We propose to develop inhibitors of NAD+-dependent deacetylase SIRT2 as new, targeted, non-toxic chemotherapeutic agents that inactivate BCL6, a key driver of tumorigenesis in B-cell lymphoma. Common genetic drivers for germinal center B cell-derived lymphomas have be identified through large scale sequencing efforts. However, transferring this knowledge into novel therapies remains challenging, particularly for loss-of-function mutations where the driver is absent and a valid therapeutic target is not immediately obvious. Up to 40% of germinal center-derived lymphomas, including both aggressive, diffuse large B-cell lymphoma (DLBCL), and indolent, follicular cell lymphoma (FL), contain loss of function mutations in histone acetyl transferases (HATs), CREBBP and p300, making loss-of-function mutations in HATs among the most common genetic alterations in lymphoma. Therapies aimed at these genetic alterations may therefore help large fraction of lymphoma patients. While loss of function mutations in HATs can be found at low frequency in other cancers, their extraordinarily high prevalence in DLBCL and FL suggests a fundamental role of dysregulated acetylation in the pathogenesis of germinal center-derived malignancies. Reduced activity of cellular HATs has been implicated in dysregulation of two critical mediators of lymphomagenesis, BCL6 and p53, which are rendered hyperactive and hypoactive, respectively, by the hypoacetylated state. We show that pharmacological inhibition SIRT2 counteracts the protein acetylation imbalance that drives lymphomagenesis, and thus constitutes a novel therapeutic strategy for treatment of germinal center-derived lymphomas. Our preliminary data validate this therapeutic strategy and provide evidence that BCL6 inactivation through SIRT2 inhibition consititues the basis for the anti-lymphoma activity. Based on this rationale and our preliminary data, we propose to: optimize SIRT2 inhibitors using medicinal chemistry and structure-based drug design; identify the mechanisms by which SIRT2 inhibitors abrogates BCL6 function, and; demonstrate in vivo anti-lymphoma activity. As a result, we will provide a novel therapeutic strategy and develop small molecule SIRT2 inhibitors, targeting one of the most common genetic alterations in germinal center-derived malignancies.
B-cell lymphoma is a very common and often deadly form of blood cancer. From our work and that of others, it is known that inhibition of specific enzymes, called sirtuins, is well tolerated in normal cells and leads to little or no toxicity, whereas inhibition of sirtuins is lethal in lymphoma cells. We propose to develop new sirtuin inhibitors as safe and effective treatments for B-cell lymphoma.
