Tackling problems of early diagnosis and prognostic stratification of mycosis fungoides using a systems medicine approach

Prof. Emmanuella Guenova (CHUV) was granted this “allocated fund” in January 2024 for 18 months.

Key strategies in the fight against cancer mortality are early detection and precise diagnosis. Especially in its early stage, mycosis fungoides (MF), the most common cutaneous T cell lymphoma, exhibits striking morphological similarities to benign inflammatory skin conditions. This results in two major problems: diagnostic delay and prognostic uncertainty. Here, we propose a large interdisciplinary effort, combining bioinformatics, biological research, and medicine to tackle the problems of early diagnosing and prognostic stratification of tumors such as MF. In the context of the Indo-Swiss research initiative, we profit from the unique opportunity to perform analysis of classical versus hypopigmented MF, a rare, distinct variant, prognostically clearly different from the classical disease. We postulate a key role of type 2-skewed immunity in MF cancer progression. We also see the naturally occurring hypopigmented MF variant with good prognosis and strong type 1 immunity as an ideal comparator to the classical MF phenotype that can help us understand disease complexity, identify negative immune regulators and define parameters for better MF patient classification and stratification.

Unravelling the rules by which T cells recognize cancer-specific epitopes

T cells play a crucial role in cancer immunotherapy by targeting and attacking cancer cells. They do so by recognizing specific molecules, called epitopes, displayed on cancer cells but not on normal cells. To maximize the chances of detecting the wide variety of epitopes found across cancer patients, different T cells are endowed with different receptors. T cell receptors recognizing cancer epitopes are promising for therapeutic applications, since T cells can be engineered to express these receptors and infused into patients.

Today, it is increasingly possible to identify the various T cell receptors and the epitopes present in a tumor. However, figuring out which T cell recognizes which epitope is still very challenging. 

In our project, we will combine experimental and computational methods to characterize the recognition of cancer epitopes by T cell receptors. We then aim to develop AI models that can analyze large collections of T cell receptors from patients, in order to identify the most promising ones for clinical use. These results will complement ongoing research at the Department of Oncology and elsewhere, and help accelerate and streamline current pipelines to prioritize T cell receptor selection for T cell-based therapy.

Mirror therapy for phantom breast syndrome

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 death^1,2, mortality due to breast cancer has decreased considerably over the last decades^1,2, 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-1900s^4,5, 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.

Combination TKI and next-generation CAR-T cells for improved treatment of sarcoma

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.

Survey on cancer patient-reported healthcare experiences in Switzerland

Collecting patients’ opinions and their healthcare experiences is essential when assessing the quality of healthcare services and evaluating how well the healthcare system meets patients’ needs. This is particularly important in cancer care, as these patients have needs on multiple levels that very often are not covered by the existing healthcare system. Beyond the numerous health issues related to the disease and its treatment, cancer can indeed have significant psychosocial consequences for patients and their loved ones, including financial repercussions.

In 2018, we conducted the SCAPE-1 (Swiss Cancer Patient Experiences) study, a first survey of patients treated for one of the six most frequent cancer types in one of four hospitals in the French-speaking part of Switzerland. This survey addressed their experiences related to oncological care. In 2021, we repeated the survey. This SCAPE-2 study was extended to include patients with any type of cancer and treated in the same four French-speaking hospitals as well as in four medical centers in the German-speaking part of the country. Amongst other topics, the survey contained questions regarding emotional support, information and communication, treatment decision making, as well as inpatient and outpatient care. A section on the impact of the COVID-19 pandemic on cancer care and the patients themselves was also added.

The results of this study will provide insight into the way patients experience cancer care, and will help determine whether these experiences vary from one cancer center to another and depending on the language spoken. Furthermore, this study will help guide the development and the implementation of local and national interventions aimed at improving cancer care by identifying aspects less well perceived by patients.

The SCAPE-2 study was initially financed by the Swiss Cancer Research foundation. The additional support granted by the ISREC Foundation will make it possible to perform an in-depth analysis of the data collected within the study, and to enhance the value of this information through scientific publications as well as presentations at conferences and seminars.

Customizing treatment in cancer patients & uncovering cancer vulnerabilities

RAS proteins are among the most important members of the MAPK pathway, a signaling cascade relevant for cell growth and survival. Altered RAS genes (HRAS, KRAS and NRAS) represent the most frequently mutated gene family in human cancers, with KRAS being accountable for the development of roughly 35% of lung adenocarcinomas, up to 50% of colorectal cancers and even up to 95% of pancreatic cancers. Despite intensive research efforts, effective inhibition of mutated KRAS remains a major obstacle in the battle against cancer. The recent development of KRAS^G12C mutation-specific drugs has shed some light on this specific variant, but clinical success of these compounds is very limited, and first resistance mutations have already been reported. As these efforts in inhibiting KRAS have not been successful, the research focus has shifted towards the inhibition of MEK1/2, a regulator found downstream of the MAPK pathway. However, as resistance mechanisms are rapidly emerging, the notion that KRAS-mutated tumors remain unassailable persists. It is therefore of great importance to develop other strategies in the identification of cancer vulnerabilities.

In the era of precision medicine, strategies to confirm therapeutic efficacy and the identification of additional treatment options have become essential to both clinicians and patients. The functional tumor pathology group, led by Prof. Dr. med. Chantal Pauli and located in the Department of Pathology and Molecular Pathology at the University Hospital Zurich, has developed a platform incorporating the genetic features of individual patient tumors and the functional testing of patient-derived tumor organoids (PDTO). The overall goal is to identify effective therapeutic strategies for individual patients by performing a screen of cancer-relevant drugs. This approach has resulted in the identification of a novel synergistic drug combination involving a MEK inhibitor and a purine analogue. Interestingly, this synergy was not found in all tumor organoids, but was restricted to those with a mutation in the MAPK pathway.

This project will further examine the therapeutic potential of the identified drug combination in a larger cohort of PDTOs, and help to understand the genetic features responsible for this vulnerability seen in certain tumors. As resistance mechanisms against KRAS^G12C are arising, we plan to test if our combination is able to bypass the resistance mechanisms and affect the tumor’s viability. Ultimately, we seek to identify patients likely to benefit from this synergistic drug combination and elucidate mechanisms of patient-related drug sensitivities or resistances.

Project

Targeting novel molecular networks underlying bladder cancer recurrence and progression

Bladder cancer (BC) is a very significant world public health problem, in terms of prevalence, mortality, clinical management and cost. For most patients (around 70%), the disease is detected as a non-muscle invasive BC (NMIBC) at the surface of the bladder. For many years, it has been treated with BCG instillation and tumor resection within the bladder. This treatment is efficient, but most patients will undergo tumor recurrence and will necessitate several rounds of treatment over the years. The disease can also evolve into muscle invasive bladder cancer (MIBC, 30%). In these cases, the treatment consists in chemotherapy and bladder removal (cystectomy). Despite this radical treatment, the overall survival is low, with half of the patients not surviving beyond five years. Survival does not exceed 15 months when the disease is metastatic. In the last years, the tremendous success of immunotherapy has also led to some success in the treatment of MIBC. Immunotherapy, in this case, will restore the capacity of the immune system to fight the disease. 20 to 30% of the patients treated with antibodies blocking the PD-1/PD-L1 pathway showed a response to the treatment. But this rate of response is lower than in other cancer types and there is a clear need to understand why the patients do not respond to the treatment in order to improve and find new immunotherapeutic treatments.

In this optic, we plan to combine the expertise of our two research teams to decipher the molecular mechanisms driving BC recurrence/progression. We will carry out studies directly in patient samples and in a genetically engineered mouse model (GEMM) of BC that recapitulates the human BC tumor progression stages. Furthermore, we will dissect and validate novel therapeutic axes and biomarkers in this GEMM, in view of phase I/II clinical trials in BC patients to improve patient survival.

Preliminary genetic studies on primary and recurrent tumor tissues of a cohort of 12 BC patients led to the discovery of a gene signature associated with BC progression/recurrence. In our study, we will focus on two pathways found in this signature that can be targeted to improve tumor control/elimination. We validated that these two pathways were higher in recurrent versus non-recurrent tumors in a larger cohort of 36 patients. This same gene signature was also detected in the progressive stage of our BC GEMM, confirming the known clinical relevance of this model. Based on these findings, we hypothesize the existence of a therapeutically targetable crosstalk between immune and BC cells that involves the studied genes and their regulation.

Understanding how clonal hematopoiesis feeds lymphoma

Patients with lymphoma who do not respond to treatment have a bleak outcome. Annually, over 1100 patients die with leukemia and lymphoma in Switzerland. Lymphoma can arise when the DNA inside a lymphocyte changes in a way that prevents the lymphocyte from responding to signals that usually keep it under control. To outgrow and disseminate, lymphoma hijacks normal inflammatory cells to acquire protection and nurturing, while at the same time deceiving them by hiding from their attack. Inflammation may be age-related and can foster manifestations such as clonal hematopoiesis or can be sustained by chronic infections of the lymphoma cell itself.

The new avenues of lymphoma therapy rely on a combination of approaches that target both tumor cells and the supporting host environment, including: i) repairing the operative system inside lymphoma cells, which can be achieved by using small molecules that precisely identify and attack the factors that led to its failure; ii) reverting the stunned inflammatory cells from lymphoma feeders to lymphoma predators. The experiments will also allow us to understand how aging-related inflammation facilitates lymphoma development. We aim to understand how aging of the normal immune functions (designed to cause inflammation) modulate the tumor and the surrounding immune system. Single cell resolution now puts us in the unique position to track the aging of cells of the immune system (locally and globally) and to connect them to the behavior of cancer cells. We will use this knowledge to develop strategies to engage the healthy immune compartment in the fight against the tumor. This is of particular interest as the advent of multiple immunotherapy approaches puts increasing emphasis on the efficacy of drugs on immune responses or the fitness (exhaustion) of the anti-tumor response.

Project