“Precision” oncology, or “personalized” oncology: These terms describe our aim, which is to be able to offer each individual patient their tailor-made therapy. While the traditional classification and therapy of cancer-related illnesses is generally based on the parent organ of the tumor, a good response to the chosen therapy is often dependent of molecular changes. These changes do not just differ in each cancer-related illness, but also from patient to patient. The Precision Oncology Program at the NCT (NCT POP) goal is to evaluate the individual pattern of change and to make optimum use of the available drugs and therapies.
The NCT Precision Oncology Program
The genetic material of the affected people is at the heart of this analysis: DNA samples from tumor cells and blood have to be compared, looking out for anomalies that only occur in the tumor. Depending on the type, tumor DNA sometimes shows only a few mutations, sometimes several hundred. Not all mutations are necessarily cancer-relevant. Ultimately, it is important to find out which mutations contribute to an individual patient's cancer.
The necessary platform to perform these analyses has been provided by the Precision Oncology Program and the Heidelberg Center for Personalized Oncology (DKFZ-HIPO). Based close by DKFZ and the NCT, DKFZ-HIPO is a genomic, proteomic and systems medicine platform and offers ideal conditions for preclinical and clinical research. With its sequencing program, it provides both human and technical resources in order to allow high-level processing of the genetic data, diagnostics and the subsequent development of a therapeutic procedure.
Entirely in the spirit of personalized medicine, today there are already certain medications that can only be prescribed if the associated mutation has been established by genetic analysis. The news now is the move away from finding evidence for one individual mutation, and towards generating a mutational profile of hundreds of mutations, a tumor's fingerprint so to speak. Setting out from here, we will investigate whether amongst the drugs available or drugs under development, there might be any that would target exactly the mutations that we have found in one of our patients.
Each mutation that presents a potential target for medications, must first be tested for its effects on body cells, the question being: Does the mutation also change the protein that provides the blueprint for the DNA? And does a mutated protein change the signaling in the cell development in such a way that cells will start growing uncontrollably, i.e. cancer develops? Only if this is the case will a drug really be effective.
Christof von Kalle, Chair of the NCT is convinced that “Genetic analyses of the tumor will allow us to assess whether a specific drug can work at all. This accelerates our choice of strategy significantly and increases the chances of survival and recovery.”
In some areas, we may have a few years to go, but our goal of personalized oncology is clearly defined: To offer each patient the treatment that gives them the best chance of survival. It is not about producing specific medicines for every patient, but about finding a combination of several therapies. By predicting which therapy will benefit which patient group, ineffective therapies can be avoided. Ultimately, unnecessary treatment cost will be pared down, potential side-effects reduced and patients will be treated more safely and more effectively, despite the additional cost for gene analysis and targeted medicines.
Herceptin is an antibody approved in 1998 and a commonly used drug. Herceptin is effective in around 25% of breast cancer patients, as it only works if a certain mutation is present. This mutation causes an overproduction of a protein molecule on the cell surface, a receptor called HER2. The cells receive intensified signals stimulating cell division. The cancer course of the disease in women affected with this mutation is considerably aggressive. However, patients with the HER2 mutation have a good chance due to to Herceptin. In the meantime, their treatment is even more successful than that of those patients without the mutation. The antibodies lock onto the overrepresented receptors, prevent them from passing on signals and at the same time, communicate to the immune defense to destroy the receptor.
BRAF blockers are one of the best examples for the combination from individualized diagnostics and targeted therapy. BRAF blockers are agents effective in 60% of skin cancer patients whose DNA has a particular mutation in the BRAF gene. The mutation effects permanent activation of the protein called BRAF, which stimulates uncontrolled cell division. The BRAF blocker binds directly to the mutated BRAF protein and thus blocks the signaling.
This does not function in all BRAF gene mutations, only in this particular one, which must be verified in the patient before treatment. Sometimes, patients suffering from a different type of cancer can still benefit from a therapy with BRAF-blockers, as the example of a patients with hairy cell leukemia demonstrated: This patient who no longer responded to chemotherapy proved to have precisely this mutation in the BRAF gene. Treated with a targeted drug that attacks this mutation, the patient went into spontaneous remission.