid Liposarcoma (MLS). MLS is characterized by a single genetic event, the chromosomal translocation t(12;16)(q13;p11), which occurs in >95% of cases. The gene product of this translocation is the constitutively active fusion protein FUS-CHOP, which alters the expression of transcription factors responsible for regulating adipocytic differentiation. This drives the cells into a perpetual state of proliferation in the absence of differentiation, thus leading to malignancy. This study uses the cell lines MLS 402 and MLS 1765, which are derived from MLS patients, and express FUS-CHOP. Cells were screened with a panel of anti-cancer treatments, including antibodies, small molecule inhibitors and chemotherapies. Axitinib was identified as an efficacious treatment both alone and in combination with other therapies. Axitinib caused cell cycle arrest and induced apoptosis as verified by Annexin V flow cytometry assay. This multi-kinase inhibitor targets the membrane-bound receptors c-Kit, PDGFRα/β and VEGFR1/2/3. Western blot and bioplex assays were utilised to determine the downstream target molecules inhibited by axitinib treatment. Axitinib significantly reduced signalling activity through the AKT/mTOR and MEK/ERK1/2 pathways. Axitinib also displayed additive and synergistic anti-tumor activity with other targeted therapies. The establishment of cell lines that retain the key genetic mutation found in rare cancers is a useful approach for identifying novel therapeutic options. 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 3711. doi:1538-7445.AM2012-3711