Dr. Sabrina Oliveira of Utrecht University has been awarded a prestigious ERC Starting Grant of 1.5 million Euros for her proposal to better understand and to advance a new form of photodynamic therapy, a cancer therapy that is local, cancer specific, and may induce long-term protection through activation of the immune system. Photodynamic therapy is already used in the clinic, but in its current form it has limited cancer specificity. In recent years, Oliveira has developed a new strategy of cancer-targeted photodynamic therapy. This grant will enable her to further research and develop this strategy, and to facilitate its future application in the clinic.
In Photodynamic therapy (PDT), the drug is a photosensitizer, which means it is only activated by a physically harmless, locally applied laser light. A solution of this drug is injected into the bloodstream, where it is distributed throughout the body. Two to four days later, the tumour is exposed to laser light of a specific wavelength. This activates the photosensitizer, which leads to the production of an active form of oxygen that destroys nearby cancer cells. However, the photosensitizers used in the clinic currently are hydrophobic and thus not cancer-specific, limiting the therapeutic efficacy.
Over the years, efforts have been made to improve cancer specificity of PDT, for instance by using antibodies to target the photosensitizers to cancer cells. However, preclinical studies show that the antibody-photosensitizer combinations used are too large to penetrate and distribute homogeneously through tumours, preventing them from completely eradicating the cancer. They also circulate in the bloodstream for several days, which delays light application. But with the Veni grant that was awarded to her in 2012, Oliveira has developed a new strategy of targeted PDT, which overcomes these disadvantages.
Ten times smaller
“Instead of an antibody, we use a so-called nanobody, which is approximately 10 times smaller, so it accumulates at the tumour within 1-2 hours after intravenous administration. At that time point, the unbound nanobody is cleared from the bloodstream, so we can immediately apply the light. And unlike the photosensitizers currently used, the one we use is not hydrophobic, so it does not stick randomly to every cell it encounters”, explains Oliveira. Studies in vitro and in vivo show that this combination binds rapidly and specifically to the cancer cells and distributes homogeneously throughout the tumour, leading to approximately 90% tumour damage. Also it can be traced in the body to help and guide the application of PDT.
Protection against recurrence
“One of the great advantages of Photo Dynamic Therapy is that it is in principle not harmful to the patient’s healthy tissues. And the more cancer-specific we make it, the lower the chances of side-effects. This may make it an excellent alternative for patients with tumours in places that are too risky to operate on, for example in the head and neck regions, because of the collateral damage that would occur”, says Oliveira. “The second main advantage is that it can activate the patient’s immune system, inducing long-term protection against the recurrence of the cancer.”
Getting closer to the clinic
With the ERC Starting Grant, Oliveira aims to develop novel nanobody-photosensitizers conjugates that not only bind to cancer cells, but also to cancer stem cells and endothelial cells of cancer vasculature. This will help ensure complete cancer eradication. She will also investigate whether their nanobody-photosensitizer combination activates the immune system, and if it is capable of inducing protection against the recurrence of cancer. Finally, a very important part of the project will focus on evaluating if this new treatment works in dogs admitted to the veterinary clinic with cancers which have developed spontaneously. “This step will be essential in determining if this treatment does indeed have the potential to be effective in human cancers. If we manage to achieve what I aim for, at the end of this project our improved targeted PDT will certainly be closer to clinical application”, Oliveira concludes.
Sabrina Oliveira (1980) was introduced to Utrecht University through an internship at the department of Pharmaceutical Sciences during her studies at the Faculty of Pharmacy of Coimbra University in Portugal. After graduation, she obtained an individual doctoral grant from the Portuguese foundation for science and technology (FCT) to return to Utrecht to do her PhD research with professors Gert Storm and Raymond Schiffelers. She then moved to Cell Biology at the Department of Biology, where she worked as a postdoc in the group led by Dr. Paul van Bergen en Henegouwen. In 2012, she was awarded a Veni grant from the Netherlands Organisation for Research, giving her the opportunity to start her own research line.