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Researchers develop breast cancer spheroid models to study drug response and resistance

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

Twenty years of the constitution of South Africa – cause for celebration and reflection

2016-05-11

Description: Judge Azar Cachalia Tags: Judge Azar Cachalia

Judge Azar Cachalia

The University of the Free State’s Centre for Human Rights and the Faculty of Law held the celebration of the twentieth anniversary of the adoption of the South African Constitution on 11 May 2016 on the Bloemfontein Campus. Students and faculty members celebrated and reflected on not only the achievements of the constitution but also on perspectives regarding its relevance in modern society, and to what extent it has upheld the human rights of all citizens of South Africa.

The panel discussion started with a presentation on the pre-1996 perspective by Judge Azar Cachalia of the Supreme Court of Appeal. Judge Cachalia reflected on his role in the realisation and upholding of the constitution, from his days as a student activist, then as an attorney representing detainees during political turmoil, and currently as a judge: “My role as an attorney was to defend people arrested for public violence. My role as a judge today is to uphold the constitution.” He stressed the importance of the constitution today, and the responsibility institutions such as the police service have in upholding human rights. Judge Cachalia played a significant role in drafting the new Police Act around 1990, an Act which was to ensure that the offences perpetrated by the police during apartheid did not continue in the current democratic era. Further, he pointed out that societal turmoil has the potential to make society forget about the hard work that was put into structures upholding human rights. “Constitutions are drafted in moments of calm. It is a living document, and we hope it is not torn up when we go through social conflict, such as we are experiencing at present.”

Thobeka Dywili, a Law student at the UFS, presented her views from the new generation’s perspective. She relayed her experience as a student teaching human rights at schools in disadvantaged communities. She realised that, although the youth are quite aware of their basic human rights, after so many years of democracy, “women and children are still seen as previously disadvantaged when they should be equal”. She pointed out that, with the changing times, the constitution needs to be looked at with a new set of eyes, suggesting more robust youth engagement on topics that affect them, using technology to facilitate discussions. She said with the help of social media, it is possible for a simple discussion to become a revolution; #feesmustfall was a case in point.

Critical perspectives on the constitution were presented by Tsepo Madlingozi of University of Pretoria and University of London. In his view, the constitution has not affected policy to the extent that it should, with great disparities in our society and glaring issues, such as lack of housing for the majority of the poor. “Celebration of the constitution should be muted, as the constitution is based on a decolonisation approach, and does not directly address the needs of the poor. The Constitutional Court is not pro-poor.” He posed the question of whether twenty years on, the present government has crafted a new society successfully. “We have moved from apartheid to neo-apartheid, as black elites assimilate into the white world, and the two worlds that exist have not been able to stand together as a reflection of what the constitution stands for.”

Prof Caroline Nicholson, Dean of the Faculty of Law, encouraged more open discussions, saying such dialogues are exactly what was intended by the Centre for Human Rights. She emphasised the importance of exchanging ideas, of allowing people to speak freely, and of sharing perspectives on important issues such as the constitution and human rights.

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