Breaking the Wall of Targeted Brain Tumor Therapy
Breaking the Wall of Targeted Brain Tumor Therapy
Global Call 2025 Finalist Interview: Life Sciences
Ingo Mellinghoff is a physician-scientist whose research focuses on the characterisation of aberrant signalling pathways in cancer and new precision medicine paradigms to target these pathways. Mellinghoff’s work has led to practice-changing advances in the treatment of central nervous system cancer. He is an elected member of the American Society of Clinical Investigation and the Association of American Physicians. Mellinghoff currently serves as Chair of the Department of Neurology and the Evnin Family Chair in Neuro-Oncology at Memorial Sloan Kettering Cancer Center.
Which wall does your research or project break?
My research is breaking the Wall of Targeted Brain Tumour Therapy.
Gliomas are the most common malignant primary brain tumour in adults. The current treatment of adult glioma includes a combination of surgery, radiation and chemotherapy. This treatment is not curative and associated with considerable toxicity. Mutations in the active site of the metabolic enzyme isocitrate dehydrogenase (IDH) occur in most younger patients with glioma. Mellinghoff’s laboratory contributed to the initial characterization of the mutant IDH enzyme, including its role in establishing the glioma CpG island methylator phenotype (CIMP) and its ability to inhibit histone demethylation resulting in a block in cell differentiation.
Ingo Mellinghoff’s laboratory later showed that a selective inhibitor of the mutant IDH enzyme induced histone demethylation, promoted the expression of genes associated with cellular differentiation and impaired the growth of IDH1-mutant--but not IDH1-wild-type--glioma cells in vitro and in vivo.
These insights provided the rationale for clinical exploration of IDH inhibitors for glioma therapy. Mellinghoff played a critical role in the development of Vorasidenib, an oral, first-in-class dual inhibitor of mutant IDH1 and mutant IDH2. Dr. Mellinghoff led the Phase 1 trial to define the tolerability of Vorasidenib. He also led a surgical trial to determine the optimal biologic dose of Vorasidenib based on inhibition of the mutant IDH enzyme in tumour biopsies and finally the pivotal international Phase 3 trial which showed that Vorasidenib significantly extended progression free survival and was well tolerated. The FDA approval of Vorasidenib in August 2024 marked the first new drug treatment for diffuse glioma in over 20 years and the first molecularly targeted drug to be approved in this disease.
What is the main goal of your research or project?
The long-term goal of Mellinghoff’s research is to improve the effectiveness and reduce the toxicity of currently available treatments for cancer patients, with a particular focus on patients with cancers of the central nervous system. This will require a deeper understanding of the molecular circuitry of brain cancer cells, their interactions with the tumour microenvironment and mechanisms of resistance to current therapies.
Ingo Mellinghoff leads a translational research group that aims to narrow the gap between target identification and validation in the laboratory and biomarker-directed clinical drug development. There are many different types of primary brain tumours, each with a unique set of genomic and epigenetic alterations that are associated with unique vulnerabilities. Dr. Mellinghoff’s group is focused on identifying and exploiting these vulnerabilities using new classes of cancer therapeutics.
In addition to his work on IDH-mutant glioma, Mellinghoff’s preclinical and clinical studies with the first-in-class Bruton Tyrosine Kinase inhibitor ibrutinib for the treatment of primary CNS lymphoma (PCNSL) led to the inclusion of ibrutinib in the NCCN treatment guidelines for recurrent or refractory CNS lymphoma. The Mellinghoff lab also identified and characterised extracellular epidermal growth factor receptor (EGFR) mutations in glioblastoma, redirecting current efforts to target EGFR in this disease.
Dr. Mellinghoff’s research spans from cell line cultures to clinical trials and includes the evaluation of emerging technologies to quantify the detection and longitudinal tracking of tumour-derived DNA in cerebrospinal fluid and the quantification and spatial mapping of tumour cells and immune cells within a complex and dynamic tumour microenvironment.
What advice would you give to young scientists or students interested in pursuing a career in research, or to your younger self starting in science?
Follow your passion and (learn to) enjoy difficult challenges. Remember that, at least in the life sciences and medicine, the status quo is rarely a good place to be.
