Researchers have identified the critical role of a cancer-promoting gene in the growth and survival of retinoblastoma cells. This discovery could lead to new treatment options.

Retinoblastoma is the most common intraocular childhood cancer. It affects approximately 300 children in the United States each year and more than 8,000 worldwide. When detected early, the cure rate is high, but if the diagnosis is delayed, it can result in the loss of an eye and even death.

Researchers at the Saban Research Institute of Children’s Hospital Los Angeles found that a protein known as MDM2 plays a critical role in the expression of another protein, MYCN, that is required for the growth and survival of retinoblastoma cells.

In previous studies, David Cobrinik, MD, PhD discovered that retinoblastoma forms from cone cells in the retina. The recent study, published in the October 17 online edition of the journal Oncogene, looked at characteristics that make these cells prone to retinoblastoma when the RB1 gene is inactivated, allowing for unchecked cell growth.

“An important way in which cone cells differ from other retinal cell types is their high expression of MDM2 and MYCN,” said first author Donglai Qi, PhD. “We have shown crosstalk between these two oncoproteins in which MDM2 promotes MYCN expression in retinoblastoma cells.”

An oncoprotein is encoded by a cancer promoting gene (oncogene). In tumor cells, oncoproteins are often mutated and expressed at high levels. Normally, MYCN provides instructions for the production of a protein that plays an important role in the formation of tissues and organs during embryonic development. But when mutated, the MYCN oncogene has the potential to cause normal cells to become cancerous.

Researchers say in addition to MCYN’s presence in retinoblastoma, it is also elevated in 20 to 25 percent of neuroblastoma tumors, and correlates with advanced disease and poor prognosis. It also plays a role in other childhood cancers.

Researchers say treatments directed at MYCN could be effective, but targeting this oncoprotein is problematic because it is difficult to block. Knowing the link between MDM2 and MYCN, researchers can now look for ways to target the mechanism through which MDM2 regulates MYCN expression.

“This identification of a critical and unexpected node in the retinoblastoma signaling circuitry could theoretically lead to pharmacologic targeting, Cobrinik said.

Despite the many vision-saving eye cancer treatments available, sometimes it becomes necessary to remove an eye. For patients facing enucleation surgery, the prospect of losing an eye is scary. Fortunately, most patients can see with their remaining eye and will most likely be able to do all the things they used to do before, including driving a car. With modern eye prosthesis, the loss of the eye is hardly noticeable.

For patients facing enucleation surgery, or those who have already experienced the loss of an eye, the website LostEye.com serves as a fantastic resource, offering both practical information and encouragement.

Jay Adkisson created and edits LostEye.com. He had his eye surgically removed after doctors diagnosed him with choroidal melanoma. Because the tumor was so close to his optic nerve, Jay opted for enucleation. Just three years later, he earned his FAA pilot license. Jay’s testimonial on the LostEye.com home page offers encouragement for anybody facing the loss of an eye.

“Believe it or not, five days later I was back at work at my law practice, and now the fact that I only have one eye is barely an inconvenience, and not even something I notice unless I think about it. My driving isn’t any different (I give myself a little more space for the cars ahead of me), and my life isn’t any different. I haven’t even noticed any significant loss of depth perception. In other words, life has returned to pretty much what it was before I went in for the surgery.”

Jay says his experience led him to create LostEye.com as a way to help other patients.

“I know, and I mean really know – personally – how stressful losing an eye can be. Thus, I have created this completely free, noncommercial website for the information and support of those who have recently lost an eye, or who may lose an eye due to surgery, disease, etc.”

LostEye.com features a wide range of information for those facing enucleation surgery, as well as those who have already lost an eye. There is an entire page devoted to what patients can expect in the days leading up to surgery and during their recovery. You will find information on how to protect the remaining good eye and how to cope with the fear of losing an eye. There are also pages devoted to driving with one eye, prosthetic eyes, and a discussion on depth perception.

But it’s not just the information available that makes LostEye.com such a good resource. It also hosts an online community through a robust discussion forum. Here, patients facing the loss of an eye can connect with people who have already gone through the experience. They can ask questions, receive encouragement and exchange information. The opportunity to connect with others who have walked the same path helps patients realize they aren’t alone.

LostEye.com provides both information and encouragement and is a resource anybody dealing with the loss of an eye will find valuable.

Ata Rajeh, MD recently completed fellowship training in ocular oncology under Yacoub Yousef, MD of Jordan. The training was supported by The Eye Cancer Foundation (ECF).

ECF fellowships are available to candidates from unserved or underserved countries. Once the doctors complete their six months of training, they agree to return to their home country to start or participate in eye cancer treatment for the unserved.

Rajeh is from the war-torn country of Syria. His fellowship ran from April to October 2016 at the King Hussein Cancer Center in Amman, Jordan. Dr. Yacoub Yousef and his team supervised Rajeh’s training. Rajeh had the opportunity to learn from a wide range of highly trained medical professionals, including retina specialists, pediatric ophthalmologists, oculoplastic surgeons, pediatric oncologists, radiotherapists, and low vision aid specialists.

Eye Cancer Foundation fellowships offer doctors specialized training in the treatment of retinoblastoma they could never receive in their home country. Retinoblastoma is the most common eye cancer in children and affects approximately 8,200 children each year. The incidence rate is somewhat higher in developing countries, where most of the children eventually succumb to metastatic retinoblastoma. In contrast, there exists a better than 96% survival rate in developed countries like the USA. Early diagnosis and treatment is key to saving retinoblastoma patients’ lives and their sight.

During his six months at King Hussein Cancer Center, Rajeh was exposed to full-range, comprehensive management of more than 100 retinoblastoma patients who were diagnosed at different stages in the disease. This allowed him to observe a wide variety of treatment regimens, including systemic chemotherapy, intraocular chemotherapy, intra-arterial systemic chemotherapy, focal consolidation therapies (e.g. laser and “freezing” cryotherapy), radioactive plaque therapy, external beam radiation therapy, and when necessary – removal of cancer-filled eyes.

In addition to his interaction with patients, Rajeh also accomplished research alongside Dr. Yousef. His primary project related to the management of conjunctival squamous cell carcinoma in Jordan.

“I am very excited about the results of our research,” Rajeh said. “I am the first author, and this manuscript will soon be submitted to a peer reviewed journal.”

Rajeh received invaluable training among the millions of displaced Syrians currently in Jordon. He hopes to open the first Retinoblastoma Center in Syria, and he expresses his deep gratitude to The Eye Cancer Foundation for the opportunity.

“I am going to work on building my experience in the field of ocular oncology, in the retinoblastoma field in specific,” he said in a recent letter to The Eye Cancer Foundation Board. “When I get home, I will work to establish a service that doesn’t exist in my home country. The Eye Cancer Foundation Fellowship King Hussein Cancer Center will help me a lot in gaining my aim.”

For more information on The Eye Cancer Foundation Fellowships, including how to apply, click HERE.

The Eye Cancer Foundation is proud to be joining forces with the International Council of Ophthalmology supporting and promoting eye cancer fellowship education for doctors from unserved and underserved countries.

Since launching its ICO fellowship program in 2001, more than 920 Fellows have completed a three month subspecialty training and 28 ICO Fellows have completed their one year training.

This partnership between the ICO and the Eye Cancer Fellowship will expand and enhance ECF’s existing fellowship programs, focusing specifically on addressing the need to reduce world-wide mortality related to retinoblastoma by ensuring that more patients have ready access to a trained eye cancer specialist in their region.

The ICO highlighted the new in its recently released program report, Fifteen Years of ICO Fellowships.

“It is out mutual goal to decrease the high rates of world-wide mortality associated with the most common primary childhood eye cancer, retinoblastoma. Towards this goal, we agree that supplying subspecialty-trained retinoblastoma specialists to unserved and underserved countries is our priority,” The Eye Cancer Foundation Chairman Dr. Paul Finger wrote.

Together, the Eye Cancer Foundation and the ICO have set a goal of saving 1,000 children by 2020.

A study recently published in the Journal of Clinical Oncology showed revamping multi-drug chemotherapy for retinoblastoma to include tropotecan maintained high cure rates while preserving vision and reducing the risk of treatment related leukemia.

Retinoblastoma ranks as the most common intraocular childhood cancer. It affects approximately 300 children in the United States each year and more than 8,000 worldwide. Better than 96% of patients in North America and Europe are cured of retinoblastoma due to early detection and treatment.

Multi-modal chemotherapy has proved to be an effective treatment, but the widely used triple-drug therapy includes etoposide, a drug that has been associated with secondary acute myeloid leukemia in some patients.

Ten years ago, Michael Dyer, Ph.D., chair of the St. Jude Department of Developmental Neurobiology, began laboratory research seeking a safer retinoblastoma therapy. Researchers began looking at topotecan because it had shown promise in the treatment of other solid tumors.

Working with retinoblastoma tumor cells grown in the laboratory and in mice, Dyer confirmed topotecan could possibly replace etoposide in retinoblastoma therapy and determined the effective dose. The laboratory findings led to a clinical trial including 26 children diagnosed with advanced, bilateral retinoblastoma that had not spread beyond their eyes.

In the trial, triple drug chemotherapy replacing etoposide with topotecan outperformed the standard chemotherapy treatment. Of the 51 diseased eyes included in the study, 78% of those treated with therapy including topotecan were salvaged. That compares to previous reports of 30 to 60% following chemotherapy that included etoposide and often required salvage radiation therapy.

Altogether, 10 eyes had to be surgically removed, including one eye removed at diagnosis prior to chemotherapy and three removed after radiation therapy failed to stop disease progression.

“Preservation of an eye is not synonymous with preservation of vision,” first and corresponding study author Rachel Brennan, M.D. said. “But this therapy provided significant improvement in survival of eyes and useful vision in patients with advanced retinoblastoma.”

Post-treatment vision screening of survivors identified 18 patients with vision of 20/40 or better in at least one eye.

“This 10-year follow-up study shows for the first time that topotecan can be used in front-line therapy to help reduce exposure of retinoblastoma patients to etoposide,” Brennan said first. “We expected patients to be cured, but we also found more than 80 percent of patients had measurable vision.”

The results of the study seem promising. Topotecan may well provide an alternative therapy that maintains or even exceed the effectiveness of traditional multi-modal chemotherapy for retinoblastoma while eliminating one potentially deadly treatment side-effect.

Castle Biosciences, Inc. recently launched a new test to help doctors better asses the risk of uveal melanoma metastasis.

Uveal melanoma ranks as the most common eye cancer in adults. About half of patients diagnosed with uveal melanoma develop metastatic disease, primarily in the liver.

Researchers have found gene expression levels of PRAME (Preferentially Expressed Antigen in Melanoma) correlate with an increased risk of metastasis in patients diagnosed with uveal melanoma. The newly developed gene expression profile (GEP) test measures levels of PRAME.

“Our research shows that the expression of PRAME above a specific threshold in uveal melanoma is a strong predictor of increased metastatic risk in patients with a Class 1 uveal melanoma who otherwise would be assumed to be at low risk,” University of Miami School of Medicine Dr. J. William Harbour, said. “By combining results of the gene expression profile and PRAME tests, we believe we can enhance the accuracy of metastatic risk stratification in patients with uveal melanoma.”

The test is designed to be used in conjunction with DecisionDx-UM, the company’s primary uveal melanoma test.

“DecisionDx-UM is the standard of care to identify patients whose eye tumors are likely to spread and become deadly,” President and CEO of Castle Biosciences Derek Maetzold said. “We believe the DecisionDx-PRAME test used in conjunction with the results of the DecisionDx-UM test can enable further precision of a patient’s predicted risk for metastasis and help guide physicians and patients to the most appropriate follow-up care regimens.”

In a study published last March in Clinical Cancer Research, researchers found that PRAME could distinguish between GEP Class 1 tumors that would metastasize versus those that would not. Through the study, researchers were able to determine a threshold to signify positivity in uveal melanoma tumors. Tumors that metastasized in the study were all positive for PRAME expression according to this threshold.

Castle Biosciences went on to perform technical validation of the threshold in a 958 patient sample study. In addition, researchers found patients with high metastatic risk Class 2 tumors who were positive for PRAME expression may be at higher risk of earlier metastasis compared to patients with Class 2 tumors that were PRAME negative.

Dr. Paul Finger said that while more study is necessary, the new test shows promise.

“Though we all look forward to an independent GEP and PRAME validation study, these tests are promising developments for measurement of the risk for uveal melanoma metastasis,”he said. “Early treatment and therefore early detection is key to prolonging life. Therefore this new PRAME-test should help doctors better define an individual patients risk for choroidal melanoma metastasis.”

A new experimental treatment offers some hope for patients with ocular melanoma that has metastasized to the liver.

Ocular melanoma is the most common eye cancer in adults. About 50% of patients diagnosed with ocular melanoma go on to develop metastatic disease. In 95% of cases, the liver is the first place metastases are discovered. This is because ocular melanoma spreads through the blood-stream as opposed to the lymphatic system, making the liver susceptible to metastasis.

A patient’s prognosis is generally poor once the melanoma spreads. According to the Ocular Melanoma Foundation, median survival time is between two and eight months without treatment. Standard chemotherapy tends to be ineffective, but a new experimental therapy called percutaneous hepatic perfusion (PHP) shows promise. It is now undergoing clinical trials led by the National Cancer Institute.

In PHP, doctors isolate the liver and fill it with the chemotherapy drug Melphalan. During the procedure, a catheter with a balloon on either end is inserted through several needle punctures in the skin. The balloons are then inflated, sealing off the vein above and below the liver. Once isolated, high-dose, heated chemotherapy is infused through the liver. Charcoal filters remove chemotherapy from the blood as it is returned to the body through a second catheter in the neck.

A 2010 study published in the American Journal of Clinical Oncology revealed the potential benefits of using PHP to treat both ocular and skin melanomas that have metastasized in the liver. In the study, researchers concluded the treatment significantly improved progression-free survival rates compared to the best available options.

Clinical trials have reinforced cause for optimism. In one case, Sabrina Frey, 43, recently underwent PHP treatment at Moffitt Cancer Center in Tampa, Florida. She was featured in news reports across the country and says the treatment visibly reduced her tumors.

“Some tumors are not actually even visible on my MRI’s anymore,” Sabrina said.

While PHP seems to have reduced the size of metastatic ocular melanoma tumors in the liver, it is not a cure. Researchers say the earlier the treatment is started, the better the outcome. It seems to be most successful in patients with strong liver function and a limited number of metastatic tumors.

Through the month of September, families, caregivers, charities, and researchers across the country observed Childhood Cancer Awareness Month. Cancer is the leading cause of death by disease in children under the age of 15. In the US alone, more than 15,000 children are diagnosed with cancer every year. While Leukemia and brain tumors are the most common cancers in children and get the most attention, eye cancer also affects kids.

Retinoblastoma is the most common intraocular cancer in young children. It typically develops by the age of five and affects approximately 8,200 children in the world each year. The average age at diagnosis is between 12 and 18 months. If not detected early, it is the most life-threatening eye cancer in kids.

Researchers say retinoblastoma has a genetic link in 40% of the cases. Patients with retinoblastoma also experience an increased frequency of second malignancies, particularly if the cancer is hereditary. These cancers most often manifest as sarcomas and occur in up to 8% of retinoblastoma patients after 18 years of follow-up.

Interestingly, retinoblastoma can begin to grow before the baby is born. The cancers develop early as the fetus begins to grow. Normally, eye cells develop in an organized manner. But sometimes the cells lining the retina divide and grow out of control, forming retinoblastoma tumors.

If caught early, retinoblastoma is treatable, and the eye can usually be saved. Unfortunately, awareness of this disease is low, and it often goes undiagnosed until the tumors are large, even fill the eye. Failure to catch retinoblastoma early is particularly problematic in developing countries. For instance, in Kenya, 8 out of 10 children diagnosed with this type of eye cancer die from it. In those cases, the tumor continues to grow out of the eye and spreads to other parts of the body.

This underscores the importance of routine eye exams for children. Parents should also be aware of signs that could indicate eye cancer. These include a white pupil, unusual squinting, changes in the color of the iris, and painless redness or inflammation of eye. White pupils are sometimes best seen as white reflections showing up in the eye in photos taken with a flash camera. White pupil can indicate the presence of a tumor in the eye.

The Eye Cancer Foundation is working to save children’s lives by improving the diagnosis and treatment of retinoblastoma in developing countries. The Foundation has partnered with the International Council of Ophthalmology (ICO) to promote and conduct eye cancer fellowship education for physicians from under-served countries.

Donate today to help the Foundation train physicians around the world to diagnose retinoblastoma and save lives .

Retinoblastoma doesn’t garner media attention like Leukemia and other more common childhood cancers. But it can be every bit as devastating to the children it affects. Like these other cancers, the key is awareness and early diagnosis.