Assistant Professor of Neurosurgery, University of Pennsylvania School of Medicine
B.A. (English and Literature)
University of Florida, 1998.
University of Florida, 1998.
Johns Hopkins School of Medicine, 2005.
The Resnick laboratory studies cell signaling cascades and their alterations in pediatric brain tumors. The goal of the laboratory is to elucidate the molecular and genetic underpinnings of pediatric brain tumors in an effort to identify and develop targeted therapies. Additional, related studies focus on the characterization of novel cell signaling cascades impinging on cancer biology, including the inositol polyphosphates and their associated metabolism.
Key words: brain, central nervous system, development, molecular oncology, neurooncology, signaling, inositol polyphosphates, and transcriptional regulation.
Dr. Resnick is focused on defining the cell signaling mechanisms of oncogenesis and tumor progression in brain tumors.
Cell signaling requires the coordinated processing and integration of information that ultimately decide a cell’s particular phenotype or response to its environment. The signaling network’s organization and topology is dynamically regulated, linking diverse processes such as cell surface receptor activation to transcriptional programs that underlie a cell’s response to a particular stimulus. Small molecule second messengers, kinase-mediated signaling, and epigenetic interactions play key roles in defining the network’s response and are often the altered culprits in the pathogenesis of cancer.
Inositol-based second messenger signaling molecules include both the water-soluble inositol polyphosphates and the membrane bound lipid phosphatidylinositols. Both play prominent roles in second messenger signaling with probably the best characterized members being IP3, the soluble calcium releasing factor and PIP3, the “oncogenic” inositide lipid generated by the actions of PI3K, often in response to receptor tyrosine kinase activation. PIP3 canonically acts to recruit and activate kinases such as AKT, initiating some of the best characterized and often aberrantly activated cancer-relevant signaling cascades. In contrast to IP3- and PI3K-mediated signaling, the “higher,” more phosphorylated inositol polyphosphates including IP7 and IP8 have lagged far behind in characterization or elucidation of function, but also appear to regulate key signaling events including AKT activation. Our laboratory focuses on characterizing the signaling roles of these novel second messengers and their importance in transcriptional regulation, central nervous system development, and cancer biology. Complementing these interests in basic cell signaling mechanisms are our efforts focused at defining cell signaling aberrations occurring in pediatric brain tumors. Pediatric brain tumors are the number one cause of cancer-related death in children and youth and represent the unique and devastating interaction of altered cell signaling events, often as a result of genetic alteration, with the environmental context of the developing brain. Our laboratory focuses on defining these genetic alterations, their mechanism of action, and ultimately, a targeted therapy approach as treatment. Such efforts are represented by our recent studies of pediatric gliomas.
Gliomas are the most common type of brain tumors in children. Treatment options are limited for children with tumors not amenable to surgical resection or that are recurrent/disseminated. Effective therapies are needed to target the oncogenic events underlying glioma tumorigenesis. In collaboration with Jaclyn Biegel we recently identified a nonrandom duplication in chromosome band 7q34 in low grade gliomas. Candidate gene analysis revealed the duplication results in a novel fusion product between BRAF, a serine-threonine kinase involved in the RAS/RAF/MEK pathway, and KIAA1549, an uncharacterized gene. Further studies have demonstrated that the BRAF fusion gene along with BRAF V600E mutations that more commonly typify malignant melanomas characterize a large number of both low and high grade gliomas. Current studies focus on the molecular mechanisms underlying altered BRAF signaling and BRAF inhibition by newly developed targeted therapies. These studies and others represent an ongoing effort aimed at the characterization of pediatric brain tumors and underlie the larger initiative of the Childhood Brain Tumor Tissue Consortium (CBTTC), a multi-institutional cooperative research program dedicated to the study of childhood brain tumors.
Dougherty MJ, Santi M, Brose MS, Ma C, Resnick AC, Sievert AJ, Storm PB, Biegel JA.: Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol Feb 2010.
Losito O, Szijgyarto Z, Resnick AC, Saiardi A: Inositol pyrophosphates and their unique metabolic complexity: analysis by gel electrophoresis. PLoS ONE 4(5): e5580, May 2009.
Resnick AC & Saiardi A: Inositol Phosphates. Wiley Encyclopedia of Chemical Biology. Begley TP (eds.). John Wiley & Sons, Inc. Page: 1-12, Jan 2009.
D.A. Hardesty, D.A. Bhowmick, P.H. Kwag, P.B. Storm, A.C. Resnick: Knockdown of Inositol Polyphosphate Multikinase Modulates GlioblastomaCellular Proliferation and AKT Activity in vitro. Presented at the 2009 American Association of Neurological Surgeons Annual Meeting 2009.
Sievert AJ, Jackson EM, Gai X, Hakonarson H, Judkins AR, Resnick AC, Sutton LN, Storm PB, Shaikh TH, Biegel JA: Duplication of 7q34 in Pediatric Low-Grade Astrocytomas Detected by High-Density Single-Nucleotide Polymorphism-Based Genotype Arrays Results in a Novel BRAF Fusion Gene. Brain pathology (Zurich, Switzerland) Oct 2008.
Bhandari Rashna, Juluri Krishna R, Resnick Adam C, Snyder Solomon H: Gene deletion of inositol hexakisphosphate kinase 1 reveals inositol pyrophosphate regulation of insulin secretion, growth, and spermiogenesis. Proceedings of the National Academy of Sciences of the United States of America 105(7): 2349-53, Feb 2008.
D. Maag, M.J. Maxwell, R. Xu, A.C. Resnick, and S. H. Snyder: Inositol polyphosphate multikinase promotes mammalian cell proliferation by activation of Akt
Presented at the Keystone Symposium on Signaling Pathways in Cancer and Development and at the AACR Special Conference. "Targeting the PI3-Kinase Pathway in Cancer" 2008.
Resnick Adam Cain, Saiardi Adolfo: Inositol polyphosphate multikinase: metabolic architect of nuclear inositides. Frontiers in bioscience : a journal and virtual library 13: 856-66, 2008.
A. J. Sievert, A. C. Resnick, P. B. Storm, H. Hakonarson, T. H. Shaikh & J. A. Biegel: Identification of a novel BRAF fusion gene in pediatric low-grade astrocytomas. Presented at the American Society for Human Genetics 2008.
A.J. Sievert, E. M. Jackson, X. Gai, H. Hakonarson, A. R. Judkins, A. C. Resnick, T. H. Shaikh, and J. A. Biegel: Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density SNP-based genotyping. Presented at the Thirteenth International Symposium on Pediatric Neuro-Oncology 2008.