In many types of cancers, drug-resistant cells arising after treatment with a targeted therapy or chemotherapy drug show a metabolic profile that is distinct from the susceptible cells. Rapidly growing cancer cells that are sensitive to current therapies typically show enhanced activity of glucose uptake and glycolytic degradation of glucose to lactate to support their energy and biosynthetic needs. In contrast, the resistant subpopulations arising from many therapeutic treatments are slow growers that are highly dependent on mitochondrial metabolic activities - Krebs cycle and oxidative phosphorylation (OXPHOS) – for their biosynthetic and bioenergetic needs. These resistant cells harbor a greater ability to metastasize and initiate tumors, and therefore, eradicating the resistant subpopulations is a crucial aspect of modern anti-cancer drug development. The resistant population’s dependence on mitochondrial metabolic activities makes it highly susceptible to the metabolic regulators targeting OXPHOS, and the combination of OXPHOS regulators has been proven to be an effective treatment option in suppressing the recurrence of cancers in a wide variety of preclinical studies. The goal of ImmunoMet’s Cancer Metabolism Program is to develop novel small compounds that selectively kill the resistant subpopulations by targeting their unique metabolic activities and to combine our drugs with current therapies to suppress cancer relapse.
Metformin, an antidiabetic drug of the biguanide class approved and available for more than
20 years, is a metabolic regulator that has been shown to inhibit tumor growth in a number of preclinical studies. However, the preclinical efficacy of metformin has so far failed to translate into clinical success. ImmunoMet has identified a series of biguanide-based molecules that show synergistic effects with current anticancer drugs in suppressing the emergence of resistant cells to current therapy drugs. ImmunoMet compounds preferentially accumulate in tumor tissues and inhibit cancer stem cell growth, metastasis and the emergence of resistant cancer cells both in vitro and in vivo. We plan to initiate the first patient studies in 2016.
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