Levi Beverly, Ph. D.
Assistant Professor of Medicine
Clinical Translational Research Building, Room 2204
University of Louisville
505 Hancock St.
Louisville, KY 40202, USA
- Investigator, James Graham Brown Cancer Center
- Institute for Molecular Diversity & Drug Design
- Associate Member, Department of Pharmacology and Toxicology
- Associate Member, Department of Bioengineering
- B.S., University of Cincinnati
- Ph.D., Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati
- Postdoctoral Fellowship, Memorial Sloan-Kettering Cancer Center, New York City
- Postdoctoral Fellowship, National Cancer Institute, National Institutes of Health
Laboratory Team Members:
The Beverly lab is interested in using models of human cancer to elucidate the mechanisms of tumor initiation, progression and regression following therapeutic intervention. To this end, we have adopted a philosophy of combining pre-clinical models with biochemistry, molecular biology and cultured human cells to dissect signaling pathways and cellular processes involved in all aspects of cancer biology. Using information gathered from these experiments, we proceed back into our model systems to determine how our understanding of the disease initiation, progression or regression has advanced. To this end the research in the lab can be broken down into multiple specific areas of interest
1. Characterizing the basic biological processes regulated by Ubiquilin proteins in human lung cancer.
The Ubiquilin family of proteins (UBQLN) consists of 5 related proteins (UBQLN1-4 and UBQLNL) which all contain ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains. Our laboratory recently discovered a link between Ubiquilin (UBQLN) protein function and processes involved in tumorigenesis. Furthermore, we found multiple somatic non-synonymous recurrent mutations in UBQLN family members and loss of either UBQLN1 or UBQLN2 in over 50% of human lung adenocarcinoma (hLAC). This data predicts that over 700,000 people die world-wide every year from lung cancer that has altered UBQLN function. Importantly, most patients who succumb to lung cancer, die from the metastatic disease and not from the primary tumor burden. Metastatic cancer progression requires the cells to acquire new aggressive properties, such as increased migration, invasion, survival and growth at the metastatic site. The identification of regulators of these properties will be crucial for our future success in decreasing cancer mortality rates. Thus, the goal of our work is to understand the detailed mechanisms by which disruption of UBQLN-family of proteins contributes to the metastatic progression of hLAC
2. Advance our understanding of how the basic cellular process of cell death is executed.
One fundamental cellular process that affects nearly all aspects of organismal biology is the cell’s basic interpretation of survival and death signals. Although this process has been studied for decades, the exact mechanism of how a cell interprets these signals is still not completely understood, however an intricate balance between proteins and lipids is know to be involved. Our lab is currently collaborating with the laboratory of Leah Siskind to understand, in detail, the biochemical interplay between BCL2-like proteins and bioactive sphingolipids and how the balance between BCL2-like proteins and sphingolipids is disrupted in human cancers. Most importantly, our labs are attempting to understand how altering the balance between BCL2-like proteins and sphingolipids can be used to treat human cancers.
3. Pre-clinical development of novel synergistic drug combinations.
In collaboration with the National Chemical Genomics Center at the National Institutes of Health we have been performing screens to identify novel combinations of drugs, that when used together lead to synergistic killing of cancer cell lines. Thus far, we have performed a number of such screens and have begun to either characterized the synergistic combinations of drugs, or identify collaborators that have expertise in the pathways affected by the individual drugs. In addition, we will use our mouse models to validate and optimize pre-clinical effectiveness of these drug combinations. Our ultimate goals from this project are two-fold; first, we hope to gain insight into the signaling pathways that work in combination to maintain cancer cell viability and second, and most importantly, we hope to find novel and effective drug combinations that we can move into the clinical space for testing on human patients.
- Patwardhan GA, Beverly LJ, Siskind LJ. Sphingolipids and mitochondrial apoptosis. J Bioenerg Biomembr. 2016 Apr;48(2):153-68. PubMed PMID: 25620271.
- Sharp CN, Doll MA, Dupre TV, Shah PP, Subathra M, Siow D, Arteel GE, Megyesi J, Beverly LJ, Siskind LJ. Repeated administration of low-dose cisplatin in mice induces fibrosis. Am J Physiol Renal Physiol. 2016 Mar 15;310(6):F560-8. PubMed PMID: 26739893; PubMed Central PMCID: PMC4796272.
- Sundaram K, Mather AR, Marimuthu S, Shah PP, Snider AJ, Obeid LM, Hannun YA, Beverly LJ, Siskind LJ. Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation-induced cell death. Biochem J. 2016 Mar 15;473(6):743-55. PubMed PMID: 26747710.
- Dupre TV, Doll MA, Shah PP, Sharp CN, Kiefer A, Scherzer MT, Saurabh K, Saforo D, Siow D, Casson L, Arteel GE, Jenson AB, Megyesi J, Schnellmann RG, Beverly LJ, Siskind LJ. Suramin protects from cisplatin-induced acute kidney injury. Am J Physiol Renal Physiol. 2016 Feb 1;310(3):F248-58. PubMed PMID: 26661653; PubMed Central PMCID: PMC4877945.
- Beverly LJ, Podsypanina K. Murine Stem Cell-Based Retrovirus Production for Marking Primary Mouse Mammary Cells for Metastasis Studies. Cold Spring Harb Protoc. 2016 Feb 1;2016(2):pdb.prot078337. PubMed PMID: 26832680.
- Kabeer F, Beverly LJ, Darrasse-Jèze G, Podsypanina K. Methods to Study Metastasis in Genetically Modified Mice. Cold Spring Harb Protoc. 2016 Feb 1;2016(2):pdb.top069948. PubMed PMID: 26832689.
- Chang KT, Anishkin A, Patwardhan GA, Beverly LJ, Siskind LJ, et al. Ceramide channels: destabilization by Bcl-xL and role in apoptosis. Biochim Biophys Acta. 2015 Oct;1848(10 Pt A):2374-84. PubMed PMID: 26215742; NIHMSID: NIHMS710990; PubMed Central PMCID: PMC4554889.
- Shah PP, Beverly LJ. Regulation of VCP/p97 demonstrates the critical balance between cell death and epithelial-mesenchymal transition (EMT) downstream of ER stress. Oncotarget. 2015 Jul 10;6(19):17725-37. PubMed PMID: 25970786; PubMed Central PMCID: PMC4627341.
- Shah PP, Lockwood WW, Saurabh K, Kurlawala Z, Shannon SP, Waigel S, Zacharias W, Beverly LJ. Ubiquilin1 represses migration and epithelial-to-mesenchymal transition of human non-small cell lung cancer cells. Oncogene. 2015 Mar 26;34(13):1709-17. PubMed PMID: 24747970; NIHMSID: NIHMS574515; PubMed Central PMCID: PMC4205225.
- Stathem M, Marimuthu S, O'Neal J, Rathmell JC, Chesney JA, Beverly LJ, Siskind LJ. Glucose availability and glycolytic metabolism dictate glycosphingolipid levels. J Cell Biochem. 2015 Jan;116(1):67-80. PubMed PMID: 25145677; NIHMSID: NIHMS630321; PubMed Central PMCID: PMC4229434.
- Saurabh K, Scherzer MT, Shah PP, Mims AS, Lockwood WW, Kraft AS, Beverly LJ. The PIM family of oncoproteins: small kinases with huge implications in myeloid leukemogenesis and as therapeutic targets. Oncotarget. 2014 Sep 30;5(18):8503-14. PubMed PMID: 25238262; PubMed Central PMCID: PMC4226700.
- Saurabh K, Scherzer MT, Song A, Yip KW, Reed JC, Li C, Beverly LJ. Dissecting the <i>in vivo</i> leukemogenic potency of BCLxl. J Leuk (Los Angel). 2014;2(5):158. PubMed PMID: 26636115; NIHMSID: NIHMS717523; PubMed Central PMCID: PMC4666309.
- Rhyasen GW, Bolanos L, Fang J, Jerez A, Wunderlich M, Rigolino C, Mathews L, Ferrer M, Southall N, Guha R, Keller J, Thomas C, Beverly LJ, Cortelezzi A, Oliva EN, Cuzzola M, Maciejewski JP, Mulloy JC, Starczynowski DT. Targeting IRAK1 as a therapeutic approach for myelodysplastic syndrome. Cancer Cell. 2013 Jul 8;24(1):90-104. PubMed PMID: 23845443; NIHMSID: NIHMS481115; PubMed Central PMCID: PMC3711103.
- Lockwood WW, Chandel SK, Stewart GL, Erdjument-Bromage H, Beverly LJ. The novel ubiquitin ligase complex, SCF(Fbxw4), interacts with the COP9 signalosome in an F-box dependent manner, is mutated, lost and under-expressed in human cancers. PLoS One. 2013;8(5):e63610. PubMed PMID: 23658844; PubMed Central PMCID: PMC3642104.