Eyeworld

June 2011 Molecular oncology and ophthalmology EyeWorld: I am wondering how im- portant Dr. Brian Drucker's discov- ery is considered within the general oncology research community. Looking back at the historical con- text of the past decade, was this a paradigm shift? Dr. O'Brien: Dr. Drucker's conviction that therapy for cancer should be di- rected at the underlying genetic al- teration responsible for a particular malignancy did create a paradigm shift in both research and therapy for cancer. His story, which demon- strates the strength of his conviction and the personal sacrifice involved in fulfilling the promise of targeted therapy, is inspirational and de- scribed in detail in the article. EyeWorld: One decade later, has "targeted therapy" become a pri- mary therapeutic research focus in the war on cancer? Dr. O'Brien: Targeted therapy is now one of the primary focuses of cancer research. To perform such research, a good target, such as the BCR-ABL gene in Dr. Drucker's work, must be identified. In cancer, these targets are frequently proteins that direct cell-signaling pathways. These sig- naling pathways regulate important cellular functions such as cell divi- sion, response of the cell to external stimuli, movement of the cell, or programmed cell death. In cancer, alterations in these central regula- tory pathways produce unrestrained cellular proliferation. When such a pathway aberration is identified in a particular cancer, in a particular pa- tient, it becomes a logical target for individualized therapeutics. EyeWorld: Has the clinical and eco- nomic success of Gleevec signifi- cantly altered the research cycle in this area of chemotherapy, with re- gard to industry investment and FDA approvals? Dr. O'Brien: The Gleevec success story has certainly driven the phar- maceutical industry and the FDA to facilitate both research and approval of targeted therapies. Examples are numerous: Estrogen receptor (ER) positive breast cancer is treated with selective estrogen receptor modula- tors including tamoxifen and toremifene; these drugs bind to the estrogen receptor and prevent estro- gen binding. Fulvestrant promotes the destruction of the ER. Aromatase inhibitors block the enzyme, aromatase, which is necessary for estrogen production. In patients with metastatic pancreatic cancer, erlotinib (Tarceva, Genentech, San Francisco, Calif.) is used to block the tyrosine kinase activity of the epi- dermal growth factor receptor. There are numerous other examples of suc- cessful targeted therapies for a wide range of diseases. EyeWorld: Are there good examples of targeted therapy in ophthalmol- ogy today? Dr. O'Brien: The best application of targeted therapy in ophthalmology today is provided by specific inter- ruption of activity of vascular en- dothelial growth factor (VEGF). VEGF is a subfamily of growth fac- tors important for both angiogene- sis, the growth of blood vessels from pre-existing vasculature vasculogen- esis, and the new growth of blood vessels. Targeted inhibition of VEGF has proven to be successful in the treatment of choroidal neovascular- ization in age-related macular de- generation and a wide spectrum of other retinal vascular diseases. EyeWorld: Are you involved in any research geared toward developing targeted therapy in ocular oncology? Dr. O'Brien: In collaboration with Boris Bastian's group, we have been involved in identifying a pair of novel oncogenes in uveal melanoma that activate a signaling pathway that is also frequently activated in cutaneous melanoma. In the uveal melanomas we analyzed, 83% had somatic mutations in GNAQ or GNA11 (N Eng J Medicine. 2010 Dec 2; 363(23): 2191-9, Nature. 2009 Jan 29; 457 (7229) 599-602). These mu- tations cause the pathway regulated by GNAQ and GNA11 to be continu- ously turned on. Inhibiting a down- stream activator of this pathway, MEK, with a drug called AZD6244 is currently being assessed in a ran- domized Phase II trial of temozolo- mide versus AZD6244 in patients ©2009 Alcon, Inc. 6/09 RES908 CAUTION: Federal law restricts this device to sale by or on the order of a physician. INDICA- TIONS: The AcrySof® IQ ReSTOR® Apodized Diffractive Optic Posterior Chamber Intraocu- lar Lens (IOL) is intended for primary implan- tation for the visual correction of aphakia secondary to removal of a cataractous lens in adult patients with and without presbyopia, who desire near, intermediate and distance vi- sion with increased spectacle independence. The lens is intended to be placed in the cap- sular bag. WARNINGS: Careful preopera- tive evaluation and sound clinical judgment should be used by the surgeon to decide the risk/benefit ratio before implanting a lens in a patient with any of the conditions described in the Directions for Use labeling. Some adverse reactions that have been associated with the implantation of intraocular lenses are: hy- popyon, intraocular infection, acute corneal decompensation, macular edema, pupillary block, retinal detachment, and secondary surgical intervention (including but not limited to lens repositioning, biometry error, visual disturbances or patient dissatisfaction). As a result of the multifocality, some visual effects (halos or radial lines around point sources of light at night) may also be expected due to the superposition of focused and unfocused mul- tiple images. A reduction in contrast sensitiv- ity may also be experienced by some patients, especially in low lighting conditions such as driving at night. In order to achieve optimal visual performance with this lens, emmetro- pia must be targeted. Patients with signifi- cant preoperative or expected postoperative astigmatism >1.0D may not achieve optimal visual outcomes. Care should be taken to achieve IOL centration, as lens decentration may result in a patient experiencing visual disturbances under certain lighting condi- tions. PRECAUTIONS: Do not resterilize. Do not store over 45° C. Use only sterile irrigat- ing solutions such as BSS® or BSS PLUS® Sterile Intraocular Irrigating Solution. Clinical studies with the AcrySof® IQ ReSTOR® IOL indicated that posterior capsule opacification (PCO), when present, developed earlier into clinically significant PCO. Studies have shown that color vision discrimination is not adverse- ly affected in individuals with the AcrySof® Natural IOL and normal color vision. The ef- fect on vision of the AcrySof® Natural IOL in subjects with hereditary color vision defects and acquired color vision defects secondary to ocular disease (eg, glaucoma, diabetic retinopathy, chronic uveitis, and other retinal or optic nerve diseases) has not been studied. The long-term effects of filtering blue light and the clinical efficacy of that filtering on the retina have not been conclusively established. ATTENTION: Reference the Physician Label- ing/Directions for Use for a complete listing of indications, warnings, and precautions. www.AcrySofReSTOR.com 1 5/24/11 2:33 PM A s a new feature, we are giving our section editors a monthly space or "corner" within EyeWorld to high- light a clinically relevant topic in their sub- specialty area. They will either poll several opinion leaders or invite a single expert to write about a topic of importance. Look for these "Corner of the world" articles every month to see what issues our section edi- tors want to highlight and whom they se- lect to provide answers. I hate to admit it, but like many oph- thalmologists, I have been generally oblivi- ous to major developments in the field of oncology. However, an article in the May issue of Smithsonian Magazine not only peaked my interest but struck me as a great read for all ophthalmologists. The occasion was the 10th anniversary of the FDA approval of a revolutionary chemotherapeutic drug Gleevec (imatinib mesylate, Novartis, Basel, Switzerland) in May 2001. This was the first successful clinical drug to target cancer cells on a molecular level. The article described a transformative event in the treatment of cancer, but the story of how Dr. Brian Drucker brought this drug from the lab into clinical practice is an inspiring tale of per- severance that every physician can under- stand and appreciate. The article, "The Triumph of Dr. Druker," can be found at www.smithsonianmag.com by going to the May 2011 issue in the archive section. This month, I asked Joan O'Brien, M.D., chair of ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, to give us some perspective on the impact of drugs such as Gleevec. Dr. O'Brien is an in- ternationally acclaimed ocular oncologist. David F. Chang, M.D., chief medical editor Chief medical editor's corner of the world continued on page 4

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