There is an urgent need for new treatment modalities for myeloid hematological disorders such as acute myeloid leukemia (AML). Outcomes for most AML patients remain dismal despite several recently approved treatment options. Unfortunately, these therapies may only benefit patients with specific molecular abnormalities and/or may only modestly extend life spans. Our preliminary studies have provided evidence that Gdf-1 can be linked to ceramide neutralization. Therefore, recombinant Gdf-1 may represent a combinatorial approach that may augment ceramide-augmenting therapeutic efficacy. The development of Gdf-1 as an anti-AML therapeutic is innovative because this serves the purpose of blunting metabolism of pro-apoptotic ceramide. Therefore, Gdf-1 therapy is well-positioned to augment the efficacy of standard of care AML therapy. The aim of this proposal is to evaluate preclinical in vivo anti-AML efficacy of the combination of ceramide-augmeenting therapeutics with recombinant Gdf-1. This will test the overarching hypothesis of this Bridge-2-Translation (BTT) proposal: that anti-AML therapeutic efficacy can be achieved by combining ceramide-augmenting therapeutics such as AraC (also known as cytarabine) or nanoliposomal C6-ceramide (Lip-C6) with recombinant Gdf-1, which will prevent the neutralization of proapoptotic ceramide. Overall, this BTT proposal will help to advance the development of recombinant Gdf-1 as a novel anti-AML therapeutic technology that regulates sphingolipid metabolism in AML. The efforts associated with this proposal will also support the training of undergraduate and graduate student researchers in the drug discovery and development process. Moreover, this BTT proposal will advance the recognition of Dr. Barth’s contribution as an independent scientist in the fields of sphingolipid biology, cancer genetics, and their roles in hematopoiesis and leukemia.
