Abstract SY18-03: New therapies based on the genetics of follicular lymphoma.

Follicular lymphoma (FL) is the most common and incurable form of indolent Non-Hodgkin9s lymphoma. Recent studies form our lab and others have catalogued recurrent genomic changes in FL. However, the functional impact of these changes in FL pathogenesis relapse and progression has not been explored. To improve FL outcome there is a critical need to decipher the biological effects of genomic aberrations in FL. My lab combines genomic analyses of primary FLs with functional genetic ad therapeutic studies. To this end we have developed a new mosaic model of FL that is based on the vavBcl2 transgenic and develops a disease that recapitulates key features of the genetics and pathology of human FL. This model enables rapid assessment of the pathogenic role and therapeutic impact of recurrent genetic lesions seen in FL. Time permitting I will touch on three recent studies from my lab: 1. The identification of EPHA7 as a soluble tumor suppressor lost in FL. We have functionally dissected large chromosomal lesions to identify key tumor suppressor genes. The deletion of Chr. 6q occurs in ~25% of FL patients and is linked to poor patient outcomes. The region has been studied for decades and we applied new, unbiased RNAi screening technology to the search for 6q target genes. This approach identified the ephrin receptor A7 (EPHA7) as tumor suppressor lost in a large fraction of FL. Importantly, EPHA7 encodes a soluble tumor suppressor and we developed an anti-CD20-EPHA7 fusion antibody that can deliver EPHA7 to FLs in vivo and exert dramatic therapeutic effects. 2. Discovery of deletion-associated genetic liabilities in cancer cells. For example, not all genes included in recurrent, hemizygous deletions in FL act as tumor suppressor genes and in fact some genes encode activities that are essential for cell survival. Our RNAi screening approach revealed several deletion-associated liabilities. As cancer cells have lost one allele of these genes, they are uniquely sensitive to inhibition of residual activity and this results in a potentially excellent therapeutic index. 3. A novel combination therapy for high-risk FL based on tumor genetics. FL is commonly considered a slow growing / indolent tumor. Hence, it comes as a surprise that ~50% of FL harbor genetic lesions that disable key cell cycle controls and include CDK4, Cyclin D3, Rb, and p16. FLs harboring these lesions are typically more advanced and patient survival reduced by several years. However, these lesions also indicate the potential of cell cycle directed therapies against FL and we show the power of combining BCL2 blockade with cell cycle inhibitory drugs as a new combination regimen for phosphorylated RB positive, high risk FL. Finally, FL is a common and deadly form of lymphoma and has been somewhat neglected scientifically. We hope that our new model and approach to study FL genetics and biology will make this tumor more accessible to research and lead to new therapies for patients. Citation Format: Hans-Guido Wendel. New therapies based on the genetics of follicular lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY18-03. doi:10.1158/1538-7445.AM2013-SY18-03