Triple targeted therapy inhibits growth in preclinical models of treatment-resistant breast cancer
Danish–Australian study shows that the effect of triple combination therapy depends on genetic changes in the tumour’s signalling pathways.
Hormone receptor-positive (ER+) breast cancer is the most common type of breast cancer worldwide. Patients with this typer of cancer in advanced stages are treated with a combination of hormone therapy and CDK4/6 inhibitors, which often inhibits tumour growth. However, most patients will eventually develop resistance to this treatment, resulting in disease progression.
This development raises an important question for clinicians and researchers alike: How can we stop cancer from progressing once it no longer responds to standard therapy?
Key findings
Researchers from the University of Southern Denmark, in collaboration with Australian partners, tested several triple combinations of targeted cancer therapies in laboratory models of treatment-resistant breast cancer. All these therapies are currently being tested in clinical trials, but none of these trials compare different therapy regimens directly, so it remains uncertain which combination is the most effective. The study was recently published in the respected journal Science Translational Medicine.
Three questions for Carla L. Alves about the study:
What is the focus of your study? We’re investigating how to inhibit hormone receptor-positive breast cancer – the most common type – when it no longer responds to standard treatment such as hormone therapy and CDK4/6 inhibitors. We do this by testing new triple-drug combinations that block key survival signals in the cancer cells, particularly the crucial PI3K/AKT/mTOR signalling pathway.
What is the most important finding? We found that the optimal treatment depends on whether the patient’s tumour carries mutations in the PI3K/AKT/mTOR signalling pathway. For treatment-resistant tumours with PIK3CA or AKT1 mutations, the drug gedatolisib was particularly effective at halting tumour growth. In contrast, tumours with loss of the protective ‘brake’ gene PTEN responded better to other compounds that inhibit the pathway in a different way.
What can the results be used for? Our findings point to new and promising treatment strategies where the choice of triple-drug combination is guided by the individual genetic alterations in each patient’s breast tumour. This could help patients whose cancer no longer responds to standard treatment.
One of the most promising combinations included hormone therapy, a CDK4/6 inhibitor, and the compound gedatolisib, which blocks two key points - PI3K and mTOR - in the PI3K/AKT/mTOR signalling pathway in cancer cells.
This combination was particularly effective when the cancer cells carried mutations in the PIK3CA or AKT1 genes. In contrast, cancer cells with a loss of PTEN responded better to treatments that targeted only one point in the PI3K/AKT/mTOR pathway. PTEN is a gene that normally acts as a brake on uncontrolled cell growth.
Relevance and perspective
– We found that the treatment’s effectiveness largely depends on the tumour’s genetic profile. This highlights that a one-size-fits-all approach isn’t suitable, and that future treatments should be tailored to each patient’s tumour on a more individual level than we do today, says Carla L. Alves, first author and assistant professor at SDU’s Cancer Research Unit.
The study shows that a more individualised treatment approach – known as precision medicine – may be necessary to keep the disease effectively under control once it no longer responds to current standard therapies.
Methodology
The study was conducted using preclinical models, including mice implanted with the patients tumours (PDX), and patient-tumour-derived organoids (PDOs) – small, three-dimensional structures grown in the laboratory from patients’ cancer tissue.
About the study:
Method: The study was conducted using preclinical models, including mice implanted with the patients´ tumours (PDX), and patient-tumour-derived organoids (PDOs) – small, three-dimensional structures grown in the laboratory from patients’ cancer tissue.
The models were genetically analysed with a focus on mutations in PIK3CA, AKT1, and PTEN. Treatment effects were assessed by measuring cell growth, tumour shrinkage, and signalling activity in the cells. The mechanisms behind the treatment effects were also explored using proteomic analyses and gene expression data.
Funding: The study was funded by the Danish Cancer Society, Health Insurance “Danmark”, and the Region of Southern Denmark’s Research Council.
The models were genetically analysed with a focus on mutations in PIK3CA, AKT1, and PTEN. Treatment effects were assessed by measuring cell growth, tumour shrinkage, and signalling activity in the cells. The mechanisms behind the treatment effects were also explored using proteomic analyses and gene expression data.
Conclusion and future outlook
The study suggests that the best way to treat advanced, treatment-resistant breast cancer is to start with the tumour’s genetic profile. In particular, breast cancer cells with mutations in PIK3CA or AKT1 responded well in the models to a combination of hormone therapy, a CDK4/6 inhibitor, and gedatolisib – a compound that simultaneously targets two central nodes in the PI3K/AKT/mTOR signalling pathway.
Compared to the already approved PI3K inhibitor alpelisib, gedatolisib showed a stronger and more prolonged effect in several cases. However, the results are preliminary and based on preclinical models.
Initial clinical trials of gedatolisib in combination with existing treatments for breast cancer have shown promising results. An international phase 3 trial is currently under way to determine whether gedatolisib, when combined with existing therapies, can improve outcomes for patients whose cancer no longer responds to standard treatment.
Funding and collaboration
The study was conducted in collaboration between the University of Southern Denmark, Odense University Hospital and clinicians and researchers at Garvan Institute of Medical Research and St. Vincents Hospital, Sydney, Australia.
The study was funded by the Danish Cancer Society, Health Insurance “Danmark”, and the Region of Southern Denmark’s Research Council.
Study contributors and institutions:
- Carla L. Alves, Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark
- Leena Karimi, Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark
- Mikkel G. Terp, Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark
- Mie K. Jakobsen, Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark
- Fiona H. Zhou, Garvan Institute of Medical Research and St Vincent’s Hospital, Sydney, Australia
- Benedetta Policastro, Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark
- Nikoline Nissen, Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark
- Lene E. Johansen, Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark
- Tina Ravnsborg, Department of Biochemistry and Molecular Biology, University of Southern Denmark
- Leila Eshraghi, Garvan Institute of Medical Research and St Vincent’s Hospital, Sydney, Australia Sana Tamboowala, Garvan Institute of Medical Research and St Vincent’s Hospital, Sydney, Australia
- Ole N. Jensen, Department of Biochemistry and Molecular Biology, University of Southern Denmark
- Elgene Lim, Garvan Institute of Medical Research and St Vincent’s Hospital, Sydney, Australia
- Henrik J. Ditzel, Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark, Department of Oncology, Odense University Hospital, Department of Clinical Research, University of Southern Denmark
Meet the researcher
Carla L. Alves is assistant professor at the Cancer Research Unit, Department of Molecular Medicine, University of Southern Denmark.
Meet the researcher
Henrik J. Ditzel is professor at the Cancer Research Unit, Department of Molecular Medicine, and at Research Unit of Oncology, Department of Clinical Research, University of Southern Denmark.