Preclinical Evaluation of Small Molecule Inhibitors of IDH1 as an effective treatment of GBM and Lung Cancers

Malignant brain and lung cancers are lethal cancers with limited treatment options. Treatment efforts, however, have not translated into improved response rates, and underlined the overarching need to identify novel drug targets and to develop novel therapeutics to combat these dismal diseases. Research on metabolic adaption in cancer has witnessed a remarkable renaissance. It has become clear that changes in metabolism represent a hallmark of the pathogenesis of many, if not all cancers. However, the underlying molecular mechanisms are not well understood, and consequently, strategies for the rational development of therapeutics to target such metabolic adaption are only beginning to emerge. We discovered that isocitrate dehydrogenase-1 (IDH1) is overexpressed in high-grade brain and lung cancers in comparison to healthy tissue, and acts as a critical driver of tumor progression and therapy resistance. Using genetic inactivation strategies, we could show that suppression of cancer-associated IDH1 reduces tumor burden and increases survival of animal subjects bearing intracranial patient-derived GBM tumors. On a cellular level, tumor growth slows down, and cancer cells become more sensitive toward targeted therapies, in particular EGFR-inhibiting erlotinib. We will leverage this mechanistical knowledge to develop and preclinically characterize small molecule inhibitors of IDH1 as a novel treatment option of patients diagnosed with GBM and lung cancers. At the culmination of the funding cycle, this compound will be poised to enter the clinic as a cancer-killing agent, to improve and save the lives of patients suffering from GBM and lung cancers, two of the most deadly forms of cancer.