美国纪念斯隆凯特琳癌症中心博士后

美国纪念斯隆凯特琳癌症中心博士后

Post-Doc in the Kolesnick Lab at the Sloan Kettering Institute

Employer

Memorial Sloan Kettering Cancer Center

Location

New York City, New York

Salary

Commensurate with education and experience

Closing date

Jan 6, 2025

Post-Doc in the Kolesnick Lab at the Sloan Kettering Institute Targeting Sphingolipid Metabolism in Acute Myelogenous Leukemia

The people of Memorial Sloan Kettering Cancer Center (MSK) are united by a singular mission: ending cancer for life. Our specialized care teams provide personalized, compassionate, expert care to patients of all ages. Informed by basic research done at our Sloan Kettering Institute, scientists across MSK collaborate to conduct innovative translational and clinical research that is driving a revolution in our understanding of cancer as a disease and improving the ability to prevent, diagnose, and treat it. MSK is dedicated to training the next generation of scientists and clinicians, who go on to pursuer mission at MSK and around the globe. One of the world’s most respected comprehensive centers devoted exclusively to cancer, we have been recognized as one of the top two cancer hospitals in the country by U.S. News & World Report for more than 30 years.

Exciting Opportunity at MSK: Post-Doc in the Kolesnick Lab Targeting Sphingolipid Metabolism in Acute Myelogenous Leukemia

Overview of Current Advancements

Translation of cutting edge lipidomic and single cell sequencing technologies to human clinical trials is revolutionizing our understanding of human cancer biology. Using these technologies, clinical investigations at the University of Virginia have identified changes in sphingomyelin intermediary metabolism as critical to evolution of Acute Myelogenous Leukemia (AML). Specifically, extent of elevation of C24-sphingomyelin levels predicts response to anti-cancer therapies and clinical outcome of disease (Paudel et al., Blood Adv 2024; 8:1137-1142). New treatments are urgently needed for patients with AML, which is the most common type of acute leukemia in adults. Current 5-year survival rate is only about 30% with few significant improvements in outcome over the past four decades. Our recent insight, combining patient lipidomic and single cell sequencing data of the enzymatic changes leading to specific alterations in patient lipid profiles provides a path forward to more deeply understand why patients with elevated C24-sphingomyelin levels are treatment resistant. In our opinion, the sphingolipid alterations observed in AML patient samples are likely to be directly responsible, in part or in whole, for a new form of drug resistance.

Research Studies in the Kolesnick Lab

During this post-doctoral fellowship represent a collaboration between the University of Virginia Cancer Center and the Sloan Kettering Institute aimed at elucidating the mechanism by which elevated C24-sphingomyelin levels confer AML cell resistance to anti-cancer therapies. These studies will leverage a 3D confocal technique recently-reported by our lab (Dorweiler et al., Cell Metabolism 2024; 36:1521-1533) to evaluate the role of a structural change in the plasma membrane termed a ceramide-rich platform in development of AML resistance to anti-cancer therapy. Ceramide-rich platforms, originally discovered by our lab (Cremesti et al., J Biol Chem 2001; 2001, 276:23954-61), represent transient macrodomains that can occupy up to 25% of the cell surface which serve as sites for insertion and complexation of multi-subunit protein components to functionalize transmembrane signaling.

Recent unpublished data from our lab indicate that equilibrative nucleoside transporter 1 (ENT1) must dimerize in a ceramide-rich platform to functionalize uptake of the anti-cancer drug gemcitabine into sarcoma cells. Pharmacologic targeting of this sphingolipid-based drug transport mechanism resulted in a large improvement in sarcoma patient response in a Phase II clinical trial performed at Memorial Sloan Kettering Cancer Center (J Clin Invest, in revision). It is our working hypothesis that altered sphingolipid metabolism in AML similarly impairs ceramide-rich platform-mediated response to standard of care treatment of patients with advanced AML. Establishing the mechanism of C24-sphingomyelin driven AML drug resistance will define a new mode of drug resistance that will likely prove amenable to ongoing therapeutic strategies directed at altering intermediary sphingolipid metabolism currently under development in our program.

Pay Range: 55,439 – 100,940

Helpful links:  

MSK's Compensation Philosophy

Benefits 

Additional information: https://www.mskcc.org/research/ski/labs/richard-kolesnick

Application Instructions:

Interested candidates please send curriculum vitae to:

Richard Kolesnick MD

Professor of Molecular Pharmacology and Medicine

Weill Cornell Medical College

Member, Sloan Kettering Institute

e-mail: r-kolesnick@ski.mskcc.org

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