Leah J. Siskind, Ph.D.

Education:

B.S., University of Maryland, College Park, MD, 1998
Ph.D., Membrane Biophysics, Biology, University of Maryland, College Park, MD, 2003
Postdoctoral Fellowship, University of Maryland, College Park, MD, 2006
Postdoctoral Fellowship, Medical University of South Carolina, Charleston, SC 2009

Curriculum Vitae

Current Positions:

Professor, Department of Medicine, Division of Medical Oncology and Hematology
Member, Brown Cancer Center

Contact Information:

Clinical Translational Research Building, Room 203
University of Louisville
505 Hancock St.
Louisville, KY 40202, USA
Phone 502-852-1283
Fax 502-852-7979

Email: leah.siskind@louisville.edu

Research Description:

The Siskind laboratory focuses on a family of bioactive lipids called sphingolipids that regulate processes fundamental to cancer initiation and progression. There is a balance between pro-death and pro-survival members of the sphingolipid family. Sphingolipid metabolism becomes unbalanced to favor cell survival in cancer cells and our data suggests that cancer cells rely on specific sphingolipids for their survival. We aim to target this weakness of cancer cells to design better combinatorial cancer treatments. To this end, we combine our expertise at the biophysical, molecular, cellular, and animal level with the goal of translating our findings to the clinic. The laboratory has several areas of focus, three of which are described briefly below.

    1. Protecting the kidney from the toxic effects of chemotherapeutics so that they can be more effectively utilized to treat cancer.

      Current chemotherapies such as cisplatin often have the deleterious side-effect of kidney toxicity which in almost 30% of cancer patients limits their use. The kidney is extremely sensitive to toxicity from chemotherapies and there are no currently available treatments to protect the kidney from the toxic effects of chemotherapies without interfering with the ability of the chemotherapies to kill the cancer cells. Data from the Siskind laboratory have identified glucosylceramide as a factor generated in the kidney in response to chemotherapies that results in toxicity. Glucosylceramides are also highly abundant in cancers and are thought to contribute to drug resistance. This project aims to utilize inhibitors of glucosylceramide generation to simultaneously protect the kidney from and sensitize the cancers to chemotherapies such as cisplatin.

        2. Targeting glucose and glycosphingolipid addiction of cancer cells as a novel therapeutic strategy.

          Developing treatment regimes that target cancer cells, whilst sparing normal cells is the goal of cancer research. Cancer cells fundamentally shift their energy metabolism to favor glucose and preferentially rely on it as their main energy source. Inhibitors of glucose metabolism are being explored as potential treatment for cancers including leukemia. However, their use as single agents is limited by their toxicity at high doses. Data from the Siskind laboratory indicate that the sphingolipid glucosylceramide is a novel therapeutic target that synergizes with inhibitors of glucose metabolism for the eradication of leukemia cells. FDA approved inhibitors are available to inhibit this novel target and thus this project has a high degree of translational potential.

            3. Determine the basic mechanisms which drive cancer cell death.

              The development of therapeutics that specifically target cancer cells, while sparing normal cells, is the ultimate goal of oncological research.  Unfortunately, the ever-evolving nature of cancer cells results in primary or acquired resistance to nearly all currently available targeted therapies.  Therefore, single agent therapeutics will not be viable treatment options for the killing of the vast majority of human cancers.  The exact molecular mechanisms responsible for cell death are highly debated, but a balance between members of the BCL2-like proteins and bioactive sphingolipids is known to be involved. Disruption of this balance plays a vital role in the resistance of cancers to some available treatments. The long-term goalof this project is to understand how the interplay between BCL2 proteins and sphingolipids initiate apoptosis and how this interplay can be exploited for the development of novel combinatorial cancer treatments.  This project is a collaboration with the laboratory of Levi Beverly and greatly benefits from not only synergistic nature with which the two laboratories function, but also the diverse expertise and training backgrounds of the two laboratories.

              Literature Cited:

              1. Stathem M, MarimuthuS, O’NealJ, RathmellJC, ChesneyJA, Beverly LJ, Siskind LJ.  Glucose availability and glycolytic metabolism dictate glycosphingolipid levels. Journal Cell Biochem. 2015 Jan;116(1). PMID: 25145677
              2. Nowling TK, Mather AR, Thiyagarajan T, Hernandez-Corbacho MJ, Jones EE, Powers TW, Snider AJ, Oates JC, Drake RR, and Siskind LJ. (2014) Renal glycosphingolipid metabolism is dysfunctional in lupus mice and patients with nephritis. Journal of the American Society of Nephrology. pii: ASN.2014050508. [Epub ahead of print] PMID: 25270066
              3. Beverly LJ*, Howell LA, Hernandez-Corbacho MJ, Casson L, Chipuk JE, and Siskind LJ*. (2013) BAK activation is necessary and sufficient to drive ceramide synthase-dependent ceramide accumulation following inhibition of BCL2-like proteins. Biochem J. 2013 May 15;452(1):111-9.  PMC3642864  PMID: 23480852. * Co-Corresponding Authors
              4. Casson L, Howell L, Mathews LA, Ferrer M, Southall N, Guha R, Keller JM, Thomas C, Siskind LJ*, and Beverly LJ*. (2013) Inhibition of ceramide metabolism sensitizes human leukemia cells to inhibition of BCL2-like proteins. PLoS One. 8(1): e54525. doi:10.1371/journal.pone.0054525. PMC3546986 PMID:23342165* Co-Corresponding Authors
              5. Chipuk JE, McStay GP, Bharti A, Kuwana T, Clarke CJ, Siskind LJ, Obeid LM, and Green DR. (2012) Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis. Cell. 148(5): 988-1000. PMID: 22385963
              6. Romero Rosales K, Singh G, Wu K, Chen J, Janes M, Lilly M, Peralta E, Siskind L, Bennett M, Fruman DA, and Edinger AL. (2011) Sphingolipid-based drugs selectively kill cancer cells by down-regulating nutrient transporter proteins. Biochem. J. in press. PMID: 21767261
              7. Hernandez-Corbaco M, Jenkins R, Clarke CJ, Hannun YA, Obeid LM, Snider AJ, and Siskind LJ. (2011) Glycosphingolipids mediate renal aging. PLoS One 6(6):e20411.
              8. Siskind LJ*, Mullen TD, Rosales, KR, Clarke, CJ, Hernandez-Corbacho MJ, Edinger, AI, and Obeid, LM (2010). The Bcl-2 protein BAK is required for ceramide generation during apoptosis. Journal of Biological Chemistry. 285(16):11818-26  *Corresponding Author
              9. Guenther GG,Peralta ER, Romero KM, Wong SY, Siskind LJ, and Edinger AL. (2008) Ceramide starves cells to death by down-regulating nutrient transporter proteins. Proceedings of the National Academy of Sciences of the United States of America. 105(45):17402-7
              10. Siskind LJ, Feinstein L, Yu T, Davis JS, Jones D, Choi J, Zuckerman JE, Tan W, Hill RB, Hardwick JM. Colombini  M. (2008) Anti-apoptotic Bcl-2 family proteins disassemble ceramide channels.  Journal of Biological Chemistry 283(11):6622-30
              11. Siskind LJ, Kolesnick RN and Colombini M. (2006) Ceramide forms channels in mitochondrial outer membranes at physiologically relevant concentrations. Mitochondrion. 6(3):118-25.
              12. Siskind LJ, Fluss S, Bui M and Colombini M. (2005) Sphingosine forms channels in membranes that differ greatly from those formed by ceramide. Journal of Bioenergetics and Biomembranes. 37(4): 227-236.
              13. Siskind LJ, Davoody A, Lewin N, Marshall S and Colombini M. (2003) Enlargement and contracture of C2-ceramide channels. Biophysical Journal 85: 1560-1575.
              14. Siskind LJ, Kolesnick RN and Colombini M. (2002) Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins. Journal of Biological Chemistry 277: 26796-26803
              15. Siskind LJ and Colombini M. (2000) The lipids C2- and C16-ceramide form large stable channels in membranes: implications for apoptosis. Journal of Biological Chemistry 275: 39640-44.

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