Clinical Cooperation Unit Molecular Hematology/Oncology
Prof. Dr. Alwin Krämer
© dkfz.de
Cancer metastasis constitutes the major cause of cancer-related mortality and a prime challenge in understanding the mechanisms at play, while translating research findings into better patient outcomes.
The Clinical Cooperation Unit Molecular Hematology/Oncology has its translational and clinical research focus on Cancer of Unknown Primary (CUP). Basic science projects center around Chromosomal Instability (CIN) as one of the major mechanisms paving the way towards metastasis.
Cancer of Unknown Primary (CUP) is a highly aggressive, primary metastatic malignancy, in which only metastases but no primary tumor can be identified. Due to the lack of an identifiable primary tumor, treatment options are limited and patients suffering from CUP experience a dismal prognosis.
Owing to its primary metastatic nature, CUP constitutes a paradigm metastatic disease and therefore enables insights into mechanisms of cancer progression and metastatic seeding in general. Moreover, as the tissue of origin remains elusive, CUP additionally serves as a true tumor-agnostic model disease. Within this scope, our translational research program aims to unravel the mechanisms underlying cancer metastasis starting with in vitro models and extending into work with primary patient samples (tumor tissue, blood, patient-derived organoids), while constantly linking the results to clinical parameters.
Using genome-wide DNA sequencing, transcriptomics and methylome analysis, we have gained essential insights into the key molecular features of the disease. Based on these findings, and with the ultimate goal of improving treatment options and developing innovative strategies to overcome treatment failure, we conduct large multi-center and international precision medicine clinical trials for newly diagnosed as well as relapsed or refractory treatment settings.
Our efforts have led to the largest randomized phase II trial ever conducted in CUP, which recently and for the first time proved the efficacy of tumor-agnostic, molecularly tailored treatments, constituting a major milestone in the treatment of CUP and a decisive step towards integrating precision oncology into standard medical practice.
Chromosomal instability (CIN), a central feature of human malignancies, contributes to genetic heterogeneity, clonal evolution and ultimately to metastasis. Accordingly, our group has a long-standing interest in exploring the molecular mechanisms underlying CIN and untangling its role in the metastatic process and the development of CUP as well as metastatic cancer in general.
Future Outlook
Future clinical trials focus on the use of antibody-drug-conjugates, a promising approach that has revolutionized the treatment of several cancer entities, in relapsed or refractory CUP syndrome. Using patient-derived samples acquired within clinical trials, we use multi-omics approaches to molecularly profile and classify CUP tumors, understand CUP biology as well as tumor-host interactions, and predict treatment efficacy based on PDO models high-throughput drug screening. Within an integrated approach, and while firmly linking research and clinical practice, we aim to determine CUP tissues of origin and their relevance for treatment results, while enabling molecularly informed therapies, thereby contributing to innovative diagnostic and treatment strategies and improved patient outcomes. Due to the tumor-agnostic nature of CUP, we will ultimately use the data assembled to transform cancer nomenclature from being based on merely clinicopathological features into a true molecular classification system.
