A new compound, discovered jointly by international pharmaceutical company Servier, headquartered in France, and Vernalis (R&D), a company based in the UK, has been shown by researchers at the Walter and Eliza Hall Institute and Servier to block a protein that is essential for the sustained growth of up to a quarter of all cancers.
The research presents a new way to efficiently kill these cancerous cells and holds promise for the treatment of blood cancers such as acute myeloid leukaemia,lymphoma and multiple myeloma, as well as solid cancers such as melanoma and cancers of the lung and breast. It is published online today in the journal Nature.
The Servier compound – S63845 – targets a protein of the BCL2 family, called MCL1, which is essential for the sustained survival of these cancer cells.
Institute scientist Associate Professor Guillaume Lessene, who led the Walter and Eliza Hall Institute’s research team in Melbourne, Australia, said the work provided the first clear preclinical evidence that inhibiting MCL1 was effective in targeting several cancer types.
“MCL1 is important for many cancers because it is a pro-survival protein that allows the cancerous cells to evade the process of programmed cell death that normally removes cancer cells from the body,” Associate Professor Lessene said. “Extensive studies performed in a variety of cancer models have shown that S63845 potently targets cancer cells dependent on MCL1 for their survival.”
The institute team of Associate Professor Lessene worked with haematologist Associate Professor Andrew Wei and Dr Donia Moujalled from The Alfred Hospital and Servier scientists, to demonstrate that not only was S63845 effective against several cancer types, but that it could also be delivered at doses that were well tolerated by normal cells.
Dr Olivier Geneste, Director of Oncology Research at Servier, said this preclinical research represented major findings regarding the druggability of MCL1, a valuable and highly challenging target. “S63845 was discovered through collaboration with the fragment and structure based discovery expertise at Vernalis,” he said. “As part of the ongoing Servier / Novartis collaboration on this target class, clinical development of a MCL1 inhibitor should be launched in the near future.”
Associate Professor Lessene said the research provided further evidence of the usefulness of a new class of anti-cancer drugs called BH3 mimetics. “BH3 mimetics inhibit a group of proteins known as the ‘pro-survival BCL-2 proteins’,” he said. “MCL1 is a member of this protein family, and inhibiting it activates the process of programmed cell death. Walter and Eliza Hall Institute researchers revealed the role of BCL-2 in cancer more than 28 years ago and the essential role of MCL1 for the survival of malignant cells four years ago.”
Cancer treatments based on laser irridation of tiny nanoparticles that are injected directly into the cancer tumor are working and can destroy the cancer from within.
Researchers from the Niels Bohr Institute and the Faculty of Health Sciences at the University of Copenhagen have developed a method that kills cancer cells using nanoparticles and lasers. The treatment has been tested on mice and it has been demonstrated that the cancer tumors are considerably damaged. The results are published in the scientific journal, Scientific Reports.
Traditional cancer treatments like radiation and chemotherapy have major side affects, because they not only affect the cancer tumors, but also the healthy parts of the body. A large interdisciplinary research project between physicists at the Niels Bohr Institute and doctors and human biologists at the Panum Institute and Rigshospitalet has developed a new treatment that only affects cancer tumors locally and therefore is much more gentle on the body. The project is called Laser Activated Nanoparticles for Tumor Elimination (LANTERN). The head of the project is Professor Lene Oddershede, a biophysicist and head of the research group Optical Tweezers at the Niels Bohr Institute at the University of Copenhagen in collaboration with Professor Andreas Kjær, head of the Cluster for Molecular Imaging, Panum Institute.
After experimenting with biological membranes, the researchers have now tested the method on living mice. In the experiments, the mice are given cancer tumors of laboratory cultured human cancer cells.
“The treatment involves injecting tiny nanoparticles directly into the cancer. Then you heat up the nanoparticles from outside using lasers. It is a strong interaction between the nanoparticles and the laser light, which causes the particles to heat up. What then happens is that the heated particles damage or kill the cancer cells,” explains Lene Oddershede.
Design and effect
The small nanoparticles are between 80 and 150 nanometers in diameter (a nanometer is a millionth of a millimeter). The tested particles consist of either solid gold or a shell structure consisting of a glass core with a thin shell of gold around it. Some of the experiments aimed to find out which particles are most effective in reducing tumors.
“As physicists we have great expertise in the interaction between light and nanoparticles and we can very accurately measure the temperature of the heated nanoparticles. The effectiveness depends on the right combination between the structure and material of the particles, their physical size and the wavelength of the light,” explains Lene Oddershede.
The experiments showed that the researchers got the best results with nanoparticles that were 150 nanometers in size and consisted of a core of glass coated with gold. The nanoparticles were illuminated with near-infrared laser light, which is the best at penetrating through the tissue. In contrast to conventional radiation therapy, the near-infrared laser light causes no burn damage to the tissue that it passes through. Just an hour after the treatment, they could already directly see with PET scans that the cancer cells had been killed and the effect continued for at least two days after the treatment.
“Now we have proven that the method works. In the longer term, we would like the method to work by injecting the nanoparticles into the bloodstream, where they end up in the tumors that may have metastasized. With the PET scans we can see where the tumors are and irridate them with lasers, while also effectively assessing how well the treatment has worked shortly after the irradiation. In addition, we will coat the particles with chemotherapy, which is released by the heat and which will also help kill the cancer cells,” explains Lene Oddershede.