Professor Camilla Krakstad has her background from research on signal transduction, and during her PhD she studied cAMP signaling in apoptotic cell death in both normal and cancer cells.
Professor Krakstad is leader of the the Bergen Gynecologic Cancer Research Group, which focuses on identifying molecular alterations underlying initiation and development of gynecologic cancers. The gained molecular knowledge from their studies will contribute to improved future clinical trials on molecularly targeted therapies. To improve disease detection and diagnosis, the aim is to identify and validate both imaging and molecular biomarkers, in close collaboration with the clinic.
During the past few years the group has done extensive work to identify biomarkers for gynecologic cancers. Among others, they have established the usefulness of Estrogen Receptor (ER), Progesterone Receptor (PR) and Androgen receptor (AR) as biomarkers in endometrial cancer. The MOMATEC2 study (ClinicalTrials.gov Identifier: NCT02543710), a phase 4 implementation trial, is currently ongoing for validation of ER/PR status as a stratifier for lymphadenectomy in endometrial cancer.
Molecular profiling of gynecologic cancers is a main focus of the group, with special interest in paired primary and metastatic lesions in endometrial cancer. This is motived by the fact that most cancer deaths are caused by development of metastases, and currently few treatment options are available for metastatic gynecologic cancers. Results from endometrial cancer were published in Nature Genetics in 2016 and is currently being followed-up in collaboration with Professor Beroukhim, The Broad Institute, USA. For cervical cancer, genetic alterations linked to subtypes of cervical cancer are of high interest and are studied in collaboration with Professor Ojesina, UAB, USA.
Combining molecular biomarkers and genetic data with imaging parameters derived from PET-CT and/or MRI provides exciting information on tumor characteristics and potential new imaging-based preoperative biomarkers. Both imaging and molecular biomarkers are explored in endometrial cancer orthotopic mouse models, based on cell lines or patient-derived xenograft (PDX) models. These models are also used for drug testing and validation of predictive biomarkers.
To aid in the differentiation between EECG1 and CAH preoperatively, Professor Krakstad and her group identified both PBK expression and preoperative imaging as promising biomarkers (Berg et al Oncotarget 2017). As a preoperative marker for aggressive endometrial cancers, they found L1CAM to be a predictive marker for lymph node metastases in preoperative curettage specimens and plasma samples, further strengthen the usefulness of this biomarker (Tangen et al British J Cancer 2017).
With focus on hormone dependent cancers, the group found high expression of GR to significantly associate with markers of aggressive disease and poor survival, also in multivariate analysis. The majority of metastatic endometrial cancer lesions express GR. GR may represent a therapeutic target in the adjuvant therapy of poor prognosis early-stage as well as metastatic endometrial cancer (Tangen et al Gynecologic oncology 2017).
In collaboration with Professor Romano, the group investigated the importance of the enzymes involved in the pathways controlling the intracrine estrogen generation in EC. High levels of the enzyme 17B-HSD1B, that generates active estrogens, associated with poor prognosis (Cornel et al, Moll Cell Endocrin 2017). In a follow-up study using various endometrial cancer models, they show that inhibition of 17β-HSD-1 efficiently blocks the generation of E2 from E1, suggesting that such inhibitors might represent a new endocrine therapeutic approach (Konings et al, J Pathol, 2017).
With focus on identifying therapeutic targets in metastatic disease, the group found that loss of HER2 expression is common in metastatic endometrial cancer lesions. Assessment of HER2 levels in the metastatic lesions may be important to define the potential benefit of anti-HER2 treatments in endometrial cancer patients (Halle et al 2017, British J Cancer).
The research group will continue to explore genetic alterations linked to progression of endometrial cancer from primary tumor to metastasis and increase the focus on genomic alterations linked to cervical cancer. They will continue the MoMaTEC2 trial and collect Quality of life (QOL) data during follow-up of endometrial cancer patients. They will also perform functional studies of identified driver genes, and study the complexity of hormones in endometrial cancer with a goal of exploring effects of drugs that are already approved for other cancer-indications.
Challenges in the field
With a tight link between endometrial cancer and obesity/high age, the incidence of endometrial cancer is expected to rise. Identifying specific patient populations that are likely to respond to therapy is therefore even more important. The increasing amount of genetic data generated from sequencing studies should be followed by functional studies to gain knowledge on tumor biology, to identify better biomarkers and to identify optimal treatment strategies for the individual patient.