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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

Guest lecture: Mr Pretorius, CEO of McCarthy Limited
2004-11-05

The challenges facing business leaders in a rapidly changing South Africa

“The world we used to know does not exist anymore. Leaders are continually dealing with crisis and opportunities, in a high-pressure environment,” said Mr Brand Pretorius, honorary professor from the University of the Free State , delivering his 13th guest lecture on the challenges facing business leaders in a rapidly changing South Africa .

Mr Pretorius, CEO of McCarthy Limited, identified certain trends which are responsible for changes to the South African business environment. He said the South African business environment is ever-changing, fast moving, complex and unpredictable. “As business people we have to deal with the impact,” he said.

“Years ago we were globally isolated. Now we live in a shrinking borderless world with crumbling trade barriers. Globilisation of our economy is accelerating. For South African business leaders this creates a sea of export opportunities,” he said.

Although there are ongoing demands for substantial profit growth from shareholders, the days of focussing only on their interests are gone, said Mr Pretorius. Stakeholder commitment now enjoys high priority and business leaders have to deal with the challenges accompanying black economic empowerment and employment equity.

Customers are also well-informed and demanding. Business leaders could easily loose the loyalty of their customers because of a hyper-competitive environment with an oversupply of goods and services.

Mr Pretorius stated that staff want to be involved and are looking for meaning in their workplace. Employers also have to deal with HIV/Aids in their workplaces. Trauma, absenteeism and financial implications could have a great effect on the viability of a business.

Against these changes Mr Pretorius pointed out the challenges business leaders are facing. In doing so a number of questions arise. The external business climate is characterised by turbulence and change. Internally there is a need for stability and meaning. How do we handle both challenges effectively?

Because of changes strategy decay is taking place and past strategies become irrelevant. Mr Pretorius said that business leaders need to modify their business models to prevent the downfall of their companies.

It is important for leaders to know what is happening in their world. “Continuous innovation is a critical success factor. The reality is that innovation is the only insurance against irrelevance,” he said.

Because of a changed environment leaders must perform and transform, simultaneously. How do we strike a balance between focused transformation and the achievement of world class performance, asked Mr Pretorius? “We need to bring about meaningful and sustainable empowerment, in order to create an inclusive economy and society. Leadership and management profiles should reflect the diversity of our teams, however at the same time every effort should be made to stop the brain drain and retain the expertise of experienced white managers.”

He also stated that leaders have an important role to play in terms of employment creation and corporate caring. “Sustainable stability and prosperity will not materialise without efforts in this regard.”

Mr Pretorius said that above challenges could be addressed by developing the ability to focus on creating a better future, rather than defending the past, a long-term vision, facing new realities, enhancing the value of brands and mobilising IT and the Internet to serve the business and customers better.

Retaining a positive vision of the future, embracing change and transformation, building your business according to the right principles and values and aspiring to be the best are some of the guidelines, according to Mr Brand, for future business success. He stated that creating a value advantage above one’s competitors, customer satisfaction and retention and inspirational leadership will add to the success of one’s business.

“We are indeed living in the era of the ultimate challenges, but also the ultimate opportunities. Let me clearly state that I have hope – in my view the tide has turned. Every day I experience small miracles inspired by ordinary people making an extraordinary difference,” said Mr Pretorius.

 

Media release
Issued by: Lacea Loader
Media Representative
Tel: (051) 401-2584
Cell: 083 645 2454
E-mail: loaderl.stg@mail.uovs.ac.za
5 November 2004

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