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Libutti Laboratory


Research Overview

Multiple Endocrine Neoplasia Type I (MEN1) is a familial cancer syndrome defined by tumor formation in distinct endocrine tissues while not in other parts of the body.  Patients with MEN1 syndrome develop tumors of the endocrine glands, including the anterior pituitary, parathyroid and endocrine pancreas.  Mutations in the gene MEN1 cause inactivation of the menin protein, which is a transcriptional modulator and tumor suppressor involved in cell proliferation, DNA repair and apoptosis.  Epigenetic alterations are a critical mechanism of tumorigenesis, including widespread aberrations in DNA methylation.  Our team has shown that the inactivation of menin results in increased activity of DNA methyltransferase 1 (DNMT1), causing a drastic increase in global DNA methylation in tumor cells.  With a focus on characterizing the role of Dnmt1 in pancreatic islet cells, which in MEN1 patients form an insulinoma, our recent work using a somatic gene transfer system in mice showed that the upregulation of Dnmt1 promotes the proliferation of pancreatic endocrine islet cells.  These findings suggest the significance of Dnmt1 in driving pancreatic neuroendocrine tumorigenesis, making Dnmt1 a potential therapeutic target for patients with MEN1 syndrome.

Another arm of the lab focuses on the immune system, specifically a new B7 immune-checkpoint protein as a target for the treatment of neuroendocrine tumors (NETs). The B7 family are an appealing target for cancer therapy because they are major immune checkpoint proteins that regulate T-cell activation and function.  Our recent analysis of patient samples and our work in our genetically engineered Men1 knockout mice demonstrates that B7x is a key mediator of tumor immunity in the tumor microenvironment of NETs.  In our preclinical studies where we evaluated the efficacy of B7x blockade with a B7x antibody, we found that the B7x antibody can inhibit tumor cell proliferation and induce apoptosis, both of which improved the tumor immune microenvironment and resulted in increased survival.  Our work has shown that the upregulation of the B7x immune checkpoint results in the inactivation of the immune system and promotes neuroendocrine tumorigenesis, and targeting B7x with a high affinity antibody is a promising cancer immunotherapy. 

Libutti Lab Team

Another research focus is to study the mechanism of action of a novel tumor suppressor, FILIP1L that enhances b-catenin degradation, thereby inhibiting WNT signaling and epithelial-to-mesenchymal transition (EMT). We showed that its expression is down-regulated by promoter methylation in various cancer types, and its down-regulation is associated with chemo-resistance and worse prognosis in colon and ovarian cancer. Recent data reveals that systemic knockout of Filip1l was embryonic lethal in mice, suggesting its crucial role in development. Currently we are in the process of analyzing the phenotypes from various tissue-specific knockout mice of Filip1l.

 
 

Laboratory Leadership

Steven K. Libutti, MD, FACSSteven K. Libutti, MD, FACS, was named Director of Rutgers Cancer Institute of New Jersey and Vice Chancellor for Cancer Programs, Rutgers Biomedical and Health Sciences in January 2017. He also serves as Senior Vice President of Oncology Services for RWJBarnabas Health; is a tenured Professor of Surgery at Rutgers Robert Wood Johnson Medical School; and is an Affiliated Distinguished Professor in Genetics, Rutgers School of Arts and Sciences. Dr. Libutti graduated from Harvard College and received his M.D. from the College of Physicians and Surgeons of Columbia University. Following his residency in Surgery, he completed a fellowship in Surgical Oncology and Endocrine Surgery at the National Cancer Institute (NCI).

Dr. Libutti’s clinical practice focuses on gastrointestinal malignancies including cancers of the liver and pancreas. His research focuses on developing novel cancer therapies through an understanding of the tumor microenvironment. He is studying the interaction between tumor cells and the components of the tumor microenvironment. His work also focuses on a better understanding of the tumor suppressor genes MEN1 and FILIP1L. Dr. Libutti is a leader in regional cancer therapy, the management of endocrine tumors and tumor targeted gene therapy. He is a past President of the American Association of Endocrine Surgeons, serves as the Editor-in-Chief of the Springer-Nature Journal Cancer Gene Therapy and holds seven U.S. patents.
 

Selected Publications

Yuan Z, Gardiner JC, Maggi EC, Adem A, Zhang G, Lee S, Romanienko P, Du YN, Libutti SK. Tissue-specific induced DNA methyltransferase 1 (Dnmt1) in endocrine pancreas by RCAS-TVA-based somatic gene transfer system promotes β-cell proliferation. Cancer Gene Ther. 2018 Sep 7. doi: 10.1038/s41417-018-0046-x. PubMed PMID: 30190513.

Nilubol N, Yuan Z, Paciotti GF, Tamarkin L, Sanchez C, Gaskins K, Freedman EM, Cao S, Zhao J, Kingston DGI, Libutti SK, Kebebew E. Novel Dual-Action Targeted Nanomedicine in Mice With Metastatic Thyroid Cancer and Pancreatic Neuroendocrine Tumors. J Natl Cancer Inst. 2018 Sep 1;110(9):1019-1029. doi: 10.1093/jnci/djy003. PubMed PMID: 29481652. 

Maggi EC, Gravina S, Cheng H, Piperdi B, Yuan Z, Dong X, Libutti SK, Vijg J, Montagna C. Development of a Method to Implement Whole-Genome Bisulfite Sequencing of cfDNA from Cancer Patients and a Mouse Tumor Model. Front Genet. 2018 Jan 23;9:6. doi: 10.3389/fgene.2018.00006. eCollection 2018. PubMed PMID: 29410677; PubMed Central PMCID: PMC5787102.

Chandra D, Selvanesan BC, Yuan Z, Libutti SK, Koba W, Beck A, Zhu K, Casadevall A, Dadachova E, Gravekamp C. 32-Phosphorus selectively delivered by listeria to pancreatic cancer demonstrates a strong therapeutic effect. Oncotarget. 2017 Mar 28;8(13):20729-20740. doi: 10.18632/oncotarget.15117. PubMed PMID: 28186976; PubMed Central PMCID: PMC5400540.

Kwon M, Kim J-H, Rybak Y, Luna A, Choi CH, Chung J-Y, Hewitt SM, Adem A, Tubridy E, Lin J, Libutti SK; Reduced expression of FILIP1L, a novel WNT pathway inhibitor, is associated with poor survival, progression and chemoresistance in ovarian cancer; Oncotarget, 2016 7(47):77052-77070.

Yuan Z, Sánchez Claros C, Suzuki M, Maggi EC, Kaner JD, Kinstlinger N, Gorecka J, Quinn TJ, Geha R, Corn A, Pastoriza J, Jing Q, Adem A, Wu H, Alemu G, Du YC, Zheng D, Greally JM, Libutti SK. Loss of MEN1 activates DNMT1 implicating DNA hypermethylation as a driver of MEN1 tumorigenesis. Oncotarget. 2016 Mar 15;7(11):12633-50. doi: 10.18632/oncotarget.7279. PubMed PMID: 26871472; PubMed Central PMCID: PMC4914310.

Smith TL, Yuan Z, Cardó-Vila M, Sanchez Claros C, Adem A, Cui MH, Branch CA, Gelovani JG, Libutti SK, Sidman RL, Pasqualini R, Arap W. AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas. Proc Natl Acad Sci U S A. 2016 Mar 1;113(9):2466-71. doi: 10.1073/pnas.1525709113. Epub 2016 Feb 16. PubMed PMID: 26884209; PubMed Central PMCID: PMC4780640.

McKimpson WM, Yuan Z, Zheng M, Crabtree JS, Libutti SK, Kitsis RN. The Cell Death Inhibitor ARC Is Induced in a Tissue-Specific Manner by Deletion of the Tumor Suppressor Gene Men1, but Not Required for Tumor Development and Growth. PLoS One. 2015 Dec 28;10(12):e0145792. doi: 10.1371/journal.pone.0145792. eCollection 2015. PubMed PMID: 26709830; PubMed Central PMCID: PMC4692498.

Kwon M, Libutti SK; Filamin A interacting protein 1-like as a therapeutic target in cancer; Expert Opinion on Therapeutic Targets, 2014 18:1435-47.

Kwon M, Lee SJ, Wang Y, Rybak Y, Luna A, Reddy S, Adem A, Beaty BT, Condeelis JS, Libutti SK; Filamin A interacting protein 1-like inhibits WNT signaling and MMP expression to suppress cancer cell invasion and metastasis; International Journal of Cancer, 2014 135:48–60.

 

 

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