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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

Inaugural lecture: Prof. Annette Wilkinson
2008-04-16

A strong plea for a pursuit of “scholarship” in higher education

Prof. Annette Wilkinson of the Centre for Higher Education Studies and Development in the Faculty of the Humanities at the University of the Free State (UFS) made as strong plea for a pursuit of “scholarship” in higher education.

She said in her inaugural lecture that higher education has to deal with changes and demands that necessitate innovative approaches and creative thinking when it concerns effective teaching and learning in a challenging and demanding higher education environment. She referred to a recent research report prepared for the Council for Higher Education (CHE) which spells out the alarming situation regarding attrition rates and graduation output in South African higher education and emphasises factors leading to the situation. These factors include socio-economic conditions and shortcomings in the school and the subsequent under preparedness of a very large proportion of the current student population. However, what is regarded as one of the key factors within the sector’s control is the implementation of strategies for improving graduate output.

She said: “The CHE report expresses concern about academics’ adherence to traditional teaching practices at institutions, which have not changed significantly to make provision for the dramatic increase in diversity since the 1980s.

“Raising the profile of teaching and learning in terms of accountability, recognition and scholarship is essential for successful capacity-building,” she said. “The notion of scholarship, however, brings to the minds of many academics the burden of ‘publish or perish’. In many instances, the pressures to be research-active are draining the value put on teaching. Institutions demand that staff produce research outputs in order to qualify for any of the so-called three Rs – resources, rewards and recognition.

“These have been abundant for research, but scarce when it comes to teaching – with the status of the latter just not on the same level as that of research. From within their demanding teaching environments many lecturers just feel they do not have the time to spend on research because of heavy workloads, that their efforts are under-valued and that they have to strive on the basis of intrinsic rewards.”

She said: “It is an unfortunate situation that educational expertise, in particular on disciplinary level, is not valued, even though in most courses, as in the Programme in Higher Education Studies at the UFS, all applications, whether in assignments, projects or learning material design, are directly applied to the disciplinary context. We work in a challenging environment where the important task of preparing students for tomorrow requires advanced disciplinary together with pedagogical knowledge.”

Prof. Wilkinson argued that a pursuit of the scholarship of teaching and learning holds the potential of not only improving teaching and learning and consequently success rates of students, but also of raising the status of teaching and recognising the immense inputs of lecturers who excel in a very demanding environment. She emphasised that not all teaching staff will progress to the scholarship level or are interested in such an endeavour. She therefore suggested a model in which performance in the area of teaching and learning can be recognised, rewarded and equally valued on three distinct levels, namely the levels of excellence, expertise and scholarship. An important feature of the model is that staff in managerial, administrative and support posts can also be rewarded for their contributions on the different levels for all teaching related work.

Prof. Wilkinson also emphasised the responsibility or rather, accountability, of institutions as a whole, as well as individual staff members, in providing an environment and infrastructure where students can develop to their full potential. She said that in this environment the development of the proficiency of staff members towards the levels of excellence, expertise and scholarship must be regarded as a priority.

“If we want to improve students’ success rates the institution should not be satisfied with the involvement in professional development opportunities by a small minority, but should set it as a requirement for all teaching staff, in particular on entry into the profession and for promotion purposes. An innovative approach towards a system of continuous professional development, valued and sought after, should be considered and built into the institutional performance management system.”

As an example of what can be achieved, Prof. Wilkinson highlighted the work of one of the most successful student support programmes at the UFS, namely the Career Preparation Programme (CPP), implemented fourteen years ago, bringing opportunities to thousands of students without matric exemption. The programme is characterised by dedicated staff, a challenging resource-based approach and foundational courses addressing various forms of under preparedness. Since 1993 3 422 students gained entry into UFS degree programmes after successfully completing the CPP; since 1996 1 014 of these students obtained their degrees, 95 got their honours degrees, 18 their master’s degrees and six successfully completed their studies as medical doctors.

Prof. Wilkinson said: “I believe we have the structures and the potential to become a leading teaching-learning university and region, where excellence, expertise and scholarship are recognised, honoured and rewarded.”

 

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