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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

Research into surrogate milk important to wildlife conservation
2017-05-08

Description: Prof Garry Osthoff Tags: Prof Garry Osthoff

Prof Gary Osthoff from the UFS Department of
Microbial, Biochemical and Food Biotechnology,
will soon work on a milk formula for elephants.
Photo: Supplied

Research is being done at the University of the Free State (UFS) to analyse and synthetically imitate the unique milk of various wildlife species. This research is not only of scientific value, but also serves the conservation of South Africa’s wildlife species. At the forefront of this research is Prof Garry Osthoff from the Department of Microbial, Biochemical and Food Biotechnology.

Orphaned rhino calf pulled through with surrogate milk
“There is still a lot of research to be done. Naturally the research is of scientific importance, but with surrogate milk having the same composition as the mother’s milk of a specific species, orphaned calves or cubs of that species could be pulled through during a difficult time of weaning. Bearing in mind that exotic animals fetch thousands and even millions of rands at auctions, it goes without saying a game farmer will do everything possible to provide only the best nourishment to such an orphaned animal. In such a case, synthetically-manufactured milk would be the right choice,” says Prof Osthoff.

The fruits of his research were recently demonstrated in Germany when a rhino calf was left orphaned in the Leipzig Zoo. Prof Osthoff’s article: “Milk composition of a free-ranging white rhinoceros during late lactation” was used as a directive for applying surrogate milk for horse foals (which is already commercially available), since the composition of horse and rhino milk largely corresponds. The surrogate milk was used with great success and the rhino calf is flourishing. He mentions that such an orphan is often given the wrong nourishment with the best intentions, resulting in the starvation of the animal despite the amount of cow’s milk it devours.

With surrogate milk having the same
composition as the mother’s milk of a
specific species, orphaned calves or
cubs of that species could be pulled
through during the difficult time
of weaning.

Milk formula for baby elephants in the pipeline
With baby elephants left orphaned due to the increase in elephant poaching for their ivory, several attempts have been made to create a milk formula in order to feed these elephants. To date, many elephants have died in captivity from side effects such as diarrhoea as a result of the surrogate formula which they were fed.

Prof Osthoff recently received a consignment of frozen milk which he, together with researchers from Zimbabwe, will use to work on a milk formula for elephants. They are studying the milk in a full lactation period of two years. During lactation, the composition of the milk changes to such an extent that a single surrogate formula will not be sufficient. Four different formulas should probably be designed.

Prof Osthoff says that of the different species he has researched, elephants are the most interesting and deviate most from the known species.

Although his research to develop surrogate milk is adding much value to the wildlife industry, and although he finds this part of his work very exciting, his research focus is on food science and nutrition. “What is currently authentic in milk research is the study of the fat globules with content, the structure and composition of the casein micelle, and the prebiotic sugars. The knowledge which is gained helps to improve the processing, development of new food products, and development of food products for health purposes,” says Prof Osthoff.

 

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