ET-15 APPLICATION OF A COMBINATORIAL NATURAL PRODUCT THERAPY FOR THE TREATMENT OF HIGH-GRADE GLIOMAS

Application of toxic compounds used at maximum tolerated dose until resistance develops is the most commonly experienced outcome in cancer therapy. Based on successful concepts borrowed from the field of ecology to manage pest populations, we developed a therapeutic strategy relying on the use of multiple independent and non-toxic stressors that enable efficient horizontal and vertical targeting of the tumor. Our treatment (CA.001) uses a combination of two distinct approaches. The first aspect of our approach involves the simultaneous application of three natural products (curcumin, epigallocatechin-3-gallate and sulforaphane) that have previously demonstrated anticancer properties and have a documented safety profile. Each individual natural product (NP) is able to inhibit in vitro the expansion of glioma cancer stem cells with the combination of all three compounds producing a synergistic effect. The NP combination also demonstrated greater ability to decrease tumor progression and increase survival in a clinically relevant orthotopic xenograft model of glioma. The second component of our treatment is a metabolic targeting through dietary alteration limiting the intake of carbohydrates, thereby reducing glucose metabolism, which represents the main source of energy production for cancer cells (for details see poster Martuscello et.al.). Animals intracranially xenografted with glioma cells show greater survival when treated with the combination of the metabolic treatment coupled with the NPs. Notably, CA.001 works synergistically with the conventional chemotherapy temozolomide (TMZ) and has proven to be an effective therapeutic against TMZ-resistant glioma cells. Interestingly, CA.001 is able to sensitize TMZ-resistant cells to TMZ. Additionally, we demonstrated the absence of toxicity related to CA.001 treatment based on organ health- evaluated by clinical chemistry measuring blood enzyme levels and by organ weight comparison, as well as hematology- using complete blood count. Collectively, these data suggest CA.001 as a viable non-toxic and affordable antineoplastic treatment to treat high-grade glioma.