Autophagyinhibition is a novel cancer therapeutic strategy in the early stages of clinical trial testing. Speaking at the 53rd Annual Meeting of the American Society of Hematology in a session titled ?Autophagy and Metabolism in Lymphoid Malignancies,? Clark Distelhorst, MD, Hematology & Oncology, Case Western Reserve University, Cleveland, OH, provided a synthesis of the latest research indicating that autophagy occurs in lymphoid malignancies and may be a novel therapeutic target for lymphoma and other lymphoid neoplasia.

Research reveals thatautophagy, a process through which cells eat parts of themselves to generate sufficient energy to stay alive, is upregulated in response to external stresses, including chemotherapy and radiotherapy.Both apoptosis and autophagy are induced by glucocorticosteroid hormone treatment of lymphoid malignancies. Since the main effects of glucocorticosteroid hormone on lymphocytes are metabolic, it is likely that apoptosis and autophagy are responses to metabolic stress.

Metabolic stress
Metabolic stress occurs because glucocorticosteroid hormone inhibits both glucose uptake and metabolism, as well as calcium signals required for optimal mitochondrial function.Distelhorst suggests that targeting autophagy may be a useful adjunct to the longstanding use of glucocorticoids, such as prednisone, to kill cancer cells.

Treatments aimed at inducing autophagy
A growing body of evidence suggests that treatments aimed at inducing autophagy have great promise in treating lymphoid malignancies and how glucocorticoids starve tumor cells of glucose and thus induce autophagy.Combining autophagy inhibition with agents that induce autophagy as a pro-survival response may therefore increase their therapeutic efficacy.

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Researchers at UH Case Medical Center and Case Western Reserve University identified the Dexamethasone-induced Gene 2 (dig2) that encodes a protein mediator of autophagy. Dig2 is a stress protein that inhibits mTOR (mammalian target of rapamycin) signaling. The mTOR signaling pathway integrates both intracellular and extracellular signals and serves as a central regulator of cell metabolism, growth, proliferation and survival.

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The absence of the Dig2 stress response in Dig2 knockout mice significantly impairs autophagy induction, decreasing lymphocyte survival in GH-treated mice.

Autophagy inhibitors
?This new cancer-fighting strategy lays the groundwork for further development of autophagy inhibitors to enhance the glucocorticoids properties,? says Distelhorst, who is vice-chair of the ASH subcommittee on Lymphoid Neoplasia. ?This is a major step forward in our research efforts to develop new therapies for lymphoid malignancies.?

Program: Scientific Program
Abstract: SCI-26 Autophagy and Metabolism in Lymphoid Malignancies
Session: (Dys-) Regulation of Cell Metabolism in Lymphoid Neoplasia
When: Saturday, December 10, 2011, 4:00 PM-5:30 PM
Where: Room 6A (San Diego Convention Center)

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