Multisystem cancer biology: targeting the interplay between intra- and extracellular proteostasis

Prof. Holger Auner

All human cells must assemble – and later break down – the right proteins at the right time and in the right quantities. To do this, they need to use and recycle building blocks such as amino acids, and provide energy for the molecular machines that make and break down proteins. The fine-tuned orchestration of these processes represents a considerable challenge that cells must continually master, as a correct cellular “proteome” (the entire set of proteins) is essential for the proper functioning of cells and for the health of the tissues and organs in which they reside.  As a result, a myriad of diseases often linked to age are linked to the inability of cells to keep the proteome in order.

Cancer cells usually grow and multiply faster than normal cells. They are therefore thought to be particularly dependent on the processes that regulate the proteome in order to keep up with high protein turnover. Disrupting these mechanisms is a promising therapeutic approach and has already led to new treatments for some cancers, such as multiple myeloma, a malignant disease of the bone marrow. Our team is working to better understand how different cancers try to keep their proteome in order, and to find ways to target these mechanisms with new drugs. One of the molecules we are interested in is called GCN2. It regulates how cells respond when their amino acid stores run low. We want to understand how to safely turn off GCN2 in cancer cells so that their proteome fails, killing them, while healthy tissue is largely spared. We know that this approach works well experimentally in some cancer cells, but not in others. One goal of our research is to identify the features that make cancer cells dependent on GCN2, which would help identify cancer patients (prior to therapy) that are likely to respond to treatments with drugs that target GCN2. To do this, we use a so-called systems biology or multi-omics approach, in which different technologies are used to study several cellular processes in parallel (e.g., to understand how cellular metabolism changes when certain genes are actively transcribed and translated into proteins). We and many others believe that such a holistic approach to molecular cancer research has great potential to identify previously unknown cancer cell vulnerabilities. To find and target these Achilles’ heels, we collaborate with academic colleagues and research partners from the biotechnology and pharmaceutical industry.

This «allocated fund » was granted to Dr. Filipe Martins (EPFL) in February 2024 for one year

Breast cancer is the most frequently diagnosed cancer in women, with more than 6000 new cases diagnosed yearly in Switzerland; an incidence which is still increasing. Although still a leading cause of cancer-related death1,2, mortality due to breast cancer has decreased considerably over the last decades1,2, thanks to the implementation of mammography screening programs, surgery improvements, and more efficient medical treatments.

Approximately 40% of breast cancer patients must undergo a mastectomy to treat their disease3. Therefore, the management of long-term consequences of this surgical procedure is advocated, in order to limit the economic and societal impacts of its related morbidity and to improve the quality of life of cancer survivors.

Phantom breast syndrome (PBS), occurring after a mastectomy, is a condition characterized by a residual sensation associated with the removed breast tissue, accompanied by neuropathic pain (similar to phantom limb syndrome after amputation). Although of varying estimated incidence in the literature, its prevalence reaches up to 30% in patients having undergone this procedure3. Accordingly, 760 women are diagnosed with PBS in Switzerland every year. In addition to painful sensations described as shooting and burning, patients may also experience other discomforts, such as pins and needles, itching, tingling, pressure, and throbbing3. PBS severely affects the quality of life as a consequence of the physical disability and emotional distress it generates. Some studies demonstrated that depression, psychiatric morbidity, and fear of cancer recurrence are more important in women suffering from PBS3.

Parallels have been drawn between PBS and phantom limb syndrome, such as the timing of their installment after surgery. There are also clues that their development occurs on the same neurological basis. Research on PBS is still sparse and often inconclusive. However, it is increasingly clear that this condition has its own specificities. Therapeutic interventions for this type of pain include oral medications, such as opiates and antidepressants, in addition to topical agents. However, such medical treatments have limited efficacy once this type of chronic pain is installed. Similarly, preventive treatments aiming at reducing PBS incidence are currently not available. Patients are often isolated with their syndrome, as the awareness of the existence of PBS is limited outside of the specialized medical community, making the management of this syndrome a major unmet clinical need.

In this study, we aim to adapt “mirror therapy”, a common non-invasive treatment for phantom limb syndrome, for the care of PBS patients. This method, effective since the mid-1900s4,5, relies on the usage of a mirror to hide the amputated limb and to replace its image with the reflection of the intact contralateral limb. By doing so, the patient’s brain is tricked by the visual perception of two functional limbs, which elicits cortical remodeling and subsequent neuropathic pain relief. After decades of research, the therapy has been improved and adapted using different combinations of physical mirrors and virtual reality.

This project aims at improving the quality of life and the performance status of women suffering from PBS thanks to non-invasive devices and accompanying physiotherapy sessions. The objective is to improve pain control and potentially reduce PBS-related disabilities and their economic and societal impacts. This project started a year ago, but requires substantial funding to achieve further improvements.

Project of Dr. Antonia Digklia, Centre hospitalier universitaire vaudois, and Dr. Melita Irving, Centre hospitalier universitaire vaudois.

This investment is intended to help the team establish the preliminary data that will provide background information required to pursue the use of next-generation CAR-T immunotherapy in the treatment of sarcoma. This project is built on strongly balanced contributions of Dr. Irving as a basic scientist with expertise in the generation of CAR-T cells, and Dr. Digklia as a clinician working in the sarcoma unit of CHUV. The team has obtained promising results in early phase I/II trials, suggesting that an inhibitor of the tyrosine kinase VEGFR (pazopanib) plus the anti-PD-L1 immune checkpoint inhibitor durvalumab may have tumor-arresting activity in soft tissue sarcoma. The team wants to combine such tyrosine kinase inhibition (TKI) with innovative CAR-T cell therapy to treat sarcoma. This is a challenging goal, but it is reasonable to test CAR-T cells as well as immune checkpoint inhibitor therapies. The scientists hope to use the erythropoietin-producing hepatoma type-A receptor-2 (EphA2), a cell surface marker specifically overexpressed in sarcoma, as a target for novel CAR-T cells. It is important that they compare patient biopsies before and after tyrosine kinase inhibitor treatment to identify the most specific targets for CAR-T cell co-engineering. As most of the team’s preliminary data were produced using prostate cancer cells, the funding is also given so that they can accumulate data that confirms EphA2 expression in sarcoma before and after TKI treatment, thereby substantiating the idea to use this marker as a CAR-T cell target.

This “allocated fund” is the fruit of a collaboration with the Jacqueline de Cérenville Foundation and the Jan Barton Mladota Foundation. It was awarded to Dr. Francesco Ceppi (CHUV) and Prof. Caroline Arber (UNIL/CHUV) in July 2023 for 5 years.

Press release

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Customizing treatment in cancer patients & uncovering cancer vulnerabilities.

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This “allocated fund” was granted to Prof. Camilla Jandus (University of Geneva) and Prof. Grégory Verdeil (University of Lausanne) in April 2022 for 2 years.

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This “allocated fund” was granted to Prof. Davide Rossi (Università della Svizzera italiana – Institute of Oncology Research IOR) in March 2022 for 3 years.

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This “allocated fund” was granted to Prof. Johanna Joyce (University of Lausanne, Oncology Department) in January 2021.

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This “allocated fund” was awarded to Prof. Curzio Rüegg (University of Fribourg) in October 2020 for 4 years.

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This allocated fund for immunotherapies was awarded in September 2020 to the research group of Prof. Lana Kandalaft (Oncology Department UNIL/CHUV).

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