The Interdisciplinary Laboratory – Part 3/4
The development of therapy resistance is the main reason for the failure of cancer therapies. In most cases, cures are achieved in patients diagnosed with localised disease that is completely removed by surgical treatment, often in combination with radiotherapy and adjuvant drug therapy. If the cancer has already spread (‘metastasised’) in patients at the time of diagnosis and in blood cancers (leukaemias and lymphomas), systemic therapies are necessary, which often improve survival time and quality of life, but rarely lead to a cure. Although the cure rates for paediatric cancers are higher than for adult cancers, there is still a large proportion of patients who cannot be cured.
There are basically two types of resistance in cancer: 1) intrinsic resistance, in which the cancer cells do not respond at all to the available therapies from the outset, and 2) acquired resistance, which develops after an initial response to therapy and leads to therapy failure and death of the patient.
Acquired resistance is much more difficult to study, as the development of resistance is the consequence of a complex evolutionary process. In order to improve our understanding of these mechanisms, model systems are required that depict the process of resistance development. However, the establishment of such models for acquired resistance alone is very time-consuming and labour-intensive. The establishment of a single resistant cell line can take a year or more. As a result of this effort, there are traditionally very few models for acquired resistance in cancer.
Prof Jindrich Cinatl and Prof Martin Michaelis have systematically addressed this gap in their work and over the years have built up the Resistant Cancer Cell Line (RCCL) Collection, by far the world’s largest collection of models for the development of resistance in cancer. The RCCL Collection currently consists of 2,800 resistance models that represent resistance to 16 types of cancer and more than 100 antitumour agents.
In its current form, the RCCL Collection is already a much sought-after tool that enables research that would not be possible without it. This is evidenced by the more than 120 academic research groups, pharmaceutical companies and biotechnology companies working with cell lines from the RCCL Collection. These include world-leading academic cooperation partners such as the German Cancer Research Centre, the Sanger Institute, the Broad Institute, the Institute for Cancer Research and the Karolinska Institutet as well as leading pharmaceutical companies such as Eli Lilly, Abbvie and Servier.
The RCCL Collection is also well networked in Frankfurt am Main. Cooperation partners at Goethe University include the Department of Paediatrics and Adolescent Medicine, the Medical Clinic 2 (Haematology, Oncology, Haemostaseology, Rheumatology, Infectiology), the Department of Urology, the Department of Dermatology, Venereology and Allergology, the Department of Radiotherapy, the Neurological Institute – Edinger Institute, the Institute for Clinical Pharmacology, the Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, the SIP – Dr. Senckenberg Institute of Pathology, the Georg-Speyer-Haus, the Institute of Pharmaceutical Technology and the Institute of Pharmaceutical Chemistry. In addition, the Interdisciplinary Laboratory co-operates with Merck KGaA, Darmstadt, using the RCCL Collection.
With the help of the RCCL Collection, numerous scientific findings have already been made that would not have been possible without its existence. By comparing sensitive cancer cell lines with their drug-adapted sublines, it was shown that a protein called SAMHD1 is suitable for predicting the response to standard therapy in a specific form of leukaemia (acute myeloid leukaemia). This will make it possible to better target therapies for acute myeloid leukaemia patients in the future. Some patients can be spared the burden of ineffective therapies and instead be offered a therapy with a higher probability of success.
In addition, previously unknown insights into the heterogeneity of resistance development processes could be gained: When the same system or cancer cell line is repeatedly adapted to the same drug, the resulting sublines exhibit different resistance mechanisms. This means that it is not possible to predict how a cancer will behave in response to a particular cancer therapy. Accordingly, methods will have to be developed to monitor the development of the cancer in response to cancer therapies using so-called ‘biomarkers’ and, in the event of failure, to adapt the treatment on an individualised basis.
Great progress has been made in the monitoring of cancer patients with so-called ‘liquid biopsies’, which make it possible to track evolutionary processes in the cancer cells in a patient using samples taken from the blood. However, the necessary understanding to evaluate the information available in the liquid biopsies in such a way that a targeted therapy adjustment would be possible is generally lacking. This is where the RCCL Collection can serve as an important bridge, as the detailed investigation of resistance mechanisms in the existing models can identify biomarkers that indicate which therapy is most likely to be effective in a particular patient. At the same time, new targets for the treatment of patients whose cancers do not respond to the drugs used to date can be discovered as part of such investigations.
In addition to the resistant cancer cell lines, the RCCL Collection also includes other exclusive cell culture models. These include chronically cytomegalovirus-infected cell lines. Cytomegalovirus is the most common opportunistic pathogen in immunosuppressed cancer patients. The cell lines make it possible to investigate the interaction of these viruses with (cancer) cells. In addition, an optimised cell culture system has been developed to identify new active substances against SARS-CoV-2, the coronavirus that causes COVID-19. Infectious diseases pose a major risk, particularly for cancer patients who temporarily lack a functioning immune system following a stem cell transplant.
