With the project SMARTdrugs, funded by the European Innovation Council, an international team comprising researchers at CIC biomaGUNE and collaboration partners in Zurich, Munich, London, and Utrecht, wants to create a new class of therapies: radiotheranostics. These drugs combine diagnostic and therapeutic radionuclides in one supramolecular compound with the aim to image and treat tumors.
The research project at CIC biomaGUNE is led by Jordi Llop, Principal Investigator of the Radiochemistry and Nuclear Imaging Group at CIC biomaGUNE. The consortium comprises five European teams that bring together complementary skills, technologies, and expertise in synthetic chemistry, radiopharmaceutical biology, as well as cancer diagnosis and therapy. Now SMARTdrugs project has been funded as a Pathfinder Open Grant by the European Innovation Council (EIC) with nearly 4 million Euros. “Our aim is to develop supramolecular compounds to treat two aggressive cancer types that currently have very poor prognosis for the patients affected,” says Llop.
Radionuclides are used for cancer diagnostic and therapy
For oncologists it’s important to recognize the size and location of cancerous tumors, for example in the lungs or brain, to choose the best therapy option for an individual and to follow the treatment over time to see if it works. Tumors can be made visible by using so-called radiotracers: a radionuclide, a radioactive isotope of an element, linked to a molecule which recognizes the cancer cells with high accuracy. Such radioactive drug molecules allow clinicians to see key signatures of tumors using state-of-the-art camera systems. The radioactive component produces light which can be detected by special imaging techniques like positron emission tomography (PET) providing highly accurate measurements.
Radionuclides can also be used to treat certain tumors. Again, the radionuclide is coupled to a drug molecule which guides the small radioactive payload in a targeted manner to the desired location. Specific accumulation of the therapeutic radiotracer in a tumor kills the cancer cells while sparing the surrounding healthy tissue. “With SMARTdrugs, we want to create a new class of therapies, which combine both diagnostic and therapeutic radionuclides in one supramolecular drug: so-called radiotheranostics,” explains Llop. Instead of linking radionuclides directly to drug molecules, the researchers will create so-called ‘supramolecular compounds’ with improved control over size, shape, and other biochemical features that determine how well the new compounds perform in human tissue.
New ways of linking radionuclides to supramolecular scaffolds
The basis to build supramolecular radiotheranostics is synthetic chemistry. “The molecules are large and very complex. Our compounds are designed and built using a natural process called ‘self-assembly’ where many small contributions from weak forces add up to create a stable and well-defined drug,” says Jordi Llop. In biology, self-assembly is used to help proteins fold into the correct shape, but understanding that process, and harnessing it for drug discovery is a major challenge.
Recently, the consortium team headed by Jordi Llop has participated in a project showing efficient tumor therapy using radioactive nanorobots that use chemical fuels to find their targets faster. Also, Llop’s group in collaboration with Prof. Angela Casini, Medicinal and Bioinorganic Chemistry professor at the Technische Universität München (TUM), Germany, and coordinator of SMART drugs, has shown that the distribution of self-assembled macromolecular structures can be modulated by using the appropriate chemical approaches. Experiments from Jason Holland, Associate Professor at the Department of Chemistry and Chair of Medicinal Radiochemistry at University of Zurich in collaboration with Prof. Casini have shown that novel therapies can be made using self-assembly.
SMARTdrugs will combine these and other ideas and explore how the new drugs can improve the therapy of lung cancers and brain tumors, conducted by the team of Tim Witney, molecular imaging specialist at King’s College London, UK, and by the group of Alex Poot, expert in radiology and nuclear medicine from Utrecht at the Princess Maxima Hospital and the University Medical Center in Utrecht, The Netherlands, respectively.
Better therapies for non-small cell lung cancer and pediatric brain tumors
SMARTdrugs will focus on non-small cell lung cancer in adults and brain cancers in children – aggressive cancer types of substantial unmet need. The 5-year survival rates are only 15% and 5%, respectively, and medicine has struggled to improve over the last 10 years despite advances in prevention, screening, and treatment. Lung cancer is the most common cause of cancer death world-wide and is classified into distinct histological subtypes, with non-small cell lung cancer accounting for approximately 85% of cases. Paediatric brain cancers contain multiple subtypes, like medulloblastoma or diffuse midline glioma, some of which have a life expectancy of less than a year after diagnosis. Current treatments often fail due to the mutations that lead to therapy-resistant tumor cells.
“Radiotheranostics present great opportunities to preselect patients most likely to response to targeted therapy and improve treatment outcomes, allowing further steps towards precision medicine”, Jordi Llop emphasizes. But first, supramolecular theranostics have to prove their selectivity and specificity in laboratory tests, before advancing toward clinical trials in cancer patients.