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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

Moshoeshoe - lessons from an African icon - by Prof Frederick Fourie
2004-11-03

(The full text of the article that appeared in City Press and Sunday Independent)

Our understanding of history informs our understanding of the present. No wonder the contestation over historical figures in South Africa’s past is so fierce and so divisive.
The question is: could it be any other way? I would like to think that it could; that black and white South Africans, across linguistic, cultural, religious and other divides, can develop a shared appreciation of our history – at least with certain periods and personalities as a starting point.

One such personality whose legacy I believe offers a possible platform for unifying our still divided country is King Moshoeshoe, who lived from 1786 to 1870, and is acknowledged as the founder of the Basotho.

King Moshoeshoe is the topic of a documentary that has been commissioned by the University of the Free State as part of its Centenary celebrations this year. It is part of a larger project to honour and research the legacy of Moshoeshoe. The documentary will be screened on SABC 2 at 21:00 on November 4th.

Moshoeshoe rose to prominence at a time of great upheaval and conflict in South Africa – the 19th century, a time when British colonialism was entrenching itself, when the Boer trekkers were migrating from the Cape and when numerous indigenous chiefdoms and groupings were engaged in territorial conquests. It was the time of the Difaqane, a period when society in the central parts of the later South Africa and Lesotho was fractured, destabilised and caught in a cycle of violence and aggression.

In this period Moshoeshoe displayed a unique and innovative model of leadership that resulted in reconciliation, peace and stability in the area that later became Lesotho and Free State. It made him stand out from many of his contemporaries and also caught the attention of his colonial adversaries.

Such an evaluation is not a judgment about which model of leadership is right and which is wrong, or which leader was better than another; but merely an attempt to explore what we can learn from a particular exemplar.
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Historians point to the many progressive leadership qualities displayed by Moshoeshoe which he used effectively in establishing the Basotho nation and in defending it.
First, there is his humanism and sense of justice worthy of any great statesman. Confronted by a situation in which cannibals murdered and devoured his grandfather, Moshoeshoe chose not to take revenge. Instead he opted to rehabilitate them and feed them as he believed hunger drove them to cannibalism.

Secondly, there is his skilful alliance-building with his contemporaries such as Shaka in an attempt to neutralize those rivals who were intent on attacking his followers. This is also displayed in the way he sought the protection of the British to keep the Boer forces at bay.
Thirdly, his emphasis on peaceful options is also seen in his defensive military strategy which saw him retreat to a mountain fortress to be able to protect and build a burgeoning nation in the face of the many forces threatening its survival.

Fourthly, there is his remarkable inclusivity and tolerance for diversity which saw him unite disparate groups of refugees from the violence and hunger that displaced them and then weld them into the Basotho nation. He also engaged with French missionaries, inviting them to stay with him and advise him on Western thought, technology and religion.
These are but some of the qualities which belie the notion that all 19th century African leaders were merely marauders and conquerors that gained their ascendancy through violence. Instead Moshoeshoe is a prime example of the human-centred, democratic and pluralist roots of South African, indeed African society.

The Moshoeshoe project that we have initiated (of which the documentary, called “The Renaissance King”, forms but one part) derives from our location as a university in the Free State, a province with a particular history and a particular political culture that developed as a result of this very model of leadership. This province has benefited tremendously from leaders such as Moshoeshoe and president MT Steyn, both of whom many observers credit with establishing a climate of tolerance, respect for diversity of opinion, political accommodation and peaceful methods of pursuing political objectives in the province. Their legacy is real – and Moshoeshoe’s role can not be overstated.
In addition the project derives from the University of the Free State being a site of higher learning in a broader geo-political sense. As a university in Africa we are called upon to understand and critically engage with this history, this context and this legacy.
Besides the documentary, the UFS is also planning to establish an annual Moshoeshoe memorial lecture which will focus on and interrogate models of African leadership, nation-building, reconciliation, diversity management and political tolerance.

In tackling such projects, there may be a temptation to engage in myth-making. It is a trap we must be wary of, especially as an institution of higher learning. We need to ask critical questions about some aspects of Moshoeshoe’s leadership but of current political leadership as well. Thus there is a need for rigorous academic research into aspects of the Moshoeshoe legacy in particular but also into these above-mentioned issues.
While the documentary was commissioned to coincide with the University of the Free State’s centenary and our country’s ten years of democracy, it is a project that has a much wider significance. It is an attempt to get people talking about our past and about our future, as a campus, as a province and as a country – even as a continent, given the NEPAD initiatives to promote democracy and good governance.

The project therefore has particular relevance for the continued transformation of institutions such as universities and the transformation of our society. Hopefully it will assist those who are confronted by the question how to bring about new institutional cultures or even a national political culture that is truly inclusive, tolerant, democratic, non-sexist, non-racial, multilingual and multicultural.

I believe that the Moshoeshoe model of leadership can be emulated and provide some point of convergence. A fractured society such as ours needs points of convergence, icons and heroes which we can share. Moshoeshoe is one such an African icon – in a world with too few of them.

Prof Frederick Fourie is the Rector and Vice-Chancellor of the University of the Free State

* The documentary on “Moshoeshoe: The Renaissance King” will be screened on SABC2 on 4 November 2004 at 21:00.

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