Meet Frank Winkler, an extraordinary medical mind leading research at the intersection of cancer and neuroscience. As a managing senior physician at the University of Heidelberg and the German Cancer Research Center, his work has transformed understanding and treatment of brain tumours. Explore how he’s breaking down disciplinary walls, revealing the connection between brain activity and tumour progression. Discover how his discoveries are revolutionising cancer treatment through tailored therapies.
Which wall does your research break?
Incurable brain tumors like glioblastomas remain a formidable challenge in modern medicine. While targeted therapies and immunotherapies have transformed other areas of oncology, these therapies are not effective in glioblastoma. The life expectancy of these brain tumor patients remains very limited, and their quality of life is affected by dysfunctions of the nervous system. Apparently, we did not understand these diseases well enough and thus were not hitting the right targets. To change that has always been the fundamental aim of my research. Therefore, my group has searched for completely novel disease mechanisms that have not been appreciated so far, and that can ideally be targeted by new therapies. The fundamental discovery was that our nervous system itself is highly relevant for brain tumor progression and therapy resistance. In other words, activity of the normal brain drives brain tumors. We demonstrated that neurons of the brain form stimulatory synapses with brain tumor cells, driving cancer growth and dissemination. Furthermore, brain tumor cells hijack mechanisms of neurodevelopment to extend long neural-like processes to invade and scan the brain, and to interconnect to one large tumor network. This network can self-repair itself and allows tumor cells to communicate with each other and with the normal brain. Based on these discoveries, two investigator-initiated clinical trials that disconnect these malignant networks have been launched in Germany, with funding from the German Ministry for Education and Research. My research breaks three walls: first, the wall to a better understanding of the “brain tumor organism”; second, the wall to novel therapy concepts that are tailored to target disease-specific mechanisms; and third, the wall between Cancer Research (Oncology) and Neuroscience (Neuromedicine) – a wall that kept both disciplines separated for a long time but that was needed to be torn down to make progress for cancer patients in the future.
What inspired or motivated you to work on your current research or project?
My primary motivation and also my inspiration comes from the brain tumor patients that I treat. The patterns of how tumors grow and recur in the brain let me think about the possibility that brain activity is stimulating tumor growth – an impression that has since been confirmed by many studies. Furthermore, the ability of the tumor to execute a (malignant) self-repair was also a strong impression from following many patients over the years. In addition, progress in science often depends on new technologies, and also on being open to follow new paths when you see unexpected things happen. This was the case when we applied a microscopy technology that I originally learned at Harvard during my postdoc, and refined and developed over the years with my research group. This so-called intravital two-photon microscopy allows us to study the behaviour and the interactions of single individual tumor cells deep in the brain of a mouse – in real time, and not just over some minutes to hours but over days to many months. This three-dimensional information with the most important fourth dimension – time – led to the unprecedented insights into neuro-cancer crosstalk that defines my research. When we first discovered how labeled brain tumors’ cells from patients scan and invade the brain and later interconnect with themselves to a neural-like network, the working hypothesis for a new research field was born: “brain-in-the-brain project”. As often in life and science, your first impression is quite valid. This very first, completely unexpected discovery stimulated our research since then, and the new field of “Cancer Neuroscience”.
In what ways does society benefit from your research?
The main benefit for society is the development of completely novel cancer therapies that target the neuro-cancer crosstalk: to stop tumors to form, to grow, to metastasize, and to resist therapies. Those therapies are aimed to disconnect neuron-tumor and tumor-tumor networks. Interestingly, since more than 100 drugs that interfere with neural signaling pathways are approved for other diseases than cancer, those can be potentially repurposed, next to drug development against early neurodevelopmental pathways that we identified to be hijacked by cancer, and not relevant for the normal functioning of the developed nervous system anymore. I have spearheaded clinical translation in all three areas, with the first clinical trials started that target neuron-tumor and tumor-tumor networks via repurposed drugs (see above), and with initiating a dedicated drug development program in my lab to discover new therapeutics. Currently working on brain tumors, we aim to translate many of those principles to tumor entities outside the brain, like melanoma, breast cancer and lung cancer. First results indicate that similar mechanisms might be in place there. All in all, the development of a new pillar of cancer treatment, “Neuroscience-instructed Cancer Therapy”, is on the horizon. Last but not least, the new research field of “Cancer Neuroscience” will not only stimulate more research in Cancer Research, but is already feeding back into basic and translational Neuroscience, including new ideas for other maladies of the nervous system, like neurodegenerative diseases.
Looking ahead, what are your hopes or aspirations for the future based on your research or project?
Being able to further develop the new research field of Cancer Neuroscience, and to see it flourish, with active participation of many cancer researchers and neuroscientists, and oncologists and physicians from neurological specialities. The first Heidelberg Conference on Cancer Neuroscience that I am organizing on July 18 and 19, 2023, exceeded all our expectations regarding the number of attendants: we expected 100, but where overwhelmed by registrations from all over the world, with 275 scientists able to attend in person. Experiences like that make be believe that we can expect much more progress in the next years and decade. This is particularly relevant for the development of Neuroscience-instructed Cancer Therapies: I would like to see this emerge to a new treatment pillar for cancer patients.