Testicular cancer: Tumour stem cells, etiology and effects after chemotherapy

Tumour stem cells and germ cell cancer

(A) Comparisons of embryonal carcinomas and embyronic stem cells (Figure and text below).
(B) Genetic risk and long-term effects of treatment as assessed from genotypes in DNA repair genes in germ cell tumour patients.

Embryonal carcinoma (EC) cells, found in certain testicular germ cell tumours (TGCTs), represent a striking paradigm for malignant cells with stemness properties. Their pluripotent state allows them to self-renew, as well as differentiate, to give a disorganized array of cell and tissue types. EC cells are morphologically similar to embryonic stem (ES) cells, and the two also share cell surface markers and overall gene expression programmes.

Overall, this imply that ES cells can be considered the non-malignant counterpart of EC cells, providing the rare situation where the "normal" counterpart of a cancer cell with stemness properties is readily accessible, and can be observed through its progression to the malignant state.

By comparing gene expression of EC and ES cells across the genome at high resolution, we aim to gain insight into the role of stem cells in the development and progression of TGCTs, in particular, and cancer in general.

Genetic variation among testicular cancer patients; predisposition, chemotherapy response and long term toxicity

Testicular germ cell tumors (TGCTs) are the most common tumors among young men, aged 15-45 years. The TGCTs are histologically classified as seminomas and nonseminomas, both believed to originate from a common precursor known as intratubular germ cell neoplasia.

Fortunately, these tumors respond well to cisplatin. More than 95% of all patients and above 80% of patients with metastasis are cured using platinum based chemotherapy. However, some patients are troubled by side effects and long term toxicities of their treatment and also some tumors do not respond to treatment. Based on previous studies of TGCTs, we have selected a number of candidate single nucleotide polymorphisms (SNPs) to be profiled among the TGCT patient population.

We aim to discover if these genetic variations could be involved in and/or contribute to predisposition and development of TGCTs, influence the tumors' response (cure or relapse) and the patients' response (long term side effects/toxicities) to treatment. We hope to identify SNPs that may be applied for more individualized diagnostics and therapy selection, and prevention of TGCT.

The research project is run jointly between the Molecular Genetics Group and the Genome Biology Group.

Malignant Peripheral Nerve Sheath Tumors: Molecular biology and translational research

Malignant peripheral nerve sheath tumors (MPNST) are rare soft tissue cancers that arise in neuroectodermal cells in the peripheral nervous system. About half of the patients carry the additional burden of Neurofibromatosis type 1 (NF1), which is a hereditary genetic disease that significantly increases risk of developing MPNST, as compared to the general population. Although MPNST is rare, there is a great need to improve the current treatment, as most patients are young adults and the survival prognosis is poor. The current treatment of MPNST patients includes surgery, chemotherapy and radiotherapy, however, there is little evidence to support the benefit of the treatment options beyond surgery.

We aim to create and transfer biological discoveries into improved management of patients with MPNST.

Ongoing research
In a European multicentre study led by Prof Lothe we have in recent years identified prognostic biomarkers that can be used for stratification of high risk patients who could benefit from additional treatment after surgery and low risk patients who might be spared from the burdens of aggressive treatment. Current research is focusing on identification of predictive markers that can guide therapy choice for patients. We also investigate preclinical models (cell lines and tumor organoids) aiming to identify novel drug sensitivities and synergistic drug combinations.  Multilevel molecular profiling are performed on fresh frozen tumor samples (n= 134 MPNST patients). Clinical translation is performed in collaboration with Dept of Oncology, OUH.
Clinical trial with Simon’s two-stage design:
A phase II, single arm interventional trial of pembrolizumab (anti-PD-1 antibody) in patients with metastatic or locally advanced/non-resectable MPNST. ClinicalTrials.gov (NCT02691026). Translational substudy ongoing.
Group members involved
Maren Høland, Barbara Niederdorfer, Kaja Christine Graue Berg, Anita Sveen, Kushtrim Kryeziu

Assoc. Prof. Bodil Bjerkehagen, Dept of Pathology
Dr Kjetil Boye, Dept of Oncology
Dr. Tormod K Guren, Trial Unit, Dept of Oncology
Prof. Sigbjørn Smeland, Division of Cancer Medicine

European Centres
Prof. Fredrik Mertens, Skåne University Hospital, Lund, Sweden
Prof. Piero Picci, Istituti Ortopedici Rizzoli, Bologna, Italy
Dr. Eva van den Berg, University Medical Centre, Groningen, the Netherlands

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