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Cancer Research

Neutrons are Aiding the Fight Against Cancer

| Author / Editor: Matthew Blakeley* / Marc Platthaus

Understanding a problematic protein

Another example of recent research taking advantage of the power of neutrons was a study of protein kinase G II (PKG II), from the protein kinase family. This protein, if not activated, can increase the risk of stomach cancer, and so researchers are keen to understand the intricacies of how the protein interacts with its known activators, enabling drug developers to exploit this information in future cancer therapy treatments. As published by a global collaboration crystals grown by researchers (Andrey Kovalevsky & Oksana Gerlits) at ORNL, using PKG II protein (provided by Choel Kim) from the Baylor College of Medicine in Texas, were exposed to neutrons at the ILL’s LADI-III beamline [2]. The resulting structure made it possible to observe the hydrogen-bonding interactions during the activation of PKG II, providing insights to the enzyme’s activation mechanisms. The results suggest that the activator’s potency depends on its ability to efficiently decrease overall protein dynamics. While further studies are needed to identify how potent activators need to be to bind the strongest, if confirmed, the results will be highly significant for future drug development across a range of diseases — particularly considering ~2% of all human genes encode for protein kinases, and over half of these are linked to various diseases such as cancer and diabetes.

How neutrons are optimizing existing treatments

As well as characterizing ordinary cell processes in order to identify drug targets, neutron beams are increasing our understanding of a growing group of cancer pharmaceuticals: the monoclonal antibodies (mAbs). These are being utilized against cancer, as well as other diseases, due to their highly specific targeting abilities. They can be refined so that they attach themselves to specific protein targets on cancerous or disease-causing cells. Despite the huge potential of mAbs as a therapeutic, they can be difficult to manipulate into a format that can be administered to patients. High concentrations of antibodies are required in each dose to be effective, which results in a solution that is viscous and thus physically impossible to inject. Their tendency to clump together — which is part of their effectiveness in tackling malignant cells — also means that the exact concentration is difficult to predict in solution.

An international collaboration between the ILL, National Center of Neutron Research, University of Delaware and biopharmaceutical company Genentech, used Small Angle Neutron Scattering (SANS) and Neutron spin-echo (NSE) to study the structure and dynamics of mAb clustering. Neutrons are exceptionally capable of analyzing the extremely high-concentrations in the mAb samples, which are required for the high-doses present in the injectable forms [3]. The ILL instruments provide unrivalled high-resolution and neutron intensity, which allowed the researchers to confirm that the inconvenient properties of the mAb solutions came from previously unnoticed small clusters in the solution. NSE is the most sensitive neutron spectroscopy technique. The IN15 Spin-Echo spectrometer has world-leading sensitivity to unravel molecular level motions and interactions. As a result, the potential of mAbs to be used in the treatment of various cancers becomes more achievable, as the administration of the drug becomes more accessible to patients and practitioners.

As our understanding of the human body expands, so does our ability to identify pathways and address causes of disease. Cancer, being so inextricably linked to both our DNA and our lifestyles, requires the most powerful and fine-tuned analytical tools to identify its inception and progression. The ILL’s arsenal of the most advanced neutron crystallography instruments in the world enables its teams of researchers to explore and discover new ways that we might treat this widespread and devastating illness, by looking directly at the molecular mechanisms that can so often go wrong.

References

[1] Francesco Manzoniet et al.: Elucidation of Hydrogen Bonding Patterns in Ligand-Free, Lactose- and Glycerol-Bound Galectin-3C by Neutron Crystallography to Guide Drug Design. J. Med. Chem., 2018, 61 (10), pp 4412–4420, DOI: 10.1021/acs.jmedchem.8b00081

Additional Information
 
What are neutron beams?

[2] Oksana Gerlits et al.: Neutron Crystallography Detects Differences in Protein Dynamics: Structure of the PKG II Cyclic Nucleotide Binding Domain in Complex with an Activator. Biochemistry, 2018, 57 (12), pp 1833–1837, DOI: 10.1021/acs.biochem.8b00010

[3] Eric J. Yearly et al.: Observation of Small Cluster Formation in Concentrated Monoclonal Antibody Solutions and Its Implications to Solution Viscosity. Biophysical Journal, Volume 106, Issue 8, P1763-1770, April 15, 2014, DOI: https://doi.org/10.1016/j.bpj.2014.02.036

* M. Blakeley Institut Laue-Langevin (ILL), 38042 Grenoble Cedex 9/France

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