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David E. Cobrinik, MD, PhD

Associate Professor of Research Ophthalmology

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Phone +1 323 361 2275
Email dcobrinik@chla.usc.edu
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Overview

Our research seeks to improve understanding of retinal development and its relationship to retinal diseases. This goal stems from my long interest in a childhood retinal tumor called retinoblastoma, a cancer that develops in response to inactivation of the RB1 tumor suppressor gene and loss of functional pRB protein. One of our goals is to understand why cells of the retina but not other tissues routinely form cancers in response to pRB loss, and to use this knowledge to develop more effective therapies for retinoblastoma and other RB1-mutant cancers. We recently found that retinoblastomas arise from cone photoreceptor precursors, and that cone precursor-specific proliferation-related signaling pathways collaborate with pRB loss to enable tumorigenesis. This finding suggests that cone precursors signaling pathways can be targeted to suppress retinoblastoma development. Current studies aim to 1) define developmental signaling pathways that sensitize retinal cells to Rb loss, 2) define the step-by-step events through which Rb loss converts normal retinal cells to malignant retinoblastomas, and 3) target novel vulnerabilities in the pRB-deficient cone precursor circuitry.

With our colleagues at the CHLA Vision Center we also model retinal development and diseases using human pluripotent stem cells. We can produce normal-appearing developing retinas in vitro, opening the door to previously unimagined vision research opportunities. Current efforts aim to define similarities and differences between human retina produced in vitro and in vivo, and to thereby improve the verisimilitude of the in vitro retinal development model.

Awards

  • James S. McDonnell Foundation Scholar, 1996-1999
  • Susan G. Komen Breast Cancer Foundation Postdoctoral Fellow, 1992-1995
  • American Cancer Society Postdoctoral Fellow, 1989-1992
  • American Cancer Society Joseph S. Silber Pre-doctoral Fellow, 1983
  • Oscar E. Schotté Award for Biological Research, Amherst College, 1982

Publications

  • Aberrant gene expression yet undiminished retinal ganglion cell genesis in iPSC-derived models of optic nerve hypoplasia Ophthalmic Genet. 2024 Feb; 45(1):1-15. . View in PubMed
  • Episodic live imaging of cone photoreceptor maturation in GNAT2-EGFP retinal organoids Dis Model Mech. 2023 Nov 01; 16(11). . View in PubMed
  • Episodic live imaging of cone photoreceptor maturation in GNAT2-EGFP retinal organoids bioRxiv. 2023 Mar 01. . View in PubMed
  • Non-synonymous, synonymous, and non-coding nucleotide variants contribute to recurrently altered biological processes during retinoblastoma progression Genes Chromosomes Cancer. 2023 05; 62(5):275-289. . View in PubMed
  • Benign Lobular Inner Nuclear Layer Proliferations of the Retina Associated with Congenital Hypertrophy of the Retinal Pigment Epithelium Ophthalmology. 2023 03; 130(3):265-273. . View in PubMed
  • Characterizing DNA methylation signatures of retinoblastoma using aqueous humor liquid biopsy Nat Commun. 2022 09 21; 13(1):5523. . View in PubMed
  • An immature, dedifferentiated, and lineage-deconstrained cone precursor origin of N-Myc-initiated retinoblastoma Proc Natl Acad Sci U S A. 2022 07 12; 119(28):e2200721119. . View in PubMed
  • Comprehensive Somatic Copy Number Analysis Using Aqueous Humor Liquid Biopsy for Retinoblastoma Cancers (Basel). 2021 Jul 03; 13(13). . View in PubMed
  • Establishing the Clinical Utility of ctDNA Analysis for Diagnosis, Prognosis, and Treatment Monitoring of Retinoblastoma: The Aqueous Humor Liquid Biopsy Cancers (Basel). 2021 Mar 13; 13(6). . View in PubMed
  • Extracellular vesicle-associated repetitive element DNAs as candidate osteosarcoma biomarkers Sci Rep. 2021 01 08; 11(1):94. . View in PubMed
  • Characterization and staging of outer plexiform layer development in human retina and retinal organoids Development. 2021 12 01; 148(23). . View in PubMed
  • Corrigendum to “Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace”Alive, with good vision and no comorbidity”” [Prog. Retina Eye Res. 73 (2019) 100764]. Prog Retin Eye Res. 2020 Apr 08; 100857. . View in PubMed
  • Simultaneous identification of clinically relevant RB1 mutations and copy number alterations in aqueous humor of retinoblastoma eyes Ophthalmic Genet. 2020 12; 41(6):526-532. . View in PubMed
  • Variability in retinoblastoma genome stability is driven by age and not heritability Genes Chromosomes Cancer. 2020 10; 59(10):584-590. . View in PubMed
  • Cell-Free DNA Tumor Fraction in the Aqueous Humor Is Associated With Therapeutic Response in Retinoblastoma Patients Transl Vis Sci Technol. 2020 09; 9(10):30. . View in PubMed
  • Chromosome 6p Amplification in Aqueous Humor Cell-Free DNA Is a Prognostic Biomarker for Retinoblastoma Ocular Survival Mol Cancer Res. 2020 08; 18(8):1166-1175. . View in PubMed
  • Improved third-generation lentiviral packaging with pLKO1C vectors. Biotechniques. 2020 06; 68(6):349-352. . View in PubMed
  • Detection of mitochondrial DNA variants at low level heteroplasmy in pediatric CNS and extra-CNS solid tumors with three different enrichment methods Mitochondrion. 2020 03; 51:97-103. . View in PubMed
  • Reciprocal Induction of MDM2 and MYCN in Neural and Neuroendocrine Cancers Front Oncol. 2020; 10:563156. . View in PubMed
  • Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace”Alive, with good vision and no comorbidity”. Prog Retin Eye Res. 2019 11; 73:100764. . View in PubMed
  • A novel thyroid hormone receptor isoform, TRß2-46, promotes SKP2 expression and retinoblastoma cell proliferation J Biol Chem. 2019 02 22; 294(8):2961-2969. . View in PubMed
  • Genomic cfDNA Analysis of Aqueous Humor in Retinoblastoma Predicts Eye Salvage: The Surrogate Tumor Biopsy for Retinoblastoma Mol Cancer Res. 2018 11; 16(11):1701-1712. . View in PubMed
  • Potential of Aqueous Humor as a Surrogate Tumor Biopsy for Retinoblastoma-Reply JAMA Ophthalmol. 2018 05 01; 136(5):598. . View in PubMed
  • Developmental stage-specific proliferation and retinoblastoma genesis in RB-deficient human but not mouse cone precursors Proc Natl Acad Sci U S A. 2018 10 02; 115(40):E9391-E9400. . View in PubMed
  • MDM2 but not MDM4 promotes retinoblastoma cell proliferation through p53-independent regulation of MYCN translation Oncogene. 2017 03 30; 36(13):1760-1769. . View in PubMed
  • Structural and Functional Characterization of Human Stem-Cell-Derived Retinal Organoids by Live Imaging Invest Ophthalmol Vis Sci. 2017 07 01; 58(9):3311-3318. . View in PubMed
  • SKP2 Activation by Thyroid Hormone Receptor ß2 Bypasses Rb-Dependent Proliferation in Rb-Deficient Cells Cancer Res. 2017 12 15; 77(24):6838-6850. . View in PubMed
  • Potential of Aqueous Humor as a Surrogate Tumor Biopsy for Retinoblastoma JAMA Ophthalmol. 2017 11 01; 135(11):1221-1230. . View in PubMed
  • Detection and Intraretinal Localization of an ‘Invisible’ Retinoblastoma Using Optical Coherence Tomography Ocul Oncol Pathol. 2016 Apr; 2(3):148-52. . View in PubMed
  • A Rapid and Sensitive Next-Generation Sequencing Method to Detect RB1 Mutations Improves Care for Retinoblastoma Patients and Their Families J Mol Diagn. 2016 07; 18(4):480-93. . View in PubMed
  • Retinoblastoma Progression EBioMedicine. 2015 Jul; 2(7):623-4. . View in PubMed
  • Retinoblastoma Nat Rev Dis Primers. 2015 08 27; 1:15021. . View in PubMed
  • Rb suppresses human cone-precursor-derived retinoblastoma tumours Nature. 2014 Oct 16; 514(7522):385-8. . View in PubMed
  • Recurrent pre-existing and acquired DNA copy number alterations, including focal TERT gains, in neuroblastoma central nervous system metastases Genes Chromosomes Cancer. 2013 Dec; 52(12):1150-66. . View in PubMed
  • Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF Oncogene. 2012 Jan 26; 31(4):446-57. . View in PubMed
  • Critical role of the Rb family in myoblast survival and fusion PLoS One. 2011 Mar 10; 6(3):e17682. . View in PubMed
  • Tumor-associated retinal astrocytes promote retinoblastoma cell proliferation through production of IGFBP-5 Am J Pathol. 2010 Jul; 177(1):424-35. . View in PubMed
  • Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/- mice Nat Genet. 2010 Jan; 42(1):83-8. . View in PubMed
  • The retinoblastoma protein and its homolog p130 regulate the G1/S transition in pancreatic beta-cells Diabetes. 2009 Aug; 58(8):1852-62. . View in PubMed
  • Retinoblastoma has properties of a cone precursor tumor and depends upon cone-specific MDM2 signaling Cell. 2009 Jun 12; 137(6):1018-31. . View in PubMed
  • Rb induces a proliferative arrest and curtails Brn-2 expression in retinoblastoma cells Mol Cancer. 2006 Dec 12; 5:72. . View in PubMed
  • Cell cycle-specific and cell type-specific expression of Rb in the developing human retina Invest Ophthalmol Vis Sci. 2006 Dec; 47(12):5590-8. . View in PubMed
  • Small molecule inhibition of HDM2 leads to p53-mediated cell death in retinoblastoma cells Arch Ophthalmol. 2006 Sep; 124(9):1269-75. . View in PubMed
  • Pocket proteins and cell cycle control Oncogene. 2005 Apr 18; 24(17):2796-809. . View in PubMed
  • The cyclin-dependent kinase inhibitor p57(Kip2) mediates proliferative actions of PTHrP in chondrocytes J Clin Invest. 2004 May; 113(9):1334-43. . View in PubMed
  • FGF signaling targets the pRb-related p107 and p130 proteins to induce chondrocyte growth arrest J Cell Biol. 2002 Aug 19; 158(4):741-50. . View in PubMed
  • Regulation of PML-dependent transcriptional repression by pRB and low penetrance pRB mutants Oncogene. 2002 Aug 15; 21(36):5557-65. . View in PubMed
  • p107 and p130 Coordinately regulate proliferation, Cbfa1 expression, and hypertrophic differentiation during endochondral bone development Dev Biol. 2002 Jul 15; 247(2):271-85. . View in PubMed
  • Rho regulates p21(CIP1), cyclin D1, and checkpoint control in mammary epithelial cells Oncogene. 2002 Feb 28; 21(10):1590-9. . View in PubMed
  • Complementary and alternative medicine: the role of the cancer center J Clin Oncol. 2001 Sep 15; 19(18 Suppl):55S-60S. . View in PubMed
  • Cdk2-dependent phosphorylation and functional inactivation of the pRB-related p130 protein in pRB(-), p16INK4A(+) tumor cells J Biol Chem. 2000 Sep 29; 275(39):30317-25. . View in PubMed
  • Growth factor-dependent induction of p21(CIP1) by the green tea polyphenol, epigallocatechin gallate Cancer Lett. 2000 Jun 30; 154(2):151-61. . View in PubMed
  • pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes Genes Dev. 1997 Jun 01; 11(11):1447-63. . View in PubMed
  • Shared role of the pRB-related p130 and p107 proteins in limb development Genes Dev. 1996 Jul 01; 10(13):1633-44. . View in PubMed
  • Regulatory interactions among E2Fs and cell cycle control proteins Curr Top Microbiol Immunol. 1996; 208:31-61. . View in PubMed
  • E2F-4 and E2F-5, two members of the E2F family, are expressed in the early phases of the cell cycle Proc Natl Acad Sci U S A. 1995 Mar 14; 92(6):2403-7. . View in PubMed
  • Cell cycle-specific association of E2F with the p130 E1A-binding protein Genes Dev. 1993 Dec; 7(12A):2392-404. . View in PubMed
  • The retinoblastoma protein and the regulation of cell cycling Trends Biochem Sci. 1992 Aug; 17(8):312-5. . View in PubMed
  • Interaction between retroviral U5 RNA and the T psi C loop of the tRNA(Trp) primer is required for efficient initiation of reverse transcription J Virol. 1992 Apr; 66(4):2464-72. . View in PubMed
  • Overlapping retrovirus U5 sequence elements are required for efficient integration and initiation of reverse transcription J Virol. 1991 Jul; 65(7):3864-72. . View in PubMed
  • A retroviral RNA secondary structure required for efficient initiation of reverse transcription J Virol. 1988 Oct; 62(10):3622-30. . View in PubMed
  • Properties of avian sarcoma-leukosis virus pp32-related pol-endonucleases produced in Escherichia coli J Virol. 1988 Jul; 62(7):2358-65. . View in PubMed
  • Avian sarcoma and leukosis virus pol-endonuclease recognition of the tandem long terminal repeat junction: minimum site required for cleavage is also required for viral growth J Virol. 1987 Jun; 61(6):1999-2008. . View in PubMed
  • Circles with two tandem long terminal repeats are specifically cleaved by pol gene-associated endonuclease from avian sarcoma and leukosis viruses: nucleotide sequences required for site-specific cleavage J Virol. 1985 Nov; 56(2):589-99. . View in PubMed

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