TH4RESPONS

Triple negative breast cancer (TNBC) and ovarian high grade serous carcinoma (HGSOC) are two poor-prognosis tumour subtypes with many molecular similarities. Recurrence and therapy resistance are related to the selection of resistant sub-clones during disease progression. Therefore, tumour heterogeneity (TH) is a major underlying mechanism for the dismal disease course of TNBC and HGSOC.
The TH4-RESPONSE project is based on the hypotheses that TH is a major mechanism of recurrence and therapy resistance of HGSOC and TNBC, and that mechanisms of TH will become evident during treatment, as part of an evolutionary adaptation of tumour cells. The impact of TH on patient outcome can be defined in large and well-characterized patient cohorts, preferably from clinical trials.
Aims of our project are (1) to define molecular features of TH as drivers of chemotherapy resistance in TNBC and HGSOC, (2) to profile TH and tumour evolution in tissue samples and liquid biopsies of ovarian cancer, (3) to assess the clinical utility of differences in molecular alterations in breast cancer between primary tumour and metastases, to (4) identify resistance mechanisms against targeted therapy in PDX models, and (5) to integrate the results for further validation including prospective validation studies as well as development of concepts for future validation trials.
This multidisciplinary project including pre-clinical, clinical, pathological, and bioinformatics expertise will assess the various aspects of tumour heterogeneity of TNBC and HGSOC. In a discovery/validation approach we will define molecular biomarkers of TH in clinical samples from primary, recurrent, and metastatic TNBC and HGSOC using multi-omics techniques. Pre-clinical investigation of PDX models will render biomarkers of PARP inhibitor resistance. Based on large biobanking resources including sample cohorts from multicenter clinical trials as well as in prospective studies, the defined biomarkers will be validated the biomarkers in terms of their clinical utility.
TH4-RESPONSE will lead to integration of results into new biomarker assays to assess and monitor tumoural heterogeneity, which will be translated into the routine diagnostic workup of cancer patients. Identification of actionable oncogenic drivers will help to design novel therapeutic strategies, and new clinical trial concepts will result in diagnostic and therapeutic options, transferrable to the clinic, with a high level of evidence. Identification of clinically relevant features of tumour heterogeneity will help to understand the biology of the two most aggressive tumour types in women. In the long run, the results of the TH4-RESPONSE project will contribute to reduce mortality from breast and ovarian cancer.