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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

Stress and fear on wild animals examined
2013-06-04

 

Dr Kate Nowak in the Soutpansberg Mountain
Photo: Supplied
04 June 2013

Have you ever wondered how our wild cousins deal with stress? Dr Kate Nowak, visiting postdoctoral researcher at the Zoology and Entomology Department at the UFS Qwaqwa Campus, has been assigned the task to find out. She is currently conducting research on the effects that stress and fear has on primate cognition.

The Primate and Predator project has been established over the last two years, following Dr Aliza le Roux’s (also at the Zoology and Entomology Department at Qwaqwa) interest in the effects of fear on primate cognition. Dr le Roux collaborates with Dr Russel Hill of Durham University (UK) at the Lajuma Research Centre in Limpopo and Dr Nowak has subsequently been brought in to conduct the study.

Research on humans and captive animals has indicated that stress can powerfully decrease individuals’ cognitive performance. Very little is known about the influence of stress and fear on the cognition of wild animals, though. Dr Nowak will examine the cognition of wild primates during actual risk posed by predators. This is known as the “landscape of fear” in her research.

“I feel very privileged to be living at Lajuma and on top of a mountain in the Soutpansberg Mountain Range. We are surrounded by nature – many different kinds of habitats including a tall mist-belt forest and a variety of wildlife which we see regularly, including samangos, chacma baboons and vervet monkeys, red duiker, rock hyrax, banded mongooses, crowned eagles, crested guinea fowl and cape batis. And of course those we don't see but find signs of, such as leopard, genet, civet and porcupine. Studying the behaviour of wild animals is a very special, and very humbling, experience, reminding us of the diversity of life of which humans are only a very small part,” said Dr Nowak.

At present, the research team is running Giving up Densities (GUD) experiments. This represents the process during which an animal forsakes a patch dense with food to forage at a different spot. The animal faces a trade-off between meeting energy demands and safety – making itself vulnerable to predators such as leopards and eagles. Dr le Roux said that, “researchers from the US and Europe are embracing cognitive ecology, revealing absolutely stunning facts about what animals can and can’t do. Hence, I don’t see why South Africans cannot do the same.”

Dr Nowak received the Claude Leon Fellowship for her project. Her research as a trustee of the foundation will increase the volume and quality of research output at the UFS and enhance the overall culture of research. Her analysis on the effect that stress and fear have on wild primates’ cognition will considerably inform the emerging field of cognitive ecology.

The field of cognitive ecology is relatively new. The term was coined in the 1990s by Les Real to bring together the fields of cognitive science and behavioural ecology.


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