Grant: Operating Grant - PA: Alberta Cancer Foundation - Research (bridge funding)

Human B cells play a critical role in fighting infection and providing immunity. Like other human cells, individual B cells can undergo a cancerous conversion and expand in number to create a life-threatening cancer. Several such B cell cancers are lumped together as B-non-Hodgkin's Lymphoma (B-NHL). Anti-cancer drugs induce B-NHL cells to undergo a sort of cellular suicide. However, most such drugs have side effects and not all B-NHL forms respond. Both normal and cancer cells possess small molecules that function as intracellular signalers, connecting biochemical events within cells. One such molecule is diacylglycerol. Analogous compounds have been isolated from natural sources or made by chemists. Other investigators showed that bryostatin-1, a diacylglycerol analogue isolated from a marine organism, kills some lymphoma cells. We have discovered that a synthetic bryostatin-1-like compound kills several types of B-NHL selectively and we have learned something about the underlying molecular mechanisms. For example, cells derived from most, but not all, mantle cell lymphoma (MCL) are induced to commit suicide after DAG analogue treatment. MCL has no standard treatment strategy, accounts for 5-10% of all B-NHL and has a very dismal prognosis. We propose to use biochemistry, molecular biology, pharmacology and genetic approaches to understand the basis of drug sensitivity versus drug resistance. Our findings will help identify patients who would benefit from drug treatment. We will study both MCL grown in culture and MCL isolated from patients. We will also study drug killing of MCL cells grown in lab animals as "proof-of-principle". Some cases of Burkitt's lymphoma and germinal center B-NHL also respond to our drug. For comparative purposes, we will pursue our strategy with these cell lines as well. We aim to provide a novel, rational treatment strategy for most mantle cell lymphoma patients and select other B-NHL types.