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04 December 2024 | Story André Damons | Photo André Damons
Breast Cancer Research 2024
The research team consist of Dr Beynon Abrahams (left), Viwe Fokazi, MMed.Sci student, and PhD student Songezo Vazi.

In an effort to better understand chemotherapeutic treatment response in triple negative breast cancer (TNBC) – known as an aggressive cancer with high recurrence and high mortality rate in breast cancer patients – researchers from the University of the Free State (UFS) developed a drug-resistant TNBC spheroid model that is physiologically more accurate in displaying the complexities involved in drug-resistance development.

Dr Beynon Abrahams, Lecturer in the Department of Basic Medical Sciences within the UFS Faculty of Health Sciences, says breast cancer remains the most frequently diagnosed cancer in women. It is also the most debilitating type of cancer responsible for the highest cancer mortality rates in women. Though various subtypes of breast cancer exist, TNBC is one that is of particular interest to his research team.

“TNBC is one of the most difficult cancer types to treat, due to lack of treatment targets. This often leads to treatment failure in TNBC patients, with drug resistance being a common occurrence, contributing to high death rates. TNBC is classified based on its lack of expression of common receptors such as the estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, which are commonly expressed in other cancer subtypes.

“Characteristically, TNBC is known as an aggressive cancer with high metastatic potential (spreading of cancer), resulting in a poor prognosis for these patients. The current prescribed therapies for TNBC, entails multidrug combination systemic therapy including chemotherapeutic agents such as doxorubicin and cisplatin as adjuvant therapy. However, despite these therapeutic interventions, drug resistance is a common occurrence,” says Dr Abrahams.

The best available preclinical cell-based models should be used

For effective drug treatments to be developed for TNBC therapeutics, he continues, the best available disease models should be used to not only improve our understanding of the disease physiology and its numerous mechanisms involved in chemotherapeutic resistance development but also to provide accurate results when determining how safe and effective newly developed drugs are, before they may be considered for further development and testing on humans.

According to him, in preclinical cancer research the conventional methods employed to study disease mechanisms, drug action and drug resistance is ineffective. Firstly, the traditionally used preclinical 2-dimensional (2-D) cell culture models do not accurately recapitulate the architectural biology observed in vivo, second, the drug responses assessed in these models may provide inaccurate results and limit its translational potential, explains Dr Abrahams. Thus, more advanced cell-based models such as 3-dimensional (3-D) spheroids and organoids to name a few, should be considered as alternatives.

The UFS research team, in collaboration with the Centre of Excellence for Pharmaceutical Sciences (Pharmacen™) at the North-West University (NWU), recently took the undertaking to establish two triple negative breast cancer 3-D spheroid models, using the clinostat rotating bioreactor ClinoStar™ system, designed by CelVivo in Denmark. The project is funded by the National Research Foundation.

The ClinoStar™ system promotes the self-aggregation of single cells, and natural formation of 3-D spheroids, through slow rotation within a cell growth chamber known as an incubator. There are various techniques and methods available to develop spheroids and organoids, however the ClinoStar™ systems allow for the development of metabolically stable spheroids, over a longer period of time, as opposed to other methods. It also eliminates the sheer-stress conditions that are normally encountered when using 2-D cell culture models.

“We successfully established one chemotherapeutic-sensitive triple negative breast cancer spheroid model and one novel cisplatin-resistant triple negative breast cancer spheroid model. The chemo-sensitive TNBC spheroid model was evaluated for responsiveness against two clinically used chemotherapeutic agents, doxorubicin and cisplatin. We suggest that this model may be useful to screen novel compounds including traditionally used phytomedicinal material for anticancer activity.

“In our second model, the cisplatin-resistant TNBC spheroid model was also exposed to cisplatin and doxorubicin and demonstrated a resistant response in terms of growth and viability. We believe that this model may be useful to further explore drug resistance mechanisms and may also be used as a tool to assess the drug reversal potential of novel compounds. The value and impact of these models lies in that they may offer predictive drug responses that are closer to that observed in in vivo (animals), as opposed to 2-D cell cultures. This however needs to be assessed. We are currently in the process to fully characterise these spheroids models.”

Aim of the research

Dr Abrahams explains their research aims to merge the gap between conventionally used 2-D cell models and in vivo models, by providing a model that is physiologically more accurate in mimicking the in vivo conditions and complex pathways associated with drug resistance, which is otherwise not observed or accurately expressed in 2D models. “Although our research is preclinical and considered fundamental basic research, the translational potential of our spheroid models may provide options for exploring and testing alternative drugs that may be considered for translational research,” Dr Abrahams says.

Characterising other advanced cell-based cancer models

The team is currently in the process of further characterising the TNBC spheroid model based on protein and genetic expression profiles to elucidate potential therapeutic biomarkers for drug treatment as well as screening various phytomedicinal plants, to assess their antiproliferative and drug-resistance reversal potential. In addition, the researchers recently commenced a new research project that aims to develop a drug-resistant prostate cancer spheroid model using the Clinostar™ system with their collaborators at the NWU.

Advanced cell-based model research is still relatively ‘new’ in South Africa and Africa, compared to the global North. As a result, says Dr Abrahams, their NWU collaborators together with other stakeholders, initiated the establishment of the Society for Advanced Cell Culture Modelling for Africa (SACCMA) in 2021, which aims to develop the fields of advanced cell modelling, three-dimensional (3D) cell cultures, 3D bioprinting and stem cell research, in Africa. Our current inter-departmental  collaboration include researchers from the Pharmacology department, but we hope to build and expand our collaboration network in the near future.

News Archive

Africa's Black Rhino conservation strategy must change
2017-07-10

 Description: Black Rhino Tags: conservation strategy, black rhino, Nature Scientific Reports, National Zoological Gardens of South Africa, extinction, decline in genetic diversity, Prof Antoinette Kotze, Research and Scientific Services, Dr Desire Dalton 

The black rhino is on the brink of extinction. The study that was 
published in the Nature Scientific Reports reveals that the
species has lost an astonishing 69% of its genetic variation. 
Photo: iStock

The conservation strategy of the black rhino in Africa needs to change in order to protect the species from extinction, a group of international researchers has found. The study that was published in the Nature Scientific Reports reveals that the species has lost an astonishing 69% of its genetic variation. 

South African researchers took part 

The researchers, which included local researchers from the National Zoological Gardens of South Africa (NZG), have highlighted the fact that this means the black rhino is on the brink of extinction. "We have found that there is a decline in genetic diversity, with 44 of 64 genetic lineages no longer existing," said Prof Antoinette Kotze, the Manager of Research and Scientific Services at the Zoo in Pretoria. She is also affiliate Professor in the Department of Genetics at the University of the Free State and has been involved in rhino research in South Africa since the early 2000s.  

DNA from museums and the wild 
The study compared DNA from specimens in museums around the world, which originated in the different regions of Africa, to the DNA of live wild animals. The DNA was extracted from the skin of museum specimen and from tissue and faecal samples from animals in the wild. The research used the mitochondrial genome.

"The rhino poaching ‘pandemic’
needs to be defeated, because
it puts further strain on the genetic
diversity of the black rhino.”


Ability to adapt 
Dr Desire Dalton, one of the collaborators in the paper and a senior researcher at the NZG, said the loss of genetic diversity may compromise the rhinos’ ability to adapt to climate change. The study further underlined that two distinct populations now exists on either side of the Zambezi River. Dr Dalton said these definite populations need to be managed separately in order to conserve their genetic diversity. The study found that although the data suggests that the future is bleak for the black rhinoceros, the researchers did identify populations of priority for conservation, which might offer a better chance of preventing the species from total extinction. However, it stressed that the rhino poaching ‘pandemic’ needs to be defeated, because it puts further strain on the genetic diversity of the black rhino. 

Extinct in many African countries 
The research report further said that black rhino had been hunted and poached to extinction in many parts of Africa, such as Nigeria, Chad, Cameroon, Sudan, and Ethiopia. These rhino are now only found in five African countries. They are Tanzania, Zimbabwe, Kenya, Namibia, and South Africa, where the majority of the animals can be found. 

 

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