Hall 123

The soft underbelly of cancer cells; Acquired vulnerability of glioblastoma cells to catastrophic vacuolization and death

Satish Kitambi

Division of Molecular Neurobiology, Karolinska Institute, Sweden

Research over past decades have provided extensive knowledge on cellular processes of growth factor signaling, apoptosis, autophagy, senescense, cell cycle and DNA repair which have been instrumental for understanding physiology as well as cancer biology. The identification of such core “driver” pathways in tumor formation has steered drug development to targeted therapies. We took an entirely new strategy by hypothesizing that the marked cellular changes in cancer cells leads to acquired vulnerabilities. Finding such “achilles heel” should open for conceptually new treatment strategies. We identified the cellular process of macropinocytosis which when targeted with a small molecule named Vacquinol-1 result in catastrophic vacuolization and cell death of patient-derived glioblastoma cells. Macropinocytosis is a unique mode of endocytosis where extracellular fluid is internalized into vacuoles in a clathrin- and calveolin-independent manner. Little is known of cellular mechanisms and pathways of macropinocytosis and even less its relation to cancer. Vacquinol-1 has very good preclinical characteristics and oral administration of Vacquinol-1 in animal models of patient-derived glioblastoma multiforme reverses disease progression and markedly prolongs survival, opening for a conceptually new mechanism and class of drugs that can be exploited for combating this deadly disease.