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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

“My time at the UFS was the golden gem of my career”
2016-07-04

Description: Zig Gibson Tags: Zig Gibson

Prof Alan St Clair Gibson
Photo: Oteng Mpete

“My time at the University of the Free State (UFS) was the golden gem of my career. I have worked at medical schools or biomedical research centres in the United Kingdom, United States and at some of the top medical schools in South Africa, but working at the UFS was one of the highlights of my career,” says Prof Alan St Clair Gibson, Head of the UFS School of Medicine.

After spending just over two years at the UFS, Prof St Clair Gibson resigned from the institution in June 2016 and will take up the position of Dean: Health and Human Performance Sciences at the Waikato University in New Zealand in mid-July, where he will assist to establish a new faculty for all the health-science disciplines. “It was a privilege to work at the UFS. I come from a strong research background and wanted to grow research at the university, which I achieved. I came to the UFS because of the Academic and Human Projects and am proud of what has been achieved at the School of Medicine during the time I was here,” he said.

Prof St Clair Gibson highlighted some of these achievements, including the development of a management infrastructure across the disciplines of the school. “The establishment of an executive management committee for the school, as well as research champions in departments, highlighted the importance of proper governance and strategic management. By developing data dashboards, my management team and I could develop an understanding of research income and productivity, how the school works, what the role of teaching and learning is, and how the school could benefit in terms of third-stream income from the many contracts obtained by its academic staff. As a result, contracts and the financial management model of the school have also been reconfigured to the benefit of the university so that the institution and school can benefit from it,” he said.

His strong belief in an open-door policy has made staff feel part of the environment and it has created an atmosphere of equality and inclusivity. He believes in staff development and has, for instance, established leadership and management courses for heads of departments. Another factor to be proud of is the increase in the number of young researchers who recently joined the school, such as Prof Ross Tucker, who is one of the foremost sport scientists in the country. “It is a fact that staff retire or resign in all schools and departments of any university. It is also true that these departures offer opportunities to bring new academic and professional staff into the UFS. In fact, for the first time virtually every department in the School of Medicine now has a full-time Head of Department and 46 new staff were appointed since January 2015,” said Prof St Clair Gibson.

“I am especially proud of contributing, together with the senior leadership of the UFS, to stabilise the relationship with the Free State Department of Health (DoH). With the assistance of these parties, as well as my executive management team, we could find a better way of working together to the benefit of the school and the province.’’

Transforming the student profile to be representative of the country’s demographics is another milestone Prof St Clair Gibson will remember. “The intake of black and white students is of such a nature that we now have a much more balanced ratio of black and white undergraduate students than before.”

“I wanted to stay longer to see the effect of all the changes I made at the school, but the deanship is an offer I cannot refuse. I would have liked to see a steadier increase in the number of permanent clinical staff and have worked hard with both the UFS management and the DoH to try and achieve that; but more work needs to be done.”

I have worked with a number of fantastic staff members at the school, who are determined to do good in a challenging environment. I am amazed at the energy of the university leadership and how the Human and Academic Projects are executed. My wish for the university is to maintain and grow its standards and for the School of Medicine to maintain its reputation as one of the best schools in the country. I will always be a proud alumnus of the UFS,” he said.

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