Understanding the viruses that kill cancer cells

Taking inspiration from virology to find better treatments for cancer

There are some viruses, called oncolytic viruses, that can be trained to target and kill cancer cells. Scientists in the field of oncolytics want to engineer these viruses to make them safer and more effective so they can be used to treat more people and different types of cancers. To achieve this, they first have to fully understand at the molecular level all the different ways that the virus has evolved to infect healthy cells and cause disease. A research team from Cardiff University set out to better understand how a protein on the surface of a virus often used to kill cancer, called an adenovirus, binds to human cells to cause an infection. Using X-ray crystallography, the team was able to determine the structure of one the key adenovirus proteins. Using this information and after extensive computational analysis, the research team realised the virus was not binding the receptor on the cells that was originally thought. This has important implications for the development of new virotherapies and engineering of viruses to treat cancer. The more thoroughly the researchers can understand how the adenoviruses interact with cancer cells at the molecular level, the more safe and effective treatments can be brought to clinical trial in the future.

>Read more on the Diamond Light Source website

Absorber captures excess chemotherapy drugs

The work opens up a new route to fighting cancer that minimizes drug toxicity and enables personalized, targeted, high-dose chemotherapy.

Most anticancer drugs are poisonous, so doctors walk a delicate line when administering chemotherapy. A dose must be sufficient to kill or stop the growth of cancer cells in the target organ, but not high enough to irreparably damage a patient’s other organs. To avoid this, doctors can thread catheters through the bloodstream to deliver chemotherapy drugs directly to the site of the tumor—a method known as intra-arterial chemotherapy. Still, typically more than half of the dose injected into the body escapes the target organ. Several years ago, researchers began working on a major improvement: placing a device “downstream” of the targeted organ to filter out excess chemo so that much less of the drug reaches the body as a whole.

>Read more on the Advanced Light Source

Image: (extract, see here the full image)
(a) Diagram of the proposed approach for drug capture using a 3D-printed cylindrical absorber. (b) Chemical structure of doxorubicin, the chemotherapy drug used in this study. (c) Schematic of the endovascular treatment of liver cancer. Excess drug molecules are captured by the absorber in the vein draining the organ. An introducer sheath guides the absorber to the desired location via a guide wire.

A new molecule could help put the STING on cancer

The protein STING (stimulator of interferon genes) is a component of the innate immune system. It plays a major role in the immune response to cancer, and abnormal STING signaling has been shown to be associated with certain cancers. Immunomodulatory approaches using agonists to target STING signaling are therefore being investigated as anticancer treatments. However, the compounds in clinical trials typically are injected intratumorally in patients with solid cancers. In this study, researchers discovered a novel STING agonist, known as an amidobenzimidazole (ABZI), which can be given by intravenous injection and could therefore potentially open up its evaluation as a treatment for hard-to-reach cancers. Using x-ray diffraction data collected at the U.S. Department of Energy’s Advanced Photon Source (APS), researchers from GlaxoSmithKline (GSK) investigated ABZI compounds and STING. Their results, published in the journal Nature, may have important implications for anticancer immunotherapy.

STING is a protein that mediates innate immunity, and one function of the STING signaling pathway is in mobilizing an immune response against tumors. STING proteins can be activated by cyclic dinucleotides, small molecules that are made by the cytosolic DNA sensor, cGAS, upon sensing of DNA leaking out of the nucleus as a result of DNA damage, including that which might be associated with cancer development.

>Read more on the Advanced Photon Source at Argonne National Lab.

Figure: X-ray crystal structure of the STING protein bound to one of the new molecules.

Clear view of “Robo” neuronal receptor opens door for new cancer drugs

During brain development, billions of neuron nerve cells must find accurate pathways in the brain in order to form trillions of neuronal circuits enabling us to enjoy cognitive, sensory and emotional wellbeing.

To achieve this remarkable precision, migrating neurons use special protein receptors that sense the environment around them and guide the way so these neurons stay on the right path. In a new study published in Cell, researchers from Bar-Ilan University and Tel Aviv University in Israel, EMBL Grenoble in France and University of Exeter in the UK report on their discovery of the intricate molecular mechanism that allows a key guidance receptor, “Robo”, to react to signals in its environment.

One of the most important protein signaling systems that guide neurons consists of the cell surface receptor “Robo” and its external guidance cue, “Slit”. “Slit and Robo can be identified in virtually all animals with a nervous system, from a 1 mm-long nematode all the way to humans,” explains researcher Yarden Opatowsky, associate professor and head of the Laboratory of Structural Biology at Bar-Ilan University and who led the research.

>Read more on the European Synchrotron website

Image: A surface representation of the crystal structure of the extracellular portion of human Robo2. The yellow region represents the domain where dimerisation takes place. Here, we see it blocked by the other domains, meaning dimerisation cannot take place and that Robo2 is inactivated.
Credit: Y. Opatowsky.

Mechanism of thiopurine resistance in acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is an aggressive lymphoid malignancy that is currently the leading cause of cancer in pediatric patients1. Despite intensified chemotherapy regimens, the cure rates of ALL only approaches 40%2. Specific mutations in the cytosolic 5’-nucleotidase II (NT5C2) gene are present in about 20% of relapsed pediatric T-ALL and 3-10% of relapsed B-precursor ALL cases3,4.

NT5C2 is a cytosolic nucleotidase that maintains intracellular nucleotide pool levels by exporting excess purine nucleotides out of the cell5.  NT5C2 can also dephosphorylate and inactivate the metabolites of the 6-thioguanine (6-TG) and 6-mercaptopurine (6-MP) commonly used to treat ALL6. Thus, relapse associated activating mutations in NT5C2 confer resistance to 6-MP and 6-TG chemotherapy. Upon allosteric activation, a disordered region of NT5C2 adopts a helical configuration (helix A) and facilitates substrate binding and catalysis (Fig. 1a)7.  Mutations in this regulatory region of NT5C2 have been modeled to strongly activate NT5C2.  However, the majority of NT5C2 mutations associated with relapsed ALL do not occur in this region.
To better understand the mechanisms by which these gain-of function NT5C2 mutations lead to increased nucleotidase activity, Dieck, Tzoneva, Forouhar and colleagues investigated additional regulatory elements that may control NT5C2 activation.  They collected crystallographic data for several mutant NT5C2 homotetramers at SSRL (NT5C2-537X D52N/D407A in active state (BL9-2), NT5C2-Q523X D52N in basal state and in active state (BL14-1) and full-length NT5C2 R39Q/D52N in basal state (BL12-2)) and used the structural information as a guide in the understanding of the mechanistic details.

>Read more on the Stanford Synchrotron Radiation Lightsource website

Figure (a) A ribbon diagram of the active structure of NT5C2 WT, in which the allosteric helix A (αA) is shown in dark purple. The N and C termini amino acids (S4 and S488), and the termini amino acids (L402 and R421) of the disordered region in the arm segment are also labeled. Panels b and c shows ribbon and surface (for subunit B) depictions of basal (b) and active dimers (c) of WT.

Encapsulation of drugs for new cancer treatments

Research develops hydrogel from silk protein with potential application in photodynamic therapy

Cancer is a set of diseases characterized by uncontrolled multiplication of cells. One of the main methods for treating this disease is chemotherapy, which uses drugs to block the growth of those cells or to destroy them. In this way, most drugs used interfere with mitosis, the cellular mechanism by which new cells are produced. Therefore, both cancerous and healthy cells are affected, leading to several side effects.
Worldwide, considerable effort has been directed at developing new methods that act directly on the target of treatment. This is the case of so-called photodynamic therapy (PDT), a minimally invasive therapeutic procedure that selectively acts on malignant cells.
The procedure involves the administration of a light-sensitive substance, called a photosensitizing agent. When irradiated at specific wavelengths, the photosensitizer releases oxygen in reactive chemical forms that promote the death of malignant cells, infectious agents and the removal of burns.

>Read more on the Brazilian Synchrotron Light Laboratory (LNLS) website

Revealing the path of a metallodrug in a breast cancer cell

Some types of cancer cannot be treated with classical chemotherapy. Scientists from Inserm, CNRS, Sorbonne University, PSL university, University Grenoble Alpes and ESRF, the European Synchrotron, are working on a metallorganic molecule as an antitumor drug. Their research has given thorough insights into its mechanism in attacking cancer cells. This study is published in Angewandte Chemie.

Triple-negative breast cancer, which represents 10-20% of breast cancers, is not fuelled by hormones. In fact, it tests negative for estrogen and progesterone receptors and excess HER2 protein. This means that it does not respond to hormonal therapy and antibody medicines. Given that it is more aggressive and often has a higher grade than other types of breast cancer, the scientific community is relentlessly trying to find a treatment.

>Read more on the ESRF website

Image: X-ray fluorescence maps of potassium, an essential physiological element of the cell (K, in pink), and, osmium a constitutive element of the metallocifen (Os, in green), in hormone-independent breast cancer cells exposed to the osmocenyl-tamoxifen derivatives.
Credit: Sylvain Bohic.

X-ray fluorescence imaging could open up new diagnostic possibilities in medicine

Using gold to track down diseases

A high-precision X-ray technique, tested at PETRA III, could catch cancer at an earlier stage and facilitate the development and control of pharmaceutical drugs. The test at DESY’s synchrotron radiation source, which used so-called X-ray fluorescence for that purpose, has proved very promising, as is now being reported in the journal Scientific Reports by a research team headed by Florian Grüner from the University of Hamburg. The technique is said to offer the prospect of carrying out such X-ray studies not only with higher precision than existing methods but also with less of a dose impact. However, before the method can be used in a clinical setting, it still has to undergo numerous stages of development.

The idea behind the procedure is simple: tiny nanoparticles of gold having a diameter of twelve nanometres (millionths of a millimetre) are functionalised with antibodies using biochemical methods. “A solution containing such nanoparticles is injected into the patient,” explains Grüner, a professor of physics at the Centre for Free-Electron Laser Science (CFEL), a cooperative venture between DESY, the University of Hamburg and the Max Planck Society. “The particles migrate through the body, where the antibodies can latch onto a tumour that may be present.” When the corresponding parts of the patient’s body are scanned using a pencil X-ray beam, the gold particles emit characteristic X-ray fluorescence signals, which are recorded by a special detector. The hope is that this will permit the detection of tiny tumours that cannot be found using current methods.

>Read more on the PETRA III at DESY website

Image: Gold nanoparticles spiked with antibodies can specifically attach to tumors or other targets in the organism and can be detected there by X-ray fluorescence.
Credit: Meletios Verras [Source]

New approach to breast cancer detection

Phase contrast tomography shows great promise in early stages of study and is expected to be tested on first patients by 2020.

An expert group of imaging scientists in Sydney and Melbourne are using the Imaging and Medical Beamline (IMBL) at the Australian Synchrotron as part of ongoing research on an innovative 3D imaging technique to improve the detection and diagnosis of breast cancer.

The technique, known as in-line phase-contrast computed tomography (PCT), has shown advantages over 2D mammography with conventional X-rays by producing superior quality images of dense breast tissue with similar or below radiation dose.
Research led by Prof Patrick Brennan of the University of Sydney and Dr Tim Gureyev at the University of Melbourne with funding from the NHMRC and the support of clinicians in Melbourne including breast surgeon Dr Jane Fox, is now focused on demonstrating the clinical usefulness of the technique.
Together with Associate Professor Sarah Lewis and Dr SeyedamirTavakoli Taba from the University of Sydney heading clinical implementation, the technique is expected to be tested on the first patients at the Australian Synchrotron by 2020.

>Read more on the Australian Synchrotron website

Image: CT reconstruction of 3D image of mastectomy sample revealing invasive carcinoma

Just like lego – studying flexible protein for drug delivery

Researchers from the Sapienza University of Rome and its spin-off company MoLiRom (Italy) are spending the weekend at the ESRF to study a protein that could potentially transport anticancer drugs.

Ferritin is a large spherical protein (20 times bigger than haemoglobin) that stores iron within its cavity in every organism. Just like a lego playset, Ferritin assembles and disassembles. It is also naturally targeted to cancer cells. These are the reasons why Ferritin is a great candidate as a drug-transport protein to fight cancer. An international team of scientists from “Sapienza” University of Rome and the SME MoLiRom (Italy) came to the ESRF to explore a special kind of ferritin that shows promising properties. “This is an archaebacterial ferritin that have transformed into a humanised ferritin to try to tackle cancer cells”, explains Matilde Trabuco, a scientist at the Italian SME MoLiRom.

The mechanism looks simple enough: “Ferritin has a natural attraction to cancer cells. If we encapsulate anti-cancer drugs inside it, it will act as a Trojan horse to go inside cells, then it will open up and deliver the drug”.

Ferritins have been widely used as scaffolds for drug-delivery and diagnostics due to their characteristic cage-like structure. Most ferritins are stable and disassemble only by a harsh pH jump that greatly limits the type of possible cargo. The humanised ferritin was engineered to combine assembly at milder conditions with specific targeting of human cancer cells.

 

>Read more on the European Synchrotron Website

 

Probing tumour interiors

X-ray fluorescence mapping to measure tumour penetration by a novel anticancer agent.

A new anticancer agent developed by the University of Warwick has been studied using microfocus synchrotron X-ray fluorescence (SXRF) at I18 at Diamond Light Source. As described in The Journal of Inorganic Biochemistry, researchers saw that the drug penetrated ovarian cancer cell spheroids and the distribution of zinc and calcium was perturbed.  

Platinum-based chemotherapy agents are used to treat many cancer patients, but some can develop resistance to them. To address this issue, scientists from the University of Warwick sought to employ alternative precious metals. They developed an osmium-based agent, known as FY26, which exhibits high potency against a range of cancer cell lines. To unlock the potential of this novel agent and to test its efficacy and safety in clinical trials, the team need to fully understand its mechanism of action.

To explore how FY26 behaves in tumours, the team grew ovarian cancer spheroids and used SXRF at I18 to probe the depth of penetration of the drug. They noted that FY26 could enter the cores of the spheroids, which is critical for its activity and very encouraging for the future of the drug. SXRF also enabled them to probe other metals within the cells, which showed that the distribution of zinc and calcium was altered, providing new insights into the mechanism of FY26-induced cell death.

>Read more on the Diamond Light Source website

Figure: (extract) A) Structure of FY26and related complexes, [(ŋ6-p-cym)Os(Azpy-NMe2)X]+. B) Bright field images and SXRF elemental maps of Os, Ca and Zn in A2780 human ovarian carcinoma spheroid sections (500 nm thick) treated with 0.7 µM FY26(½ IC50) for 0 or 48 h. Raster scan: 2×2 µm2 step size, 1 s dwell time. Scale bar 100 µm. Calibration bar in ng mm-2. Yellow squares in bright field images indicate areas of the spheroid studied using SXRF. Red areas in SXRF elemental maps indicate the limits of the spheroids. C) Average Os content (in ng mm-2) as a function of distance from A2780 3D spheroid surface, after treatment for 16 h (green), 24 h (blue) or 48 h (red) with 0.7 µM FY26. 

Insights into the development of more effective anti-tumour drug

Natural killer cells are powerful weapons our body’s immune systems count on to fight infection and combat diseases like cancer, multiple sclerosis, and lupus. Finding ways to spark these potent cells into action could lead to more effective cancer treatments and vaccines.

While several chemical compounds have shown promise stimulating a type of natural killer cells, invariant natural killer T cells (iNKT) cells in animal models, their ability to activate human iNKT cells has been limited.

Now, an international team of top immunologists, structural biologists, and chemists published in Cell Chemical Biology the creation of a new compound that appears to have the properties researchers have been looking for. The research was co-led by Monash Biomedicine Discovery Institute’s (BDI) Dr Jérôme Le Nours, University of Connecticut’s Professor Amy Howell and Albert Einstein College of Medicine’s Dr Steve Porcelli. Dr Le Nours used the Micro Crystallography beamline (MX2) at the Australian Synchrotron as part of the study.

The compound – a modified version of an earlier synthesized ligand – is highly effective in activating human iNKT cells. It is also selective – encouraging iNKT cells to release a specific set of proteins known as Th1 cytokines, which stimulate anti-tumour immunity.

>Read more on the Australian Synchrotron website

Image: 3D structure of proteins behind interaction of new drug that stimulates immune response to cancer cells. (Entire image here)

Success in clinical trials driving a shift in the treatment of blood cancers

The Australian Synchrotron is proud to be growing Australia’s capacity for innovative drug development, facilitating the advance of world-class disease and drug research through to local drug trials. Recent success in clinical trials of Venetoclax, the chronic lymphocytic leukaemia (CLL) drug developed by researchers from the Walter and Eliza Hall Institute and two international pharmaceutical companies is driving a major shift in the treatment of a range of blood cancers, according to a media information from the Peter MacCallum Cancer Centre.

>Read more on the Australian Synchrotron website

 

Gold protein clusters could be used as environmental and health detectors

Peng Zhang and his collaborators study remarkable, tiny self-assembling clusters of gold and protein that glow a bold red. And they’re useful: protein-gold nanoclusters could be used to detect harmful metals in water or to identify cancer cells in the body.
“These structures are very exciting but are very, very hard to study. We tried many different tools, but none worked,” says Zhang, a Dalhousie University professor.

Peng Zhang and his collaborators study remarkable, tiny self-assembling clusters of gold and protein that glow a bold red. And they’re useful: protein-gold nanoclusters could be used to detect harmful metals in water or to identify cancer cells in the body.

“These structures are very exciting but are very, very hard to study. We tried many different tools, but none worked,” says Zhang, a Dalhousie University professor.

>Read more on the Canadian Light Source website

Image: The protein-gold structure. The protein, which both builds and holds in place the gold cluster, is shown in grey.

Supporting World Cancer Day 2018

Diamond is proud to be supporting World Cancer Day and highlighting our role, working with our user community, in pioneering synchrotron research in every area of cancer – from developing a better understanding of how cancer cells work to delivering new cancer therapies.
Despite major advances in diagnosis and treatment, cancer still claims the lives of 8.8 million people every year around the world. About 4 million of these die prematurely (under the age of 70). World Cancer Day aims to raise the awareness of cancer and its treatment around the world. With the tagline ‘We can. I can.’, World Cancer Day is exploring how everyone can play their part in reducing the global burden of cancer.

Diamond has published over 900 publications in the last 12 months, with around 10% of these focusing on cancer. The wide-ranging research currently covers at least 12 cancer types, with many more general studies on the structure of cancer cells and pathways, potential drug targets and possible drug candidates. Building on last year’s review of some of the key studies in cancer that have taken place at Diamond, here is an update on studies that have been published in the last 12 months.

>Read more on the Diamond Light Source website

 

Modified antibody clarifies tumor-killing mechanisms

The structure of an antibody was modified to selectively activate a specific pathway of the immune system, demonstrating its value in killing tumor cells.

Immunotherapy—the use of the immune system to fight disease—has made tremendous progress in the fight against cancer. Antibodies such as immunoglobulin G (IgG) can identify and attack foreign or abnormal substances, including tumor cells. But to control and amplify this response, scientists need to know more about how elements of the immune system recognize tumor cells and trigger their destruction. There are two main pathways for this: antibody-dependent mechanisms and complement-dependent mechanisms.

The antibody pathway involves coating the surfaces of tumor cells with antibodies that recruit “natural killer” (NK) cells and macrophages (a type of white blood cell) to destroy the tumor cells. The complement pathway (so named because it complements the antibody pathway) also engages NK cells and macrophages and includes a third mechanism—a cascade of events culminating in tumor-cell destruction via a membrane attack complex (MAC).

>Read more on the ALS webpage

Image: extract of a schematic illustration (see on the ALS webpage)