Novel photodynamic therapy method can eradicate ocular melanoma, study shows

The study is the first to show that femtosecond pulsed laser irradiation is effective and safe in mice with induced ocular melanoma, paving the way for minimally invasive targeted treatment of the disease in future.

By Julia Moióli  |  Agência FAPESP – Researchers at the Optics and Photonics Research Center (CePOF) in Brazil and collaborators at the University of Toronto and Princess Margaret Cancer Center in Canada have reported for the first time the effective use of a specific type of phototherapy to eradicate ocular melanoma in mice. Based on pulsed laser, the technique involves the application of a large amount of light in a short period of time to activate a drug.

CePOF is a Research, Innovation and Dissemination Center (RIDC) funded by FAPESP and hosted by the University of São Paulo’s São Carlos Institute of Physics (IFSC-USP).

The study is described in an article published in Proceedings of the National Academy of Sciences. The results pave the way for less drastic treatment of the disease in future. Current strategies are not highly effective, and in many cases involve ionizing radiation and removal of the affected eye.

Already used to treat basal cell carcinoma, the most common type of skin cancer, photodynamic therapy involves the use of light to activate drugs in appropriate radiation conditions and in the presence of oxygen (all cells, whether cancerous or normal, need oxygen to perform their metabolic functions). Melanoma, one of the most aggressive types of cancer, however, has proved challenging because melanin, a dark pigment, competes with the photosensitizing medication by absorbing much of the light.

Another difficulty is that biomolecules like melanin make photons (light particles) change direction and disperse, so that very few penetrate to underlying tissue. 

In previous research, the same group of scientists successfully tested a method of optimizing the response to photodynamic therapy in skin melanomas via topical application of optical clearing agents to modify the optical properties of the tumor and enhance light penetration. In this study, which was funded by FAPESP, they tested the effectiveness of a strategy for ocular melanoma, which is even harder to treat because of its location in the eye.

The scientists investigated a femtosecond pulsed laser irradiation regime. This type of laser emits high levels of energy in ultrafast bursts (a femtosecond is a quadrillionth of a second) with sufficient precision to minimize collateral damage to healthy adjacent tissue. In mice with ocular melanoma, no visible residual tumor was left after they were submitted to photodynamic therapy with Visudyne, a drug used to treat macular degeneration.

“We found that the method lets us deliver two photons, each with half the necessary energy, and the extremely short period of time involved means the biological molecule basically doesn’t notice, so that it can hit the target. It’s the first time this has been reported in scientific publications,” said Cristina Kurachi, a professor at IFSC-USP and leader of the study on the Brazilian side. The Canadian team was led by Brian Wilson, a professor in the Department of Medical Biophysics at the University of Toronto’s Medical School. 

“Even more interestingly, the technique was most effective in treating pigmented tumors, showing that melanin acts as a mediator,” said Layla Pires, a researcher at Princess Margaret Cancer Center and IFSC-USP. “These results offer a new perspective in the field of biophotonics, breaking the paradigm that pigmented lesions can’t be eradicated with light-based therapies.” 

The method was also shown to be safe, as no damage was done to adjacent structures. “The treatment proved highly selective and effective,” Karachi said, pointing to another possible advantage of photodynamic therapy: several studies conducted around the world have shown that it can induce an immune response, improving the capacity of the organism’s immune system to combat cancer.

Prospects

The discovery lays a foundation for more effective treatment of ocular melanoma in future, with a minimum of collateral damage. The treatments available now are mainly ineffective, and in 50% of cases the cancer can become metastatic, with a survival time of four to 13 months.

Despite the positive prospects, however, several more steps and many more years of research are required before the treatment can be used in clinical practice. “We’ve successfully completed the first phase, showing that the method is effective and safe. Next steps will include trials involving humanized mice engrafted with human melanoma cells, and a first round of trials in humans,” Kurachi said.

In addition, the specific instruments needed for the technique are still under development. During the study, the researchers used a microscope, but the goal is to use an adjusted ophthalmoscope, an instrument for inspecting the retina. This technology is currently being developed by other research groups. 

“We expect our study to serve as a basis for extending the use of the technology to treat other types of tumor, such as retinoblastoma, which affects children,” Pires said.

The research group that conducted the study includes specialists in several fields, such as biophotonics, optics and translational medicine. Funding was also contributed by the Cancer Prevention and Research Institute of Texas (USA), the National Council for Scientific and Technological Development (CNPq, Brazil), the Ministry of Education’s Coordination for the Improvement of Higher Education Personnel (Brazil), the Texas Governor’s University Research Initiative (USA), Henry Farrugia Research Fund (Canada), Princess Margaret Cancer Center Foundation Invest-in-Research Fund (Canada), and the Vision Science Research Program Awards (Canada).

The article “Femtosecond pulsed laser photodynamic therapy activates melanin and eradicates malignant melanoma” is at: www.pnas.org/doi/10.1073/pnas.2316303121.