Talking at the Broad Institute September 2016

 

Contribution to Science

 

I am a physician who believes in translational science. In addition to the numerous research fields to which I have directly contributed over the past years, (as can be seen from the below relevant specific investigative fields), I am confident that I have also made a major contribution to the education of students in the field of science. For more than 30 years I have invested significantly in teaching medical students, undergraduates and graduates, and through these educational sessions have influenced them to take part in the world of translational medicine. Many of these students have then continued on to complete MD/PhD programs. In addition, I also taught residence physicians many of whom conducted PhDs after completing their MD or residency studies. At any given   time during my academic career I have personally had at over 40 PhD/MSc students. Accordingly, I view my educational investment in students as well as in peers as a major contribution to science.

 

As a clinical hepatologist, most of my studies result from questions that initiated, directly or indirectly, in the clinic. To date, my articles have over 7000 citations. Below are some of the specific scientific areas in which I have conducted research and to which I have contributed:

 

Gene Therapy:  Although it may seem simple and straightforward, gene therapy is a very challenging field of translational medicine. One major difficulty is the implementation of efficient and effective drug delivery systems. The cited work below highlights key programs that I have been involved in - most of them aimed at overcoming delivery obstacles. We have completed a phase 1 clinical investigation with our most recent delivery platform and this is now under FDA IND discussions (the phase 1 was performed in Israel). In this study we show that a biodegradable scaffold is able to shed from within a tumor siRNA targeting K-RASmut and encounter a significant anti tumor effect. The pre-clinical results of this study are published in PNAS as depicted below:

Figure: Using low energy laser for the introduction of expression plasmid into the retinal cells of a rat. Part B shows the introduction of pGFP to the retina using laser. A, C & D are controls.

 

Lippin Y, Dranitzki-Elhalel M, Brill-Almon E, Mei – Zahav C, Mizrachi S, Liberman Y, Iaina A, Kaplan E, Podjarny E, Shani N, Galun E. (2005). Human erythropoietin gene therapy for patients with chronic renal failure. Blood 106:2280-2286.

Freeman AI, Zakay-Rones Z, Gomori JM, Linetsky E, Panet A, Libson E, Linda R, Greenbaum G, Irving CS, Galun E, Siegal T. (2006).

PhaseI/II trail of intravenous NDV-HUJ (OV001) oncolytic virus in recurrent glioblastoma multiforme. Molecular Therapy  13:221-228.

Zeira E, Manevitch A, Manevitch Z, Kedar E, Gropp M, Daudi N, Barsuk R, Harati M, Yotvat H, Troilo P, Griffiths T, Pacchione S, Roden D, Niu Z, Nussbaum O, Zamir G, Pappo O, Hemo I, Lewis A, Galun E. (2007). Femtosecond laser - A new intradermal DNA delivery method for efficient, long-term gene expression and genetic immunization. FASEB J 21:3522-33.

Zorde Khvalevsky E,Gabai R,Rachmut I-H, Horwitz E, Brunschwig Z, Orbach A, Shemi A, Golan T, Domb A, Yavin E, Giladi H, Rivkin L, Simerzin A, Elyakim R, Kalila A, Hubert A, Lahav M, Kopelman Y, Goldin E, Dancour A, Hants Y, Arbel-Alon S, Abramovitch R, Shemi A, Galun E. (2013). Mutant KRAS as a druggable target for pancreatic cancer. Proc Natl Acad Sci (USA) 110:20723-8.

Golan T, Zorde Khvalevsky E, Hubert A, Malka Gabai R, Hen N, Segal A, Domb A, Harari G, Ben David E, Raskin S, Goldes Y, Goldin E, Eliakim R, Lahav M, Kopleman Y, Dancour, Shemi A, Galun E. (2015). RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients. Oncotarget 6:24560-70.

 

Hepatitis B virus (HBV) and Hepatitis C virus (HCV): Until quite recently, I have been engaged in the attempt to develop novel approaches for the treatment of HBV and HCV. Two decades ago, it was obvious that the most essential barrier for the development of efficient anti hepatitis drugs, in addition to the basic understanding of HBV and HCV biology, was the fact that there was no animal model to assess the drugs. In addition, the recurrence of both HBV and HCV infection in transplanted liver in patients who are carriers of either virus was a major challenge. Accordingly, we developed the first HBV and HCV small animal models – the Trimera mice with HBV and HCV. In these models we could investigate the properties of anti-hepatitis drugs for the relevant clinical indications. We could assess anti-HBV and anti-HCV human monoclonal antibodies that we developed and also tested these later in humans in clinical studies. The most prominent reports on the animal models, the effect of the anti-hepatitis monoclonal antibodies in the animal models and the clinical development are depicted below:

 

Ilan E, Burakova T, Dagan S, Nussbaum O, Lubon I, Eren R, Ben-Moshe O, Arazi J, Berr S, Neville L, Yuen L, Mansour TS, Gillard J, Eid A, Jurim O, Shouval D, Reisner Y, Galun E. (1999). The HBV - Trimera mouse: A model for human HBV infection and evaluation of anti-HBV therapeutic agents. Hepatology 29:553-62.

Ilan E, Arazi J, Nussbaum O, Zauberman A, Eren R, Lubin I, Ben-Moshe O, Kischitzky A, Litchi A,  Margalit I, Gopher J, Mounir S, Cai W, Daudi N, Eid A, Jurim O, Czerniak A, Galun E, Dagan S. (2002). The hepatitis C virus - Trimera mouse: A model for evaluation of anti-HCV therapeutic agents. J Infectious Disease 185:153-61.

Galun E, Eren R, Safadi R, Ashour Y, Terrault N, Keeffe EB, Matot I, Mizrachi S, Terkieltaub D, Zohar M, Lubin I, Gopher J, Shouval D, Dagan S. (2002). Clinical evaluation (phase I) of a combination of two human monoclonal antibodies to HBV: safety and antiviral properties. Hepatology 35:673-679.

Eren R, Landstein D, Terkieltaub D, Nussbaum O, Zauberman A, Ben-Porath J, Gopher J, Buchnick R, Kovjazin R, Rosenthal-Galili Z, Aviel S, Ilan E, Shoshany Y, Neville L, Waisman T, Ben-Moshe O, Kischitsky A, Foung SKH, Keck Z-Y, Pappo O, Eid A, Jurim O, Zamir G, Galun E, Dagan S. (2006). Preclinical evaluation of two neutralizing human monoclonal antibodies against HCV: A potential treatment to prevent re-infection  in liver transplant patients. J Virology 80:2654-2664.

Galun E, Terrault N, Eren R, Zauberman A, Nussbaum O, Terkieltaub D, Zohar M, Buchnik R, Ackerman Z, Safadi R, Ashur Y, Misrachi S, Liberman Y, Rivkin  L,  Dagan S. (2007). Clinical Evaluation (Phase I) of a Human Monoclonal Antibody against Hepatitis C Virus: Safety and Antiviral Activity. J Hepatology 46:37-44.

Liver inflammation: The liver is a very unique organ in the sense that upon chronic inflammation  it responds by regeneration to overcome the tissue loss. However, numerous pathological conditions develop which contribute later to the development of hepatocellular carcinoma (HCC). Prior to the investigation, and later on in parallel

to the studies aimed to understand the mechanism of how inflammation in the liver causes HCC, we were interested to identify the mediator of regeneration in the inflamed liver. We also wished to better understand the contribution of these factors both to the inflammatory process as well as to the regenerative process.  We are currently investigating this, and in a preparatory report  we have shown that microRNA 675, which is derived from the lncRNA H19, targets FADD and by this shifts the inflammatory signal of TNF coming from macrophages to necroptosis.

Lavon I, Goldberg I, Amit S, Jung S, Tsuberi BZ, Barshak I, Kopolovic J, Galun E, Bujard H, Ben-Neriah Y. (2000). High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-kappaB activation. Nature Medicine, 6:573-7.

Khvalevsky E, Rivkin L, Rachmilewitz J, Galun E, Giladi H. (2007) TLR3 signaling in a hepatoma cell line is skewed towards apoptosis. Journal of Cellular Biochemistry 100:1301-12.

Ben Moshe T, Barash H, Kang TB, Kim JC, Kovalenko A, Gross E, Schuchmann M, Abramovitch R, Galun E, Wallach D. (2007).  Role of caspase-8 in hepatocyte response to infection and injury in mice.

Hepatology. 45:1014-24.

Zorde-Khvalevsky E, Abramovitch R, Harel-Barash H, Rivkin L, Spivak-Pohis I, Rachmilewitz J, Galun E, Giladi H. (2009). TLR3 signaling attenuates liver regeneration. Hepatology 50:198-206.

Rivkin M, Zorde-Khvalevsky E, Simerzin A, Chai C, Yuval JB, Rosenberg N, Harari-Steinfeld R, Schneider R, Amir G, Condiotti R, Heikenwalder M, Weber A, Schramm C, Wege H, Kluwe J, Galun E*, Giladi H. (2016). Inflammation-Induced Expression and Secretion of MicroRNA 122 Leads to Reduced Blood Levels of Kidney-derived Erythropoietin and Anemia. Gastroenterology 151:999-1010.  (* corresponding author)

 

IL6 signaling:  While investigating the inflammatory process in the liver as a result of injury we have detected IL6 as a central “player”. We have initiated a program to both understand the mechanism of how IL6 contributed to liver regeneration, while at the same time developing a therapeutic approach of how to utilize this signaling to overcome major liver injury. It appears that IL6-transsignaling (TS) is a major contributor to the regenerative effects of IL6. We have recently also shown that IL6 TS overcomes senescence that is induced by radiation. This last effect is currently being developed into a potential therapeutic platform. Salivary glands are targeted at the radiation zone upon radiating head and neck tumors. The resulting   effect on  the glands from radiation causes a dry mouth syndrome. We found that this is a result of senescence of the cells in the salivary gland. Pre-treating the salivary gland, by retrograde local administration of an IL6 designer protein that induces TS, prevents senescence and salivary loss of function, thus enabling salivation.  We have also shown direct capability of leveraging our molecular techniques for detecting and assessing IL-6 for RF ablation studies.

Figure: PH generates micronuclei in hepatocytes of Mdr2 –/– mice and is prevented by IL6 blockade. (A) Representative confocal microscopic photomicrographs of immunofluorescently stained liver sections from naive Mdr2 –/– and WT mice, double-stained for lamin (red) and b-catenin (green) and counterstained with DAPI to show DNA (blue) in nuclei and MNi (arrows). Scale bars,20 lm. (B) Quantification of MNi hepatocytes in immunofluorescently stained livers of WT and Mdr2 –/– mice before PH and 2and 6 days following PH in mice treated with control IgG or anti-IL6 mAbs.

Galun E,  Zeira E, Pappo O, Peters M, Rose – John S. (2000). Liver regeneration induced by a designer human IL-6/sIL-6R fusion protein reverses severe hepatocellular injury. FASEB J 14: 1979-1987.

Hecht N, Pappo O, Shouval D, Rose-John S, Galun E, Axelrod JA. (2001). Hyper-IL-6 gene therapy reverses fulminant hepatic failure. Molecular Therapy 3: 683-687.

Nechemia-Arbely Y, Shriki A, Denz U, Drucker C, Scheller J, Raub J, Pappo O,Rose-John S, Galun E, Axelrod JH.(2011). Early Hepatocyte DNA Synthetic Response Posthepatectomy is Modulated by IL-6 Trans-Signaling and PI3K/AKT Activation . J Hepatology 54:922-9.

Marmary Y, Adar R, Gaska S, Wygoda A, Maly A, Cohen J, Eliashar R, Mizrachi L, Orfaig-Geva C, Baum B, Rose-John S, Galun E, Axelrod JH. (2016). Cellular Senescence Drives Radiation-Induced Loss of Salivary Gland Function and is Prevented by IL-6 Modulation. Cancer Res 76:1170-80.

Lanton T, Shriki A, Nechemia-Arbely Y, Abramovitch R, Levkovitch O, Adar R, Rosenberg N, Paldor M, Goldenberg D, Sonnenblick A, Peled A, Rose-John S,  Galun E, Axelrod JH. (2017). IL6-Dependent Genomic Instability Heralds Accelerated Carcinogenesis Following Liver Regeneration on a Background of Chronic Hepatitis. Hepatology (in press).

Inflammation induced liver cancer: As a hepatologist one major interest I have is the development of drugs that will prevent or treat HCC. However, prior to developing such a therapeutic approach it is of the utmost importance  that we understand the mechanism of inflammation induced HCC. We have identified pivotal factors through which the inflammatory process in the liver causes cancer. This is primarily NF-kB. We have adopted the Mdr2 knockout mice as the animal model in which we investigate the significance of the various inflammatory factors contributing to HCC following a prolonged inflammatory process. One pivotal cell, the macrophage, appears to be central to the development of HCC. We show that in  CCR5 knockout mice, which prevent macrophage migration to the liver, HCC is significantly attenuated. We also show that macrophages in the liver are central in DNA-damage response. We are now investigating the contribution of this to HCC development.

 

Abramovich R, Tavor E, Jacob-Hirsch J, Zeira E, Amariglio N, Pappo O, Rechavi G, Galun E,  Honigman A.  (2004). The pivotal role of CREB in tumor progression. Cancer Res 64:1338-46.

Pikarsky E, Porat RM, Stein I, Abramovich R, Amit S, Kasem S, Gutkovich-Pyest E, Galun E, Ben-Neriah Y. (2004). NF-kB functions as a tumor promoter in a mouse model of inflammation-associated liver cancer. Nature 43:461-6.

Barasa H, Gross E, Edrei Y, Israel A, Cohen I, Ben-Moshe T, Pappo O, Pikarsky E, Goldenberg D, Shiloh Y, Galun E, Abramovitch R. (2010). The accelerated carcinogenesis following liver regeneration is associated with chronic inflammation induced double strand DNA breaks. Proc Natl Acad Sci (USA) 107:2207-12.

Barashi N, Weiss ID, Wald O, Wald H, Beider K, Abraham M, Klein S, Goldenberg D, Axelrod J, Pikarsky E, Abramovitch R, Zeira E, Galun E, Peled A. (2013). Inflammation induced hepatocellular carcinoma is dependent on CCR5. Hepatology 58:1021-30.

Galun E. (2016). Liver inflammation and cancer: The role of tissue microenvironment in generating the tumor-promoting niche (TPN) in the development of hepatocellular carcinoma. Hepatology 63:354-6.

Simerzin A, Zorde-Khvalevsky E, Rivkin M, Adar R, Zucman-Rossi J, Couchy G, Roskams T, Govaere O, Oren M, Giladi H, Galun E. (2016). The liver-specific miR-122*, the complementary strand of miR-122, acts as a tumor suppressor by modulating the p53-Mdm2 circuitry. Hepatology 64:1623-1636.

Guedj A, Geiger-Maor A, Galun E, Amsalem H, Rachmilewitz J. (2016) Early Age Decline in DNA Repair Capacity in the Liver: In Depth Profile of Differential Gene Expression. Aging 8:3131-3146.

Stoyanov E, Mizrahi L, Olam D, Schnitzer-Perlman T, Galun E, Goldenberg D. (2017). Short-term S-adenosylmethionine supplementation suppresses tumor development in a murine model of inflammation-mediated hepatocarcinogenesis. Oncotarget (in press)

Figure (from the editorial on our miR122* paper):

miR-122/miR-122* biogenesis and activity. miR-122 gene expression is positively controlled by some transcription factors and negatively regulated by epigenetic modifications. In the nucleus, the primary miRNA is cleaved by the Microprocessor complex to originate precursor miR-122, which is then exported to the cytoplasm. Precursor miR-122 is further processed by DICER; at this stage, some factors could regulate the miRNA guide-to-passenger strand ratio. miR-122 exerts its suppressive function by targeting several genes involved in control of cell growth and differentiation and of inflammation; among the targets critical for miR-122* suppressive function is Mdm2, a negative regulator of p53.

Systemic tumorigenic effects of RF ablation:  We  recently developed an additional line of collaborative investigation into the secondary systemic effects of local thermal ablation that may contribute to unwanted ‘off-target’ stimulatory effects on distant tumors present elsewhere in the body.  We have completed several studies characterizing post-ablation tumorigenic effects, including identifying key mechanisms responsible, such as periablational inflammation and growth factor production.  Together with Profs. Ahmed and Goldberg of Boston, we have successfully combined RFA with adjuvant drug inhibitors of IL-6, c-Met, and VEGFR to block such tumorigenic effects. The following four publications support my expertise in the field.:

 

Rozenblum N, Zeira E, Scaiewicz V, Bulvik B, Gourevitch S, Yotvat H, Galun E, Goldberg SN. (2015). Oncogenesis: An "Off-Target" Effect of Radiofrequency Ablation. Radiology  276:426-32.

Ahmed M, Navarro G, Wang Y, Gourevitch S, Moussa MH, Rozenblum N, Levchenko T, Galun E, Torchilin VP,

Ahmed M, Kumar G, Moussa M, Wang Y, Rozenblum N, Galun E, Goldberg SN. (2016). c-Met receptor inhibition can suppress hepatic radiofrequency ablation-induced stimulation of distant subcutaneous tumor growth. Radiology 279:103-17.

Bulvik BE, Rozenblum N, Gourevitch S, Ahmed M, Galun E, Goldberg SN.  (2016). IRE versus RFA: A comparison of local and systemic effects in a small animal model.  Radiology 2016 [on-line]

Kumar G, Goldberg SN, Wang Y, Velez E, Gourevitch S, Galun E, Ahmed M. (2016). Hepatic radiofrequency ablation: markedly reduced systemic effects by modulating periablational inflammation via cyclooxygenase-2 inhibition. Eur Radiol 27:1238-1247

Kumar G, S. Goldberg NS, Gourevitch S, Levchenko T, Torchilin V, Galun E, Ahmed M. (2017). Targeting STAT3 to suppress systemic pro-oncogenic effects from hepatic RF ablation. Radiology (in press).

 

The role of microRNAs in pathological and physiological conditions: It is becoming more and more apparent that microRNAs are functioning in metabolism, cancer and numerous other conditions. Our group recently generated data which actually shows that microRNAs act as hormones. They are expressed and secreted from one organ and function at a remote organ. We also show their effects in cancer other than HCC. We find that microRNAs are very cell lineage specific. These effects are expressed in the below reports:

 

Abraham M, Klein S, Bulvik B, Wald H, Weiss ID, Olam D, Weiss L, Beider K, Eizenberg O, Wald O, Galun E, Avigdor A, Benjamini O, Nagler A, Pereg Y, Tavor S, Peled A. (2017). The CXCR4 inhibitor BL-8040 induces the apoptosis of AML blasts by down-regulating ERK BCL-2, MCL-1 and cyclin-D1 via altered miR-15a/16-1 expression. Leukemia (in press). 

Chai C, Rivkin M, Berkovits L, Simerzin A, Zorde- Khvalevsky E,  Rosenberg N, Klein S, Durst R,  Shpitzen S, Udi S, Tam Y,  Heeren J, Worthmann A, Schramm C, Kluwe J, Giladi H, Galun E. A Metabolic Circuit Involving Free Fatty Acids, MIR122 and Triglyceride Synthesis in the Liver and Muscle Tissues. Gastroenterology (under revision).

 

 

Complete list of published work in My Bibliography:

http://www.ncbi.nlm.nih.gov/pubmed/?term=galun+e