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Precision Medicine

Fighting Cancer with SMARTdrugs

With “SMARTdrugs”, funded by the European Innovation Council, an international team of researchers from UZH with partners in Munich, London, San Sebastian and Utrecht aims to create a new class of therapies: “radiotheranostics”. These drugs combine diagnostic and therapeutic radionuclides in a supramolecular compound with the purpose of imaging and treating tumors.
Radiotheranostics: specifically designed supramolecular compounds for the diagnosis and treatment of aggressive cancers such as lung and brain tumors. (Image: Johannes Richers)

At UZH the research project is led by Jason Holland, Associate Professor at the Department of Chemistry and Chair of Medicinal Radiochemistry. “Our goal is to develop supramolecular compounds to treat two aggressive cancer types that currently have a very poor prognosis for the patients affected: lung and brain tumors,” says the chemist. The consortium consists of five European teams that bring together complementary skills, technologies and expertise in synthetic chemistry, radiopharmaceutical biology and cancer diagnosis and therapy. Now, SMARTdrugs has been awarded a Pathfinder Open Grant from the European Innovation Council (EIC) of nearly 4 million euros.

Radionuclides in cancer diagnostic and treatment

For oncologists, it’s important to recognize the size and location of cancerous tumors to choose the best treatment option for a patient, and to follow the treatment over time to see if it is working. Tumors can be visualized by using so-called radiotracers: a radionuclide, which is a radioactive isotope of an element, attached to a molecule that 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 that can be detected by specialized imaging techniques, such as positron emission tomography (PET), providing highly accurate measurements.

Radionuclides can also be used to treat specific tumors. Again, the radionuclide is coupled to a drug molecule that directs the small radioactive payload to the desired location. The targeted 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 that combine both diagnostic and therapeutic radionuclides in a single supramolecular drug: so-called radiotheranostics,” explains Jason Holland. Instead of attaching radionuclides directly to drug molecules, the researchers will create so-called ‘supramolecular compounds’ with greater control over the size, shape and other biochemical properties than other big molecules like proteins. These characteristics determine how well the new compounds perform in human tissue.

Jason P. Holland

Our goal is to develop supramolecular compounds to treat two aggressive cancer types: lung and brain tumors.

Jason P. Holland
Professor for Radiochemistry and Imaging Science

New ways of linking radionuclides

The basis for building supramolecular radiotheranostics is synthetic chemistry. “The molecules are large and highly complex. Our compounds are designed and built using a natural process called ‘self-assembly’, in which many small contributions from weak forces add up to create a stable and well-defined drug,” says Jason Holland. Nature is the model for this: In biology, self-assembly is used to help proteins fold into the correct shape, however, understanding this process and harnessing it for drug discovery is a major challenge.

Recent experiments by UZH and collaborators led by Angela Casini, Professor of Medicinal and Bioinorganic Chemistry at the Technische Universität München (TUM), Germany, have shown that self-assembly can indeed be used to create novel therapies. Separately, the consortium team led by Jordi Llop, expert in radiochemistry and nuclear imaging at the Center for Cooperative Research in Biomaterials (CICbiomaGUNE) in San Sebastian, Spain, has pioneered an efficient tumor therapy with radioactive nanorobots that use chemical fuels to find their targets faster.

SMARTdrugs will combine these ideas and explore how the new drugs can improve the treatment of lung cancer in research conducted by the team of Tim Witney, molecular imaging specialist at King’s College London, UK, and the treatment of brain tumors in research conducted by the group of Alex Poot, expert in radiology and nuclear medicine at the Princess Máxima Hospital and the University Medical Center in Utrecht, the Netherlands.

Making tumors visible: Positron emission tomography (PET) imaging of human lung cancer in an advanced preclinical mouse model. (Image: Tim Witney, King’s College London)

Better treatments for lung cancer and brain tumors

SMARTdrugs will focus on non-small cell lung cancer in adults and brain cancer in children – aggressive cancer types with significant unmet needs. The 5-year survival rates are only 15% and 5%, respectively, and medical care has struggled to improve over the past decade despite advances in prevention, screening and treatment. Lung cancer is the leading cause of cancer death worldwide and is classified into different histologic subtypes, with non-small cell lung cancer accounting for approximately 85% of cases. Pediatric brain tumors include multiple subtypes, such as medulloblastoma or diffuse midline glioma, some of which carry a life expectancy of less than one year after diagnosis. Current treatments often fail due to the mutations that lead to therapy-resistant tumor cells.

“Radiotheranostics offers great opportunities to pre-select patients most likely to respond to targeted therapy and improve treatment outcomes, enabling further steps toward precision medicine,” says Jason Holland. But first, supramolecular theranostics must prove their selectivity and specificity in laboratory tests before they can advance to clinical trials in cancer patients.

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    Radiotheranostics: specifically designed supramolecular compounds for the diagnosis and treatment of aggressive cancers such as lung and brain tumors. (Image: zVg)