Group leader:

Professor Anna-Mart Engelbrecht, PhD, Medical Physiology

Biographic details:

Anna-Mart Engelbrecht is currently professor in the Department of Physiological Sciences at Stellenbosch University. She completed a BSc (Hons) in Physiology at Stellenbosch University, a MMedSc at the University of the Free State and received her PhD in 2005 at Stellenbosch University. She received several prestigious awards which include the Dean's and Senate's Medals as well as the Gencor Bronze Medal from the University of the Free State, the Marie Curie Scholarship of the European Union, the Rector's award for Excellence in Research and the Vice-Rector's Research Award for exceptional achievement from Stellenbosch University as well as the Lasec Award for Excellence in Physiology Research from the Physiological Society of Southern Africa (PSSA). Twenty one MSc and 18 PhD students completed the degrees under her supervision. She has published more than 96 peer reviewed, research articles and presented invited lectures at national and international conferences. She established the Cancer Research Group (CRG) where they investigate chemo-resistance and mechanisms to counteract chemotherapy-induced damage to the heart and skeletal muscle; markers for the early detection of cancer, as well as metabolic pathways in the cancer micro-environment.

Research Focus:

Cancer does not distinguish between race, gender, age or socioeconomic position; it is merciful to no-one and despite the political will driving a concerted global effort, only marginal progress has been made in the War against Cancer. One aspect which contributes to the poor progress in the management of cancer relates to the severe collateral damage associated with the current treatment strategies. Although anthracyclines such as doxorubicin has proven to be of the most successful approaches to cancer treatment, it induces various side effects such as nausea, vomiting, hematopoietic suppression and cumulative, dose-dependent cardiac toxicity. However, this is not the only challenge that researchers and clinicians are faced with; cancer cells are becoming increasingly resistant to chemotherapy-induced cell death. The specific focus of our research is to explore new avenues of chemotherapy and adjuvant treatments that would favour the use of lower chemotherapy concentrations with less side-effect to normal healthy cells, while maintaining satisfactory levels of cancer cell death.

Current Student's and Projects:

Improving cancer patient outcomes through molecular and genetic profiling based on a personalized medicine approach.

Dr Carla Fourie, Postdoctoral Research Fellow. Email: fouriecarla@sun.ac.za

I am currently a Postdoctoral Research Fellow in the Cancer Research Group. In South Africa, breast and cervical cancers are reported as two of the most invasive cancers. However, patients are often receiving suboptimal treatment which can result in relapse and cancer recurrence. Hence my strong passion to adopt a personalized medicine approach in our healthcare system, which will ensure that each individual patient is receiving the care that they will benefit from most. Currently, our project involves culturing cancer cells harvested from biopsies to assess genetic markers often associated with chemo/treatment resistance.

The functional impact of a rare TP53 germline variant identified in breast cancer patients with Li-Fraumeni-like syndrome.

Claudia Christowitz, PhD student. Email: claudiac@sun.ac.za

The application of personalized medicine can significantly improve patient prognosis and care. To this extent, a pathology-supported genetic testing framework was established for breast cancer patients in South Africa, consisting of point-of-care BRCA1/2 variant screening prior to whole exome/genome sequencing (WES/WGS). As part of this process, family screening, bioinformatics analyses, genetic counselling and functional studies are essential, especially when variants of uncertain significance are discovered that can have clinical implications. Recently, a rare TP53 germline variant (NM_001126114.2, c.1018A>G, p.N340D) was detected by WES in an index patient diagnosed with three primary invasive breast carcinomas. Further family screening, using WGS and Sanger sequencing, confirmed co-segregation of the variant with cancer on the maternal side of the family. Protein modeling and structural bioinformatics analysis predicted a deleterious effect on protein function. Functional studies were still required to classify this variant as pathogenic. As such, the aim of my study is to identify the functional impact of the variant on the proliferative, death, migratory, invasion, and cell signalling response of peripheral blood mononuclear cells (PBMCs) isolated from the blood of these patients, as a translational ex vivo model.

The green synthesis of gold nanoparticles using Tulbaghia violacea and Dodonaea viscosa for breast cancer treatment.

Nireshini Reddy, PhD student. Email: 18644538@sun.ac.za

An estimated 22% of women diagnosed with cancer in South Africa are afflicted with breast cancer. Current treatment options have many challenges, including severe adverse effects and chemoresistance. The rapidly growing field of nanotechnology has prompted great interest in its application for the diagnosis and treatment of cancers. Gold nanoparticles, particularly, have been widely investigated for their use in cancer therapeutics. The green synthesis approach is favourable in that it is cost-effective, sustainable, and makes use of plant materials used in traditional medicine. The selected plants for this study have already been shown to induce apoptosis in triple negative breast cancer cells. My study will use extracts of these plants to synthesis gold nanoparticles, in turn, imparting their anticancer properties to the nanoparticles. Therefore, the aim of my study is to investigate the applicability of green gold nanoparticles synthesised using aqueous extracts of T. violacea and D. viscosa for breast cancer treatment by using both in vitro and in vivo methods.

Investigating the role of exosomes in cancer treatment resistance: a personalized medicine approach to improve patient outcomes.

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Michelle van der Merwe, PhD student. Email: 20331193@sun.ac.za

Although significant advances in cancer treatment have been made in the last century, treating advanced-stage tumours remains a problem due to the ability of certain cancer cells to resist treatment. Emerging literature indicates that exosomes play critical roles in mediating resistance which has been previously overlooked. Exosomes are tiny membrane-bound vesicles that are released by most cells in the body, containing molecules such as DNA, RNA, proteins, and lipids, that serve as a communication mechanism between cells. Although most bodily cells secrete exosomes, cancer cells secrete significantly more exosomes compared to healthy non-cancerous cells. Exosomes released by tumour cells contain information and when donated to neighbouring cancer cells, it can make these cells more aggressive and resistant to treatment. Additionally, tumour-derived exosomes can also be donated to non-cancerous cells in the close vicinity of the tumour to make the environment in which the tumour resides more favourable for its progression. Therefore, the specific cargo within exosomes can provide us with information that will allow us to better understand the functionality of the specific cancer, and possibly help guide the decision for a best-suited treatment. Currently, my project involves culturing cancer cells harvested from cervical cancer biopsies to assess the involvement of exosomes in cancer progression and response to treatment.

Creating the foundation for a systems-based personalized medicine approach to cervical cancer diagnosis and treatment.

Atarah Rass, PhD candidate. Email: 19142609@sun.ac.za

Cancer is a complex disease with various role players, including lifestyle factors, genetic factors and intratumoural interactions. Patient care is therefore a complex process, that is also influenced by inherent differences between tumours. Developing a computational systems engineering-based approach to use in cancer diagnostics and treatment, and potentially prediction, will provide of integrated and global view of tumour dynamics. Downstream benefits of such an approach are immense. It allows all the important components, that are often neglected, to be considered, and may provide insight into novel interactions and system dynamics. Of particular interest to us is the contribution to personalized medicine and what it entails for patients, including receiving the best treatment possible. This study entails using computational modelling to simulate cervical cancer.

The possible anti-cancer role of Allium sativum L. in combination with chemotherapeutic agent, 5-fluorouracil, on colon cancer.

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Elizka van Heerden, MSc student. Email: 21556229@sun.ac.za

Cancer presents as a major public health crisis worldwide with colorectal cancer (CRC) being one of the most common cancers among men and women. It is responsible for 9.4% of deaths worldwide and is the third most commonly diagnosed cancer. 5-Fluorouracil (5-FU) is a chemotherapeutic agent commonly used in the treatment of various cancers and is the treatment of choice for CRC. Although there are numerous strategies in action to fight CRC, none are capable of completely destroying this disease. The reasoning behind this is the fact that these strategies have limitations which lead to drug resistance and adverse effects on normal cells. Therefore, novel therapeutic options are consistently needed to improve cancer therapy and overcome current challenges. In recent times, the use of natural sources has become a popular concept worldwide. Natural products (NPs) show more favourable behaviour when compared to synthetic molecules, due to their biological properties. Recent studies linked the intake of garlic with a protective effect on a wide range of cancers, concluding that the health benefits of raw garlic are worth looking in to. Therefore, this review will investigate the possible relationship between administering garlic in combination with 5-FU and the effect thereof in colon cancer patients.

Investigating the effects of chemotherapeutic agents, Doxorubicin and Paclitaxel, in combination with Dodonaea viscosa on breast cancer.

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Janke van Eck, MSc student. Email: 21687374@sun.ac.za

To this day, breast cancer remains a detrimental health burden being the most frequently diagnosed malignancy in women worldwide. Currently, conventional chemotherapeutic agents such as Doxorubicin (DXR) and Paclitaxel (PXT) are used to treat breast cancer patients. However, its use is associated with severe adverse effects, cardiotoxicity, and chemoresistance. Therefore, an urgent need for novel treatment regimens which are effective in inducing cancer cell cytotoxicity – paired with little adverse effects – has emerged. The field of phytotherapy has spiked considerable interest as a possible treatment avenue, with the hopes of improving clinical outcomes for cancer patients. Studies has linked Dodonaea viscosa with strong antioxidant and anti-inflammatory properties. Furthermore, the cytotoxic effects associated with D. viscosa could prove useful in promoting cell death in various cancers, raising the question whether combining conventional chemotherapies with phytotherapies could increase the efficacy of cancer treatment. Therefore, my project aims to investigate DXR and PXT in combination with D. viscosa and the effects thereof on breast cancer.

Investigating the effects of chemotherapy on metastasis in cervical cancer using a personalized medicine approach.

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Cayleigh de Sousa, MSc student. Email: 22666990@sun.ac.za

Cancer cells are known for their aggressive nature and ability to spread rapidly around the body. Therefore, it is important to find new and improved ways to try and limit or even prevent this spreading from occurring. My research focuses on investigating the potential for various chemotherapeutic drugs to prevent the spreading of cervical cancer cells from their original tumour site, to form distant secondary tumour sites around the body. In addition, a personalized medicine approach will be utilized with its main objective being to develop a patient-specific treatment plan in an attempt to avoid the possibility of treatment resistance and recurrence within cancer patients.

Investigating the effects of chemotherapy on metastasis in ovarian and endometrial cancer patients.

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Madré Meyer, MSc student. Email: 22550380@sun.ac.za

The main focus for my master's project is studying gynaecological cancers and utilising a personalized medicine approach to potentially treat this heterogenous disease. Gynaecological cancers typically include cancer of the cervix, endometrium, and ovaries. For the purpose of my study, I shall be focusing on endometrial cancer and ovarian cancer. Better knowledge of ovarian and endometrial cancer disease progression and responses to treatment are necessary in order to develop better biomarkers and novel therapeutic approaches. One such novel approach, is personalized medicine, which uses an individual's genetic profile to guide medical decision making for prevention, diagnosis, and treatment of diseases. Based on literature, generic treatment approaches for gynaecological cancers such as ovarian and endometrial cancer are ineffective in preventing treatment resistance, cancer recurrence and metastasis. Therefore, personalized medicine approaches could be beneficial to ultimately improve the prognosis of these patients and to prevent the onset of treatment resistance. The proposed study is therefore designed to examine individual patients' molecular and genetic profiles to improve cancer treatment resistance, prevent metastasis and to ultimately reduce mortality.

The functional effects of a rare TP53 germline variant on the prognostic plasma cytokine and clotting parameters in breast cancer patients.

Enrico Binneman, MPhil (Cancer Science) student. Email: 21603014@sun.ac.za

My research project forms part of a functional study to determine the classification of a rare tumour suppressor protein 53 (TP53) variant identified for the first time in the germline DNA of breast cancer patients. My project involves the assessment of the variant's involvement in the coagulation cascade, inflammatory response and response to various antineoplastic agents used to combat breast cancer. Clotting and viscoelastic parameters of the patient's blood plasma are assessed using Thromboelastography (TEG) to determine whether the variant's involvement in blood coagulation results in hypercoagulability, hypocoagulability or has no effect on the clotting of the patients. The inflammatory response will be assessed by measuring circulating pro- and anti-inflammatory cytokines in the patient's plasma. The above-mentioned assessments are performed due to its potential critical role in disease progression, symptom severity and response to antineoplastic agents utilised to combat cancer. Lastly, conventional chemotherapeutic agents used for breast cancer, such as etoposide, doxorubicin, paclitaxel and 5-flurouracil will be used to assess their efficacy on the isolated peripheral blood mononuclear cells of these patients to determine the effects of this variant on drug response.

Investigating the relationship between Covid-19 and cancer initiation, progression and metastasis.

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Kayla Field, Honours student. Email: 23561947@sun.ac.za

Following the recent Covid-19 pandemic and the rising global incidence of long covid, many studies have elucidated the pathogenesis of the SARS-CoV-2 virus. Consequences of SARS-CoV-2 infection include systemic inflammatory activation and a so-called cytokine storm, an excessive immune response characterised by the upregulation of pro-inflammatory cytokines. The inflammatory profile seen during Covid-19 infection may promote the initiation, progression and metastasis of cancer. My honours project, therefore, aims to investigate the effect of the SARS-CoV-2 on breast cancer cells. A key aim of the study is to evaluate the inflammatory profile of breast cancer cells exposed to the SARS-CoV-2 spike protein. Thus, the proposed study is designed to address the lack of information regarding the role of the systemic immune response of Covid-19 in mediating the immune-related tumour microenvironment and tumour progression.

Recent publications

Fourie C., Shridas P., Davis T., De Villiers W.J.S., Engelbrecht A-M. 2020. Serum amyloid A and inflammasome activation: A link to breast cancer progression? Cytokine Growth Factor Reviews, 59:62-70. DOI: 10.1016/j.cytogfr.2020.10.006.

Van Niekerk G., Christowitz C., Conradie D., Engelbrecht A-M. 2020. Insulin as an immunomodulatory hormone. Cytokine & Growth Factor Reviews, 52:34-44. DOI: 10.1016/j.cytogfr.2019.11.006.

Du Plessis M., Fourie C., Riedemann J., De Villiers W.J.S., Engelbrecht A-M. 2021. Cancer and Covid-19: Collectively catastrophic. Cytokine and Growth Factor Reviews, 63:78-89. DOI: 10.1016/j.cytogfr.2021.10.005.

Van der Merwe M., Van Niekerk G., Fourie C., Du Plessis M., Engelbrecht A-M. 2021. The impact of mitochondria on cancer treatment resistance. Cell Oncology, 44(5):983-995. DOI: 10.1007/s13402-021-00623-y.

Van der Merwe M., Van Niekerk G., Botha A., Engelbrecht A-M. 2021. The onco-immunological implications of Fusobacterium nucleatum in breast cancer. Immunology Letters, 232:60-66. DOI: 10.1016/j.imlet.2021.02.007.

Van Niekerk G., Van der Merwe M., Engelbrecht A-M. 2021. Diabetes and susceptibility to infections: Implication for COVID-19. Immunology, 164(3):467-475. DOI: 10.1111/imm.13383.

Van Niekerk G., Christowitz C., Engelbrecht A-M. 2021. Insulin-mediated immune dysfunction in the development of preeclampsia. Journal of Molecular Medicine, 99:889-897. DOI: 10.1007/s00109-021-02068-0.

Fourie C., Du Plessis M., Mills J., Engelbrecht A-M. 2022. The effect of HIF-1α inhibition in breast cancer cells prior to doxorubicin treatment under conditions of normoxia and hypoxia. Experimental Cell Research, 419 (2):113334. DOI: 10.1016/j.yexcr.2022.113334.

Sedeman M., Christowitz C., De Jager L., Engelbrecht A-M. 2022. Obese mammary tumour-bearing mice are highly sensitive to doxorubicin-induced hepatotoxicity. BMC Cancer, 22(240): 1-15. DOI: 10.1186/s12885-022-10189-z.

Du Plessis M., Fourie C., Stone W., Engelbrecht A-M. 2023. The impact of endocrine disrupting compounds and carcinogens in wastewater: Implication for breast cancer. Biochimie, 209:103-115. DOI: 10.1016/j.biochi.2023.02.006.