Research
Our cells are instructed on how to behave by many external signals, which come from contact with neighboring cells, from signaling molecules that enter the circulation from elsewhere in the body to affect distant cells, and from signaling molecules from invading organisms (viruses, bacteria, fungi, parasites) that alert us to their presence. The signals are conveyed from the outside of the cell to the inside by specialized receptors on the cell surface. Responses to signals result in changes in cellular functions, for example, by increasing the level of antiviral proteins in response to an infection. These changes are carried out by increasing the amounts of specific proteins or by changing their properties. We study the details of these complex interactions in innate immunity and in cancer.
My laboratory has developed important new techniques in biochemistry and molecular biology, including the Northern and Western blot methods. We used genetic methods in mammalian cells in culture to contribute to the discovery of the JAK-STAT pathway, together with Ian Kerr and Jim Darnell. We developed innovative genetic methods to obtain and select mutant mammalian cells in culture, providing novel insights into mechanisms of signaling and drug resistance.
A major current goal of my laboratory is to uncover novel aspects of the complex pathways that human cells use to respond to interferons and to activators of STATs and NF-kB. These pathways have profound effects in cancer and inflammation and are the targets of major efforts to develop novel therapeutics and to improve existing drugs. We have a long history of novel ideas and sustained productivity in signal transduction. We identify new applications for established drugs and then test their effects in novel contexts. We then proceed to preclinical models and clinical trials. For example, we have developed a single molecule called PALA (N-phosphonacetyl-L-aspartate) that has strong activity against many forms of cancer in preclinical models. We have developed a PALA-based ointment that is very effective in treating skin cancer, even preventing recurrences, in preclinical models.
We also discover new drug targets by probing deeply into the mechanistic details of signaling pathways, using discovery genetics, including promoter insertion and CRISPR-mediated deletion strategies. We then examine these pathways carefully, especially by discovering novel post-translational modifications of the relevant proteins.
Biography
Dr. Stark has spent more than 60 years pioneering research into the body’s fundamental processes.
He joined Cleveland Clinic in 1992 as the chair of the Lerner Research Institute after running labs in the Department of Biochemistry at Stanford University at the Imperial Cancer Research Fund in London, where he also served as an Associate Director of Research. As chair, Dr. Stark led unprecedented growth in basic and translational science at Cleveland Clinic while building out his own research program.
He has served on the editorial boards of numerous leading journals, including Cell and the Journal of Biological Chemistry, and scientific advisory councils at numerous cancer research institutions.
Education & Professional Highlights
Appointed: 1992
Education
A.B.: Columbia College, New York ,1955, Chemistry
PhD: Columbia University, New York, 1959, Chemistry
Postdoctoral fellowship: Rockefeller University, New York, 1963, studying protein chemistry
Professional experience
2002-Present: Distinguished Scientist of The Cleveland Clinic Foundation, Cleveland, OH
2009-2020: Member, Executive Committee, Case Comprehensive Cancer Center
2005-2009: Associate Director for Basic Research, Case Comprehensive Cancer Center
1992-2002: Chairman, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH
1989-1992: Associate Director of Research, Imperial Cancer Research Fund, London, United Kingdom
1985-1989: Assistant Director of Research, Imperial Cancer Research Fund, London, United Kingdom
1983-1985: Senior Scientist, Imperial Cancer Research Fund, London, United Kingdom
1971-1983: Professor, Department of Biochemistry, Stanford University, Stanford, CA
1966-1971: Associate Professor, Department of Biochemistry, Stanford University, Stanford, CA
1963-1966: Assistant Professor, Department of Biochemistry, Stanford University, Stanford, CA
Current professional memberships
1964-Present: American Society of Biochemistry and Molecular Biology
Honors & awards
2021: Centennial Anniversary Award for Excellence, Cleveland Clinic Lerner Research Institute
2019: Steven C. Beering Award, University of Indiana School of Medicine
2011: Herbert Tabor Lectureship, American Society for Biochemistry and Molecular Biology
2006: R.E.Dyer Lecturer, NIH 2002: Member, National Academy of Medicine (USA)
2000: Fellow, American Association for the Advancement of Science, Washington, DC
1999: William B. Coley Award for Distinguished Research in Basic and Tumor Immunology
1998: Hugh Clark Distinguished Lectureship, Department of Molecular & Cell Biology, University of Connecticut
1997: Milstein Award, International Society for Interferon and Cytokine Research
1990: Fellow of the Royal Society
1990: Member of EMBO Council
1986: Member, National Academy of Science (USA)
1986: H. A. Sober Memorial Lectureship, American Society of Biological Chemists
Research
Novel therapies for lung, colorectal, skin cancer prevention and treatment
We are working on many therapeutic options to help people treat and potentially avoid different types of cancer:
- We have developed an ointment from a drug called PALA (N-phosphonacetyl-L-aspartate) that treats, and even helps to prevent, skin cancer. Further testing has revealed PALA to be a pan-cancer agent with in vitro and in vivo success in treating preclinical models of lung, breast, and skin cancer, with potential to treat many other forms of cancer. We are collaborating with other labs to further, understand PALA’s mechanisms of action and demonstrate its pan-cancer potential.
- We are studying the new drug CBL0137 in lung cancer and are collaborating with other labs to evaluate its potential use in combination with other modalities, including cis-platin and ionizing radiation.
- Finally, we are also studying the anti-osteoporosis drug bazedoxifene, which inhibits STAT3 activation, as a potential therapeutic agent in glioblastoma (GBM).
Insertional mutagenesis
We use a lentiviral vector to insert a strong promoter in or near genes in human cells, generating populations of millions of cells, each of which can over-express a different specific protein. We then enrich the population for cells with a specific phenotype of interest, for example, resistance to a drug.
Sequencing the RNAs that are linked to vector sequences gives us candidate genes whose products may mediate the phenotype. This methodology has very broad applications. We have used it to identify novel methylations of STAT3 that modulate function and to identify mechanisms of resistance to ionizing radiation. We also collaborate enthusiastically with other labs who wish to use this method.
Responses to interferon (IFN)
The response to type I IFNs is modulated by a growing number of secondary mechanisms, some of which have profound effects on the roles of IFN in tumorigenesis and resistance to infections.
Tyrosine phosphorylation of STAT1 and STAT2 are vital for the primary transcriptional response to IFN, but we now know that phosphorylation of two threonine residues of STAT2 have major regulatory effects. Furthermore, without tyrosine phosphorylation, STAT2 has important roles in driving gene expression, including genes whose products mediate drug resistance in cancer.
Interferon synthesis in cancer
Cancer cells make endogenous Type I IFN in response to internal signals, especially dsRNA produced from endogenous retroviral elements in the DNA and cytoplasmic DNA, produced in response to intrinsic DNA damage, which activates the cGAS/STING pathway, leading to IFN synthesis.
In response to endogenous IFN, cancer cells upregulate resistance to DNA damaging agents.
Cell-intrinsic roles of PD-L1
A new interest in the lab concerns the ability of PD-L1 to modulate how cells respond to IFN-1. This aspect is separate from the well-studied PD-1/PD-L1 interaction.
Our Team
Selected Publications
View publications for George Stark, PhD
(Disclaimer: This search is powered by PubMed, a service of the U.S. National Library of Medicine. PubMed is a third-party website with no affiliation with Cleveland Clinic.)
Selected Publicatoins
IRF9 and unphosphorylated STAT2 cooperate with NF-κB to drive IL6 expression.Nan J, Wang Y, Yang J, Stark GR.Proc Natl Acad Sci U S A. 2018 Apr 10;115(15):3906-3911. doi: 10.1073/pnas.1714102115. PMID: 29581268
The FACT inhibitor CBL0137 Synergizes with Cisplatin in Small-Cell Lung Cancer by Increasing NOTCH1Expression and Targeting Tumor-Initiating Cells.De S, Lindner DJ, Coleman CJ, Wildey G, Dowlati A, Stark GR.Cancer Res. 2018 May 1;78(9):2396-2406. doi: 10.1158/0008-5472.CAN-17-1920. PMID: 29440145
Responses to Cytokines and Interferons that Depend upon JAKs and STATs.Stark GR, Cheon H, Wang Y.Cold Spring Harb Perspect Biol. 2018 Jan 2;10(1). pii: a028555. doi: 10.1101/cshperspect.a028555. Review.PMID: 28620095
Negative regulation of type I IFN signaling by phosphorylation of STAT2 on T387.Wang Y, Nan J, Willard B, Wang X, Yang J, Stark GR. EMBO J. 2017 Jan 17;36(2):202-212. doi: 10.15252/embj.201694834. PMID: 27852626
IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage.Cheon H, Holvey-Bates EG, Schoggins JW, Forster S, Hertzog P, Imanaka N, Rice CM, Jackson MW, Junk DJ, Stark GR.EMBO J. 2013 Oct 16;32(20):2751-63. doi: 10.1038/emboj.2013.203. PMID:24065129
Research News
PALA’s fifty-year journey to a promising multi-cancer treatment highlights the importance of basic science in research.
The topical ointment uses the small molecule PALA, first developed to treat cancer 50 years ago.
The former chair of the Lerner Research Institute, George Stark, PhD, was celebrated with a day-long cancer symposium with talks from collaborators and colleagues on July 7.
A new program funded by a National Cancer Institute grant aims to advance treatments that target the mechanisms tumors use to grow and survive.
Lerner Research Institute's George Stark, PhD, Department of Cancer Biology, was honored with the 2019 Steven C. Beering Award, presented earlier this month following a lecture and reception at the Indiana University School of Medicine.
CBL0137 was discovered by Cleveland Clinic researchers, and has been shown to have positive effects in several types of cancer, and in combination with cisplatin for lung cancer treatment.