The long-term objective of this proposal is to improve ophthalmic care for patients with a pediatric ocular tumor, retinoblastoma (RB). We propose to provide rapid diagnosis and improved prognosis for patients with heritable ocular RB through improved genetic testing, and to innovate more effective and less toxic therapies for this ophthalmic disease.In pursuit of these objectives, two specific aims are proposed. These are: I. To develop and validate a protein truncation test (PTT) for detection of germline retinoblastoma gene (RB1) mutations and to determine whether mutation analysis can be used to predict ocular disease expression.
This aim will be accomplished in 3 stages. We propose to: A. Develop PTT. B. Perform focused DNA sequencing to characterize RB1 mutations detected by PTT. C. Determine whether mutation analysis can be used to predict ocular disease expression .II. To determine the potential clinical utility of selected new pharmacologic agents in RB. These are: A. Cyclosporin A, and two potential alternatives, PSC-833 and FK506. B. Retinoids, including all-trans retinoic acid, ALRT1550, AM80, fenretinide, Targretin, 9-cis retinoic acid, and 13-cis retinoic acid.C. The alkylating agent, temozolomide. D. The blood-brain barrier permeabilizer, RMP-7 (Cereport).E. The tumor-specific viral agents, ONYX-015 and ONYX-RB1.These agents are chosen for their relatively low toxicity and potential efficacy in the management of this ocular tumor. These agents also have potential utility in the management of other ophthalmic disorders.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY013812-01A1
Application #
6544745
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Mariani, Andrew P
Project Start
2002-08-01
Project End
2007-06-30
Budget Start
2002-08-01
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$338,625
Indirect Cost
Name
University of California San Francisco
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Shah, H R; Conway, R M; Van Quill, K R et al. (2008) Beta-lapachone inhibits proliferation and induces apoptosis in retinoblastoma cell lines. Eye (Lond) 22:454-60
Dalgard, Clifton Lee; Van Quill, Kurtis R; O'Brien, Joan M (2008) Evaluation of the in vitro and in vivo antitumor activity of histone deacetylase inhibitors for the therapy of retinoblastoma. Clin Cancer Res 14:3113-23
Tsui, Janet Y; Dalgard, Clifton; Van Quill, Kurtis R et al. (2008) Subconjunctival topotecan in fibrin sealant in the treatment of transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci 49:490-6
Conway, R Max; Poothullil, Antony M; Daftari, Inder K et al. (2006) Estimates of ocular and visual retention following treatment of extra-large uveal melanomas by proton beam radiotherapy. Arch Ophthalmol 124:838-43
Conway, R M; Chew, T; Golchet, P et al. (2005) Ultrasound biomicroscopy: role in diagnosis and management in 130 consecutive patients evaluated for anterior segment tumours. Br J Ophthalmol 89:950-5
Tong, C T; Howard, S A; Shah, H R et al. (2005) Effects of celecoxib in human retinoblastoma cell lines and in a transgenic murine model of retinoblastoma. Br J Ophthalmol 89:1217-20
Eckstein, Lauren A; Van Quill, Kurtis R; Bui, Steven K et al. (2005) Cyclosporin a inhibits calcineurin/nuclear factor of activated T-cells signaling and induces apoptosis in retinoblastoma cells. Invest Ophthalmol Vis Sci 46:782-90
Van Quill, Kurtis R; Dioguardi, Phyllis K; Tong, Candice T et al. (2005) Subconjunctival carboplatin in fibrin sealant in the treatment of transgenic murine retinoblastoma. Ophthalmology 112:1151-8

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