DRES-20. APPLICATION OF ECOLOGICAL PRINCIPLES TO MANAGE TUMOR POPULATIONS: ADAPTIVE THERAPY
Authors: Brent A Reynolds, Loic P Deleyrolle
Journal: Neuro-Oncology (2017)

One of the more important enterprises in applied ecology has been the battle to control populations of damaging species that will wreck economic havoc on local economies. This “war on pests”, which may be seen in an analogous light to the “war on cancer”, has employed an array of approaches including chemical, predator, parasites and pathogens. As the initial attempts using high dose chemicals were unsuccessful in eliminating these pests the focus has changed to control; defined as reducing the pest below a target threshold defined by economic burden. The principal lessons that can be learned from the effort to control pest populations is: (1) more is not better, (2) resistance is multi-factorial involving several coexisting mechanisms & (3) complete eradication is not possible. Here we explore the feasibility of applying a successful tactic used in ecology to control pest populations, to a tumor population. The approach, referred to as adaptive therapy, is simple in that it modifies an existing treatment protocol using a well-established clinically applicable chemotherapy agent. Chemotherapy dosage is modulated on how the tumor is responding to treatment. If the tumor is stable or shrinking in size, the dosage of the chemotherapy is reduced. If the tumor is growing, the dosage is increased. We have applied this protocol to Patient Derived Xenograft [PDX] models of GBM in both a sub-q and orthotopic setting. In comparison to a metronomic dosing of TMZ we have found the adaptive dosing regimen to increase survival by 300% compared to the vehicle treated animals and by 50% compared to the metronomic dosing protocol. The cumulative dose of TMZ was significantly reduced [50%] and animals in the adaptive group maintained their body weight and had a higher Body Conditioning score when compared to the metronomic treated animals. The carbamate derivative, Disulfiram (DSF), a potent inhibitor of aldehyde dehydrogenase 1, ALDH1, crosses the blood-brain barrier and is used in treating alcohol dependency. Relatively nontoxic at low doses, DSF exhibits significant anticancer effects, when combined with heavy metals, such as, Cu or Zinc. In previous studies, we showed that, in glioblastoma cells, a copper-DSF complex inhibited the DNA repair protein, O6methyguanine-DNA methyltransferase, MGMT, a mediator of tumor resistance to temozolomide. Here, we examined, in greater detail, using a panel of four glioblastoma cell lines, the anti-tumor efficacy of the DSF-copper combination and investigated the underlying mechanisms underlying the actions of the combination. The effects of DSF-copper on temozolomide resistance was examined in vitro and in vivo in two methylator+ve GBM cell lines. DSF and copper, up to 100 uM, had little to no toxicity on any of the GBM cell lines in vitro. In contrast, combined with copper, DSF at 10 uM or less, was highly toxic in all the cell lines. The efficacy of the combination was highly dependent on the time and modestly dependent, on the schedule of exposure of the cells to DSF-copper and was correlated with the levels of cellular ROS production, MAP kinase activation and ALDH1 inhibition. The temozolomide sensitivity of all cell lines was enhanced significantly by the DSF-copper combination and only modestly by each agent alone. In vivo growth of two temozolomide-resistant, methylator+ve GBM cell lines was significantly suppressed and their temozolomide sensitivity enhanced by DSF-copper, effects that correlated with significant inhibition of MGMT in the tumor cells. GBM cells are highly sensitive to DSF-copper, dose-, time- and schedule dependently and reverses temozolomide-resistance in methylator+ve GBM cells. The findings support the use of DSF-copper as a treatment strategy for GBM.