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Month: April 2023

‘Vein-on-a-chip’ could help scientists study blood clots without animal models

Blood clot researchers could benefit from a new device that mimics a human vein, replacing the need for animals for some studies.

The vein-on-a-chip model has been developed by scientists at BHP founder-member the University of Birmingham, and can be used in experiments to understand mechanisms of blood clot formation in conditions such as deep vein thrombosis (DVT).

DVT is the development of blood clots in veins, usually in the legs. It is a serious condition because the clot can detach and travel to the lungs, where it may block blood vessels, causing breathing difficulties that prove be fatal. DVT is the third most common cardiovascular disease after myocardial infarction and stroke, with tens of thousands of people in the UK developing this condition every year. Mechanisms of deep vein thrombosis require further research to improve clinicians’ understanding and ability to treat or prevent the condition.

The new device, described in a recent paper published in Frontiers in Cardiovascular Medicine, is a tiny channel, which includes structures called valves that ensure the correct direction of blood flow.

UoB researchers Dr Alexander Brill from the Institute of Cardiovascular Sciences, together with Drs Daniele Vigolo and Alessio Alexiadis from the School of Chemical Engineering, led the development of the new device.

Dr Brill said: “The device is more advanced than previous models because the valves can open and close, mimicking the mechanism seen in a real vein. It also contains a single layer of cells, called endothelial cells, covering the inside of the vessel. These two advances make this vein-on-a-chip a realistic alternative to using animal models in research that focuses on how blood clots form. It is biologically reflective of a real vein, and it also recapitulates blood flow in a life-like manner.

“Organ-on-a-chip devices, such as ours, are not only created to help researchers move away from the need for animal models, but they also advance our understanding of biology as they are more closely representative of how the human body works.

“The principles of the 3Rs – to replace, reduce and refine the use of animals in research – are embedded in national and international legislation and regulations on the use of animals in scientific procedures. But there is always more that can be done. Innovations such as the new device created for use in thrombosis research are a step in the right direction.”

This research was funded by the NC3R, British Heart Foundation and Wellcome.

Drug combination could overcome tumour resistance in paediatric cancers

Children with some solid tumours may benefit from receiving a combination of inhibitor drugs, according to interim results of research presented at the American Association of Cancer Research’s Annual Meeting 2023, held April 14-19.

The ongoing research being conducted by an international team including the University of Birmingham suggests that a combination of the PARP inhibitor olaparib (Lynparza) and the investigational ATR inhibitor ceralasertib showed clinical benefit in paediatric patients with solid tumours exhibiting DNA replication stress and/or DNA repair deficiencies.

Dr Susanne Gatz, associate clinical professor in pediatric oncology at the Institute of Cancer and Genomic Sciences of the University of Birmingham presented the study.

Dr Gatz said: “To our knowledge, the combination of PARP inhibitors and ATR inhibitors has not been widely investigated in adult tumour types. This is the first proof of principle that the combination is well tolerated and can lead to clinically relevant responses in paediatric cancers.”

AcSé-ESMART is an international European proof-of-concept platform trial intended to match paediatric, adolescent, and young adult patients with relapsed or treatment-refractory cancers with a treatment regimen targeted to their cancer’s mutational profile. Gatz and colleagues, including Birgit Geoerger, MD, PhD, head of the AcSé-ESMART trial, have so far evaluated 15 different treatments, mostly combination strategies, in more than 220 children following mandatory high-throughput genomic profiling of their tumours.

Arm N of AcSé-ESMART is tailored toward patients with malignancies that exhibit defects in DNA replication and damage repair. Impairments in homologous recombination (HR), a type of DNA repair, can sensitize cells to drugs called PARP inhibitors. PARP inhibitors have proven effective against specific adult cancers with HR deficiencies—most notably, mutations in BRCA1 or BRCA2. How to best use PARP inhibitors in paediatric patients where BRCA1/2 mutations are rarely found remains unclear.

Dr Gatz said: “Paediatric cancer cells proliferate rapidly and have some element of replication stress and a dependency on ATR. We think there might be a kind of primary resistance of paediatric cancers to PARP inhibitors and that combination with an ATR inhibitor could potentially overcome that.”

Gatz also explained that paediatric cancers are often driven by complex mechanisms, making it difficult to identify an effective treatment regimen. Single-agent therapies targeting one mutated protein are often insufficient in paediatric patients, necessitating additional research into combination therapies and mechanisms of response.

“So far, it is unclear if the molecular alterations based on which the patients were enrolled in this trial are the sole reasons for response,” Gatz said.

“Further, it may be difficult to identify patterns of response in specific tumour types due to the tumour-agnostic nature of the study. Nevertheless, this study design can give preliminary indications of signals in specific alterations and tumour types and can provide the basis for future clinical trials.”

Gatz and colleagues plan to evaluate biomarkers of response from the raw sequencing data of the enrolled patients, from the expression of key target proteins such as ATM, and from RNA sequencing data.

Gatz noted that these analyses may identify “molecular constellations” indicative of response to olaparib plus ceralasertib.

“There are enormously valuable drugs currently in development and, provided there is a good clinical or preclinical rationale, we need to apply them more creatively to diseases for which the drug is not currently indicated,” Gatz said.

Limitations of this study include a small, non-randomized sample intended primarily as a proof of concept and to determine the optimal dose for study expansion.

The study is as yet unpublished.