Faculty

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David E. Cobrinik, MD, PhD
Associate Professor of Research Ophthalmology
Pediatrics
CHL 4650 W Sunset Blvd Off Campus Los Angeles
+1 323 361 2275

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

Susan G. Komen Breast Cancer Foundation Postdoctoral Fellow

American Cancer Society Postdoctoral Fellow

American Cancer Society Joseph S. Silber Pre-doctoral Fellow

Oscar E. Schotté Award for Biological Research, Amherst College

Publications

Structural and Functional Characterization of Human Stem-Cell-Derived Retinal Organoids by Live Imaging. Invest Ophthalmol Vis Sci. 2017 Jul 01; 58(9):3311-3318. View in: PubMed

MDM2 but not MDM4 promotes retinoblastoma cell proliferation through p53-independent regulation of MYCN translation. Oncogene. 2017 Mar 30; 36(13):1760-1769. 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 Jul; 18(4):480-93. 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

Retinoblastoma Progression. EBioMedicine. 2015 Jul; 2(7):623-4. View in: PubMed

Retinoblastoma. Nat Rev Dis Primers. 2015; 1:15021. 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

Critical role of the Rb family in myoblast survival and fusion. PLoS One. 2011; 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

Rb induces a proliferative arrest and curtails Brn-2 expression in retinoblastoma cells. Mol Cancer. 2006; 5:72. 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

pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes. Genes Dev. 1997 Jun 1; 11(11):1447-63. View in: PubMed

Shared role of the pRB-related p130 and p107 proteins in limb development. Genes Dev. 1996 Jul 1; 10(13):1633-44. 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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