Standardized Next Generation Diagnostics for Molecular Tumor Pathology - A Prerequisite for Predictive Translational Medicine
Cancer research has shown that the molecular characteristics of tumors can vary significantly between patients, even in tumors from the same organ. However, it is these molecular characteristics that determine which treatment a tumor will respond to. Cancer researchers are also developing new treatments that target molecules with tumor-specific changes. Using molecular diagnostics to identify the molecular characteristics of cancer cells for each patient would make it possible to offer personalized treatment with a higher chance of success.
The scientists working on this project are developing methods for molecular cancer diagnosis that are suitable for broad application in a large number of cancer centers. With new sequencing methods it is already technically possible to detect the cancer genome – and the molecular profile of individual tumors – in a time- and cost-efficient manner. These methods are already been used in research. The DKTK scientists are now establishing and verifying high-throughput methods that will enable reliable, time- and cost-efficient application of these sequencing methods for many types of cancer and large numbers of patients. To start with, they are improving the necessary processes for preparing samples and sequencing. Then they are comparing and standardizing the diagnostic methods at the participating university hospitals – initially through parallel sequencing of the relevant sections of the cancer genome for three types of cancer: breast cancer, colon cancer and lung cancer. As a result, this project will provide a standardized molecular diagnostic method for broad application in oncology – a necessary precondition if increasing numbers of cancer patients are to benefit from personalized cancer treatment.
INFORM - INdividualized Therapy FOr Relapsed Malignancies in Childhood and Adolescence
Cancer in children can now be cured in around 75 percent of cases. This is due in large part to the systematic development of combination chemotherapy. If the cancer returns, however, cure rates are, with a few exceptions, very low: the children’s cancer cells have become resistant to the chemotherapy. In recent years, scientists have increasingly been able to identify molecular changes in cases of childhood cancer using cancer genome sequencing. They have discovered numerous new cancer-specific molecules that are suitable targets for targeted cancer drugs. Some of these drugs are already licensed for treating other types of cancer, while some are still at the development stage and are not yet used to treat relapsed tumors in children. For this, physicians would first have to identify characteristic molecular changes in the cancer cells of each young patient.
The aim of INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood and Adolescence) is to establish an innovative clinical process to analyze the tumor cells of children with cancer recurrence so that they can be offered an individualized treatment strategy if the relevant molecular changes are present. For this, the researchers need to take a tumor sample and a blood sample, prepare the samples and employ various sequencing methods, followed by a computer analysis of the complex data, to identify the individual molecular changes in the cancer cells and draw up a personalized treatment recommendation. Experts in 11 different types of children’s cancer, including brain tumors, leukemia and bone cancer, are involved in INFORM. In an initial phase, the register trial, the processes mentioned above will be established nationwide across Germany, involving all children’s cancer centers. Sequencing will take place at one location, so the processes will be standardized. The intention of the physicians and scientists is to establish the necessary standardized processes in a minimum timeframe. In the second phase, the clinical trial, the pediatric oncologists will use these molecular diagnostic processes to offer children throughout Germany with cancer recurrence personalized treatments wherever possible. These new treatment methods will be accompanied by scientists, who will study how well the patients’ cancer cells respond to the various drugs. This is a unique opportunity to further improve cancer treatment in children.
DKTK-RadPlanBioPlatform: Focus on glioma and rectal carcinoma
With radiotherapy, patients are treated with different radiation strategies (different radiation doses, radiation techniques, combination treatments, etc.), depending on the characteristics of their tumor, and they respond differently to treatment. The tumor is analyzed carefully before and after treatment, e.g. using imaging processes and tumor biopsies. Documenting the treatment parameters and outcome, in compliance with current data protection legislation, is extremely valuable for improving radiation therapy. However, the necessary data are very complex and are usually recorded in different ways by the different clinics, yet in order to obtain valid results, the analyses have to include data from several clinics (multicenter studies).
The aim of this project is therefore to develop DKTK-wide research infrastructure (the RadPlanBio platform) and to start using it for scientific research. Firstly, the results of completed radiotherapy treatments for brain tumors and rectal cancer from all DKTK sites will be recorded in a standardized database covering all the centers. This will enable scientists to analyze the treatment methods and outcomes, as well as biological, technical and imaging parameters, to identify patient groups that might respond particularly well or particularly poorly to certain treatments. In addition, the scientists are formulating specific questions to be answered in multicenter, randomized clinical trials. One of the aims is to identify molecules and tumor changes – through tumor biopsies and imaging methods respectively – which could be used to predict a successful treatment outcome. This will form the basis of subsequent trials to personalize cancer treatment.
PSMA: A multicenter study for clinical evaluation of the novel PET tracer Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)]([68Ga]-PSMA) for diagnostis in prostate cancer patients using PET
Prostate cancer is the most common form of cancer affecting men in Germany and the second most common worldwide. In Germany alone, 77,300 new diagnoses and 10,400 deaths were registered in 2012 (GLOBOCAN 2012 (IARC)). The mortality rate is due in large part to the fact that patients often suffer a relapse after initial treatment of the primary tumor.
This is why the DKTK scientists have set themselves the goal of developing a new noninvasive diagnostic method for early detection of primary and recurrent tumors for prostate cancer. Tumors can be treated more effectively in the early stages. The scientists are concentrating on a particular receptor molecule, prostate-specific membrane antigen (PSMA), which is overexpressed in all stages of prostate cancer. It is a membrane-bound protein that is 100 to 1000 times more abundant in prostate cancer cells than in normal prostate cells. A PSMA-binding molecule, or PSMA ligand, should therefore accumulate in the prostate tumor. Scientists in Heidelberg recently developed a radioactively marked PSMA ligand (68Ga-PSMA-11) for positron emission tomography (PET) that does in fact accumulate specifically in tumors and can be used for PET/CT imaging. Initial research using a limited number of patients indicates that this method will enable improved diagnosis of prostate cancer. Thanks to cooperation between the DKTK centers and other national and international university hospitals, it will be possible to run a prospective multicenter clinical trial (Phases 1 and 2) using the new 68Ga-PSMA-11 PET radioligand. A radioligand produced under standard conditions will be used to test the PSMA diagnostic method for safety and accuracy in a larger number of patients and to improve it further. This is a necessary step before the new method can be used in routine diagnostic practice. If the physicians and scientists involved in the trial confirm the diagnostic benefits of the PSMA ligand for prostate cancer, it will have a fundamental impact on the direction of prostate cancer therapy and treatment. In particular, it will open up a new avenue for cancer therapy: radioactively marked PSMA ligands can be administered intravenously and used for targeted “internal radiation” of the prostate tumor. In this process, the radionuclides bound to the PSMA ligands and accumulated in the tumor release a therapeutic dose of radiation for a limited time. A similar nuclear medicine treatment (radioiodine therapy) has long been used for the successful treatment of thyroid cancer.
LACID: LSD1 as anticancer target in the clinic (TRANSATRA) and in drug discovery
In cases of acute myeloid leukemia (AML), particularly in older patients, standard chemotherapy treatment is often unsatisfactory. Scientists believe that a protein that is overexpressed in this type of cancer, lysine-specific histone demethylase 1 (LSD1), is a very promising target for a new AML therapy. This protein modifies genetic expression, a phenomenon referred to as epigenetic regulation, which is involved in the development of cancer.
In the first stage of this project, DKTK physicians are researching treatment based on LSD1 inhibition in AML patients. They are making use of the fact that an LSD1 inhibitor, TCP (tranylcypromine), is already licensed for use in human medicine – to treat depression – and has few side effects. In cell cultures and animal experiments, TCP has been found to be very effective in combination with another active substance, ATRA. Together, they block the growth of the AML cells. Now the physicians are offering AML patients who do not respond to established therapies this TCP/ATRA combination therapy as part of a clinical trial. They are studying how well patients tolerate the treatment and the molecular impacts on their tumor cells. In a second approach, scientists are studying namoline, another LSD1 inhibitor. They are using structural analyses to produce improved versions of the inhibitor, testing their effectiveness in the laboratory initially. They are particularly interested in seeing how the molecular impacts on AML cells compare with the TCP results in patients with AML.
Since LSD1 also plays a role in other types of cancer, such as brain tumors, colon cancer and prostate cancer, experts at the various DKTK centers are testing the effectiveness of the new LSD1 inhibitors in these tumor cells as well. The focus is on discovering the modes of action in the various tumors. The scientists also aim to use the findings from the treatment of AML patients to develop better therapies for other types of cancer.