Abstract IA38: Identification of targetable vulnerabilities in lymphoma.
Authors: Shipp Margaret 
Published: August 2015

Diffuse large B- cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in adults and a clinically and genetically heterogeneous disorder. With current therapy, over 60% of patients with DLBCL can be cured; however, the remaining patients succumb to their disease. DLBCL largely originates in germinal center (GC) B cells, which have high growth rates and increased genomic instability. As a consequence, DLBCLs exhibit multiple low frequency genetic alterations including chromosomal translocations, somatic mutations and copy number alterations (CNAs). We have used several complementary comprehensive strategies to characterize the molecular heterogeneity of DLBCL and identify associated rational therapeutic targets.

Using a combination of high-density – SNP arrays, whole exome sequencing, gene expression profiling and pathway analyses, we have comprehensively defined CNAs, candidate driver genes and perturbed signaling pathways in large series of newly diagnosed DLBCLs. The approach revealed a complementary set of CNAs and somatic mutations that decreased p53 activity and perturbed cell cycle regulation. The genetic signature of p53 deficiency and cell cycle deregulation was highly predictive for unfavorable outcome and potentially amenable to targeted therapy.

We previously applied consensus clustering methods to the transcriptional profiles of primary DLBCLs and identified 3 highly reproducible tumor groups: BCR (B-cell receptor), OxPhos (oxidative phosphorylation) and HR (host response). “BCR” DLBCLs have increased expression of multiple components of the BCR signaling pathway and increased reliance on BCR-mediated survival signals. We recently characterized distinct BCR/SYK/PI3K-dependent survival pathways in DLBCLs with high or low baseline NF-κB activity and defined specific survival mechanisms in BCR-dependent NF-κB low DLBCLs. In these studies, SYK/PI3K/AKT-dependent cholesterol biosynthesis was found to be a feed-forward mechanism of preserving the integrity of BCRs in lipid rafts in DLBCLs with low- or high-baseline NF-κB. Consistent with the roles of SYK and PI3K/AKT as important mediators of BCR survival signals in primary DLBCLs, SYK amplification and PTEN deletion were identified as selective and largely mutually exclusive genetic alterations in “BCR”-type tumors. These studies suggest potential strategies for specifically targeting BCR-dependent survival signals in defined subtypes of DLBCL.

In additional studies, we found that predominant fuel utilization pathways in BCR and OxPhos DLBCLs differ. Whereas BCR DLBCLs primarily utilize aerobic glycolysis, OxPhos DLBCLs largely depend upon fatty acid oxidation and exhibit selective sensitivity to targeted inhibition of this fuel utilization pathway. These findings further define molecular subsets of DLBCLs with distinct metabolic features that are linked to the functional state of upstream BCR signaling components.

Citation Format: Margaret Shipp. Identification of targetable vulnerabilities in lymphoma. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA38.