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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

Media: ANC can learn a lesson from Moshoeshoe
2006-05-20


27/05/2006 20:32 - (SA) 
ANC can learn a lesson from Moshoeshoe
ON 2004, the University of the Free State turned 100 years old. As part of its centenary celebrations, the idea of the Moshoeshoe Memorial Lecture was mooted as part of another idea: to promote the study of the meaning of Moshoeshoe.

This lecture comes at a critical point in South Africa's still-new democracy. There are indications that the value of public engagement that Moshoeshoe prized highly through his lipitso [community gatherings], and now also a prized feature in our democracy, may be under serious threat. It is for this reason that I would like to dedicate this lecture to all those in our country and elsewhere who daily or weekly, or however frequently, have had the courage to express their considered opinions on pressing matters facing our society. They may be columnists, editors, commentators, artists of all kinds, academics and writers of letters to the editor, non-violent protesters with their placards and cartoonists who put a mirror in front of our eyes.

There is a remarkable story of how Moshoeshoe dealt with Mzilikazi, the aggressor who attacked Thaba Bosiu and failed. So when Mzilikazi retreated from Thaba Bosiu with a bruised ego after failing to take over the mountain, Moshoeshoe, in an unexpected turn of events, sent him cattle to return home bruised but grateful for the generosity of a victorious target of his aggression. At least he would not starve along the way. It was a devastating act of magnanimity which signalled a phenomenal role change.

"If only you had asked," Moshoeshoe seemed to be saying, "I could have given you some cattle. Have them anyway."

It was impossible for Mzilikazi not to have felt ashamed. At the same time, he could still present himself to his people as one who was so feared that even in defeat he was given cattle. At any rate, he never returned.

I look at our situation in South Africa and find that the wisdom of Moshoeshoe's method produced one of the defining moments that led to South Africa's momentous transition to democracy. Part of Nelson Mandela's legacy is precisely this: what I have called counter-intuitive leadership and the immense possibilities it offers for re-imagining whole societies.

A number of events in the past 12 months have made me wonder whether we are faced with a new situation that may have arisen. An increasing number of highly intelligent, sensitive and highly committed South Africans across the class, racial and cultural spectrum confess to feeling uncertain and vulnerable as never before since 1994. When indomitable optimists confess to having a sense of things unhinging, the misery of anxiety spreads. It must have something to do with an accumulation of events that convey the sense of impending implosion. It is the sense that events are spiralling out of control and no one among the leadership of the country seems to have a handle on things.

I should mention the one event that has dominated the national scene continuously for many months now. It is, of course, the trying events around the recent trial and acquittal of Jacob Zuma. The aftermath continues to dominate the news and public discourse. What, really, have we learnt or are learning from it all? It is probably too early to tell. Yet the drama seems far from over, promising to keep us all without relief, and in a state of anguish. It seems poised to reveal more faultlines in our national life than answers and solutions.

We need a mechanism that will affirm the different positions of the contestants validating their honesty in a way that will give the public confidence that real solutions are possible. It is this kind of openness, which never comes easily, that leads to breakthrough solutions, of the kind Moshoeshoe's wisdom symbolises.

Who will take this courageous step? What is clear is that a complex democracy like South Africa's cannot survive a single authority. Only multiple authorities within a constitutional framework have a real chance. I want to press this matter further.

Could it be that part of the problem is that we are unable to deal with the notion of "opposition". We are horrified that any of us could become "the opposition". In reality, it is time we began to anticipate the arrival of a moment when there was no longer a single [overwhelmingly] dominant political force as is currently the case. Such is the course of change. The measure of the maturity of the current political environment will be in how it can create conditions that anticipate that moment rather than ones that seek to prevent it. This is the formidable challenge of a popular post-apartheid political movement.

Can it conceptually anticipate a future when it is no longer overwhelmingly in control, in the form in which it currently is and resist, counter-intuitively, the temptation to prevent such an eventuality? Successfully resisting such an option would enable its current vision and its ultimate legacy to our country to manifest itself in different articulations of itself, which then contend for social influence.

In this way, the vision never really dies, it simply evolves into higher, more complex forms of itself. If the resulting versions are what is called "the opposition" that should not be such a bad thing - unless we want to invent another name for it. The image of flying ants going off to start other similar settlements is not so inappropriate.

I do not wish to suggest that the nuptial flights of the alliance partners are about to occur: only that it is a mark of leadership foresight to anticipate them conceptually. Any political movement that has visions of itself as a perpetual entity should look at the compelling evidence of history. Few have survived those defining moments when they should have been more elastic, and that because they were not, did not live to see the next day.

I believe we may have reached a moment not fundamentally different from the sobering, yet uplifting and vision-making, nation-building realities that led to Kempton Park in the early 1990s. The difference between then and now is that the black majority is not facing white compatriots across the negotiating table. Rather, it is facing itself: perhaps really for the first time since 1994. It is not a time for repeating old platitudes. Could we apply to ourselves the same degree of inventiveness and rigorous negotiation we displayed up to the adoption or our Constitution?

Morena Moshoeshoe faced similarly formative challenges. He seems to have been a great listener. No problem was too insignificant that it could not be addressed. He seems to have networked actively across the spectrum of society. He seems to have kept a close eye on the world beyond Lesotho, forming strong friendships and alliances, weighing his options constantly. He seems to have had patience and forbearance. He had tons of data before him before he could propose the unexpected. He tells us across the years that moments of renewal demand no less.

  • This is an editied version of the inaugural Moshoeshoe Memorial Lecture presented by Univeristy of Cape Town vice-chancellor Professor Ndebele at the University of the Free State on Thursday. Perspectives on Leadership Challenges In South Africa

 

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