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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

UFS receives multimillion rand international funding for Advancement

2013-01-21

21 January 2013

We are one of four South African universities that have been selected to take part in a multimillion-rand programme to bolster private fund-raising and Advancement efforts.

The UFS will receive US$640 000 (R5 612 800) over a period of five years to use in advancement efforts.

In total, the US-based Kresge Foundation will make US$2.5 million available to the four universities, which includes the UFS, Durban University of Technology (DUT), Tshwane University of Technology (TUT) and the University of Johannesburg (UJ), over the next five years as part of a joint initiative with Inyathelo: The South African Institute for Advancement, to support the long-term financial sustainability of higher education institutions in South Africa.

Kresge will also provide programmes and support aimed at enhancing student access to universities and improving graduation rates.

Bill Moses, who directs Kresge’s education programme, says declining government support means that South African university officials need to tap into diversified philanthropic and private funding if they want to enhance their institutions’ ability to serve students better. “Stronger Advancement skills are critical to their success and ultimately to getting more South African students into universities and completing degrees. Advancement is not just about raising funds. It is the practice of building, maintaining and improving support, skills and other resources to ensure the sustainability of an institution,” explains Moses.

This latest Kresge initiative follows the success of a five-year partnership with Inyathelo that helped five high-profile South African institutions - the University of the Witwatersrand (Wits); the University of Pretoria (UP); the University of the Western Cape (UWC); the Cape Peninsula University of Technology (CPUT) and the Children’s Hospital Trust - increase their private fund-raising revenue threefold. The four universities will receive additional funding over the next five years and will serve as mentors to the new group of institutions.

In April last year, Kresge announced a new commitment to South African higher education that builds on its efforts in the United States to improve university access and help students succeed academically. Their ‘Promoting access and success at South African universities’ programme will seek to strengthen pathways to and through universities, especially for students who are often unprepared for university study. Moses says enhancing the ability of universities in South Africa to graduate the next generation of knowledge workers, will make it possible for the country to compete more effectively in the global economy. “Access to higher education in South Africa has improved dramatically since the end of Apartheid. A doubling of enrolment since 1994 has, however, contributed to serious challenges, including under-prepared students and disappointing graduation rates. We are confident that our programme will help address some of these obstacles to success,” says Moses.

Kresge has already funded several efforts that support its interest in strengthening pathways to and through universities this year, including a grant to the University of the Free State to expand the South African Survey of Student Engagement, as well as funding to the University of Pretoria to support a conference in January, which will highlight opportunities to promote access and success at South African universities.

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