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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

“To forgive is not an obligation. It’s a choice.” – Prof Minow during Reconciliation Lecture
2014-03-05

“To forgive is not an obligation. It’s a choice.” – Prof Minow during the Third Annual Reconciliation Lecture entitled Forgiveness, Law and Justice.
Photo: Johan Roux

No one could have anticipated the atmosphere in which Prof Martha Minow would visit the Bloemfontein Campus. And no one could have predicted how apt the timing of her message would be. As this formidable Dean of Harvard University’s Law School stepped behind the podium, a latent tension edged through the crowded audience.

“The issue of getting along after conflict is urgent.”

With these few words, Prof Minow exposed the essence of not only her lecture, but also the central concern of the entire university community.

As an expert on issues surrounding racial justice, Prof Minow has worked across the globe in post-conflict societies. How can we prevent atrocities from happening? she asked. Her answer was an honest, “I don’t know.” What she is certain of, on the other hand, is that the usual practice of either silence or retribution does not work. “I think that silence produces rage – understandably – and retribution produces the cycle of violence. Rather than ignoring what happens, rather than retribution, it would be good to reach for something more.” This is where reconciliation comes in.

Prof Minow put forward the idea that forgiveness should accompany reconciliation efforts. She defined forgiveness as a conscious, deliberate decision to forego rightful grounds of resentment towards those who have committed a wrong. “To forgive then, in this definition, is not an obligation. It’s a choice. And it’s held by the one who was harmed,” she explained.

Letting go of resentment cannot be forced – not even by the law. What the law can do, though, is either to encourage or discourage forgiveness. Prof Minow showed how the law can construct adversarial processes that render forgiveness less likely, when indeed its intention was the opposite. “Or, law can give people chances to meet together in spaces where they may apologise and they may forgive,” she continued. This point introduced some surprising revelations about our Truth and Reconciliation Commission (TRC).

Indeed, studies do report ambivalence, disappointment and mixed views about the TRC. Whatever our views are on its success, Prof Minow reported that people across the world wonder how South African did it. “It may not work entirely inside the country; outside the country it’s had a huge effect. It’s a touchstone for transitional justice.”

The TRC “seems to have coincided with, and maybe contributed to, the relatively peaceful political transition to democracy that is, frankly, an absolute miracle.” What came as a surprise to many is this: the fact that the TRC has affected transitional justice efforts in forty jurisdictions, including Rwanda, Sierra Leone, Cambodia and Liberia. It has even inspired the creation of a TRC in Greensborough, North Carolina, in the United States.

There are no blueprints for solving conflict, though. “But the possibility of something other than criminal trials, something other than war, something other than silence – that’s why the TRC, I think, has been such an exemplar to the world,” she commended.

Court decision cannot rebuild a society, though. Only individuals can forgive. Only individuals can start with purposeful, daily decisions to forgive and forge a common future. Forgiveness is rather like kindness, she suggested. It’s a resource without limits. It’s not scarce like water or money. It’s within our reach. But if it’s forced, it’s not forgiveness.

“It is good,” Prof Minow warned, “to be cautious about the use of law to deliberately shape or manipulate the feelings of any individual. But it is no less important to admit that law does affect human beings, not just in its results, but in its process.” And then we must take responsibility for how we use that law.

“A government can judge, but only people can forgive.” As Prof Minow’s words lingered, the air suddenly seemed a bit more buoyant.

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