Project Term
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Project Summary
Certain genetic alterations in Diffuse Large B Cell Lymphomas (DLBCL) render these tumors highly aggressive. Aggressive DLBCLs may also form secondary lymphomas in the brain. The research proposed here will examine the role of a specific class of lipids in the growth of these lymphomas and assess the utility of strategies to lower these lipids or inhibit their production in halting tumor growth.
Lay Abstract
Cancer cells depend on specific cellular communication systems known as signaling pathways, which sustain their survival and growth. As such, factors contributing to or regulating the activity of these pathways are attractive therapeutic targets. Diffuse Large B Cell Lymphomas (DLBCLs) can be classified into several molecular subtypes based on their genomic features, with each subtype relying on distinct survival signaling pathways. We have a long-standing interest in discovering and targeting metabolic pathways in cancer, especially lipid-dependent metabolic processes that regulate survival signaling pathways and control DLBCL growth.
By investigating the spectrum and distribution of distinct types of lipids in cellular models of different DLBCL subtypes as well as patient tumor biopsies, we have found that aggressive subtypes of DLBCLs are highly enriched in a certain class of lipids and in the biochemical process that produces these lipids. Aggressive lymphomas that are enriched in such lipids also include DLBCLs that frequently form secondary lymphomas in the brain. The specific lipids we have identified are not only enriched in these tumors but also appear to promote tumor cell survival and growth. Our initial observations also suggest that these lipids are involved in the regulation of key tumor promoting signaling pathways in aggressive lymphomas.
Here, we propose to elucidate the mechanism by which these lipids influence signaling pathways and the growth of aggressive subtypes of DLBCLs and related lymphomas in the brain (Specific Aim 1). We also plan to determine if these lipids or biochemical processes that generate them can be targeted to diminish tumor growth in pre-clinical models (Specific Aim 2). If successful, the proposed studies have the potential to reveal novel targetable vulnerabilities in aggressive lymphomas that may, in the fullness of time, lead to new treatment strategies. We will also determine whether changes in these lipids alter the response of aggressive lymphomas to clinically relevant targeted agents (Specific Aim 3). This line of research has the potential to reveal if/how the combination of such targeted agents with strategies to inhibit this lipid pathway may work synergistically to restrict tumor growth.
Program
