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Developing More Effective Treatments for Ocular Melanoma

SKCC Research Discoveries Translate to More Effective Treatments for Ocular Melanoma

Guest blog post by Andrew Aplin, PhD, Associate Director for Basic Science and the Program Leader for Cancer Cell Biology and Signaling (CCBS) in the NCI-designated Sidney Kimmel Cancer Center at Thomas Jefferson University. Dr. Aplin was the recipient of the 2016 CURE OM Unite! research award, selected by both a peer-reviewed scientific panel and, in a historic first, representatives from the CURE OM patient and caregiver community.

Ocular melanoma is a rare form of melanoma that arises in the eye, affecting about 2,000 patients annually in the United States. Although ocular melanoma has a similar origin as the more frequent skin form of melanoma — both types of cancer are generated by melanocytes, which are cells that produce pigment — they are genetically and clinically distinct from each other. Thus, they are driven by different cellular factors and respond differently to forms of therapy administered to patients. Patients with primary ocular melanoma that has not spread to other parts of the body typically undergo surgery or radiation. However, about half of ocular melanoma cases metastasize to distant sites, usually involving the liver. These patients can face a very poor prognosis, so there is a critical need for new and improved strategies to treat this aggressive form of cancer.

In order to better treat these advanced ocular melanoma patients, it is essential to elucidate the molecular and cellular basis of the cancer’s development and progression. Using this knowledge, we can develop new clinical interventions that are designed to reduce cancer incidence and mortality. With this goal in mind, my colleagues and I have assembled a multidisciplinary group of scientists and clinicians from the Sidney Kimmel Cancer Center (SKCC) at Thomas Jefferson University and the nearby Wills Eye Hospital to tackle the challenge of ocular melanoma through a collaborative, team-based approach. By identifying and studying the aberrant cellular processes that contribute to ocular melanoma, we hope to develop effective new inhibitory drugs that target key signaling pathways involved in ocular melanoma progression.

Important clues in this research have come from studying the genetic alterations that occur in ocular melanoma. In particular, mutations in two genes—GNAQ and GNA11—occur in nearly all ocular melanoma cases, so we are developing multiple approaches to determine how these mutations drive this cancer and we are testing novel strategies to target these mutations. In this regard, the Benovic and Wedegaertner laboratories at Thomas Jefferson University and other groups have recently discovered that a compound derived from the Christmas berry primrose plant blocks the activities of these two mutated genes, halting cancer progression. Although still in the early stages, the study is promising, leading us one step closer to a potential new treatment. In a related development, our researchers have also developed a vaccine that causes an “alarm” to go off in the immune system that recognizes and kills the mutated GNAQ and GNA11 cells. Mouse model tests of this approach have been successful and are now being extended to create a human-grade vaccine to prevent metastatic progression of ocular melanoma.

In another inhibitor-based approach, the Aplin laboratory at Thomas Jefferson University recently published a study with their clinical colleagues that examined a combination of two different drugs in treating ocular melanoma. One of the drugs targets bromodomain and extraterminal (BET) proteins and the other targets the fibroblast growth factor receptor (FGFR), based on previous research findings that implicated these molecules in ocular melanoma. The drug combination resulted in a more durable growth suppression of ocular melanoma cells transplanted into mice, suggesting that co-targeting the FGFR signaling pathway along with the BET proteins might offer a new approach to treating patients. We are exploring this idea further in the lab and hope to evaluate its therapeutic efficacy in future clinical trials.

Cancer growth is influenced not only by intrinsic cellular events, but also by growth factors and other molecules emanating from surrounding tissues, generally referred to as the tumor microenvironment. In the case of ocular melanoma, the liver microenvironment produces various molecules that affect the ability of ocular melanoma cells to either be eliminated by or develop resistance to therapeutic agents. The Aplin laboratory has identified factors from the liver that bind tumor cell receptors which are critical to ocular melanoma’s ability to tolerate targeted therapies. This discovery will help SKCC investigators to identify better ways to tackle ocular melanoma that is resistant to treatment.

In the course of these studies, changes in dormancy pathways, which enable cells to enter an inactive, senescent state, were found to be associated with ocular melanoma progression and metastasis. This observation sheds light on the long-standing but still unanswered question of why ocular melanoma can remain dormant and asymptomatic for over a decade after the initial diagnosis and treatment before resuming metastatic growth. In collaboration with the group of Dr. Julio Aguirre-Ghiso at the Icahn School of Medicine at Mount Sinai, we are beginning to understand the underlying causes of dormancy, with the goal of developing a clinical trial focused on eliminating dormant cells. This new research direction may provide a valuable alternative to the other approaches described above by allowing dormant cells to be identified and neutralized before they can evade inhibitor treatments, disseminate, and seed new metastases at distant sites in the body.

These research advances are now being translated into numerous clinical applications for ocular melanoma by our SKCC team of investigators. For example, the Sato and Aplin laboratories have surgically implanted individual patient tumors into mice to test the tumor’s drug sensitivity. Each patient’s tumor has unique characteristics that affect its response to treatments, and this novel approach allows the team to develop a customized treatment plan for each patient with metastatic ocular melanoma. In addition, the Sato group has pioneered a new therapy called immunoembolization, an approach that combines a liver-targeted embolization technique with systemically administered immune checkpoint inhibitor therapy. Previous studies had revealed that while metastatic skin melanoma has responded quite well to these checkpoint inhibitors, the drugs have not shown as dramatic of an effect in metastatic uveal melanoma. SKCC investigators are now conducting a clinical trial to determine whether immunoembolization improves the effectiveness of these checkpoint inhibitors in ocular melanoma that has metastasized to the liver. Finally, another exciting clinical trial is studying the compound ImmTAC (Immune Mobilizing mTCR Against Cancer). This drug harnesses T-cell receptor technology in patients expressing HLA A2 positive, a tissue type found in almost half of all Americans. SKCC is the world’s leading study site for this new approach.

In addition to the laboratory-based work and clinical trials described above, a third approach that the SKCC is taking against ocular melanoma is the use of population-based studies. At present, the genetic and environmental factors underlying the etiology of ocular melanoma are poorly understood. Dr. Marlana Orloff and team at SKCC have recently identified geographically localized clusters of ocular melanoma patients and are now developing a national registry of patients that will be of tremendous value to the broader melanoma research community. They are also researching potential environmental factors that may cause ocular melanoma, based on the striking observation of highly elevated incidences of ocular melanoma in genetically unrelated individuals who reside in close proximity to one another. Ultimately, these population-based analyses will provide new leads about other cellular pathways and environmental influences that will inform future directions for research and clinical testing in the ocular melanoma field.

Collectively, SKCC research has deepened our understanding of ocular melanoma’s progression and has already yielded potential treatment breakthroughs, as evidenced in the novel clinical trials now available to patients. It is critical that we continue our multi-pronged laboratory research, clinical applications, and population-based efforts to develop truly effective treatments for ocular melanoma and thereby transform cancer care for patients with this deadly form of cancer.

The MRF’s CURE OM initiative is proud to support the pioneering scientific work conducted by researchers like Dr. Aplin. Your support makes these life-saving advances possible, leading to more effective treatments and, one day, a cure.