One of the best known plant disease outbreaks of all time was the Irish potato famine of 1845 to 1847 when the late blight pathogen, Phytophthora infestens, devastated the potato crop and caused more than one million deaths in Ireland. Potatoes are still plagued by disease but luckily most countries do not depend on potato as much as they did in Ireland in the 1800s. Producing disease-free potatoes, however, has come at a huge cost. To combat major diseases, such as late blight and common scab, 64 × 10 6 kg of pesticides are sprayed on potato fields each year. The costs associated with these measures are not only financial; environmental costs, although less easy to quantify, are significant and include negative impacts on natural ecosystems and the contamination of groundwater, lakes, and rivers. Our search for the "perfect" potato, i.e., one that has good processing qualities and disease resistance, has gained new momentum with the emergence of genomic technologies. Through functional genomics we will gain a better understanding of the genes responsible for tuber quality traits and those responsible for disease resistance. With a collection of desirable genes in mind, we can again use genomics as a diagnostic tool to search for these genes in the wide variety of potatoes around the world and to follow their transfer by classical breeding. This paper describes a research program currently underway in Canada that uses functional genomics to improve the potato.

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Glioblastoma (GBM) displays aberrant expression of several receptor tyrosine kinases (RTKs) leading to worse prognosis. Despite aggressive treatment including surgery, radiation and the alkylating agent temozolomide (TMZ), GBM tumors counteract deleterious effects of treatment-induced reactive oxygen species (ROS) leading to resistance to standard treatment. Likewise, expression of the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT) plays a key role in resistance to TMZ.We previously reported a potential link between MGMT expression and decreased angiogenesis in GBM. The differential expression of MGMT affected response to sunitinib, a multitargeted RTK inhibitor with anti-angiogenic properties FDA-approved in different cancer types. Notably, TMZ-resistant GBM MGMT-positive cells were more vulnerable to sunitinib treatment compared to isogenic MGMT-negative cells. We further provided evidence for a positive relationship between MGMT and the antioxidant enzyme, thioredoxin reductase 1 (TrxR1) in GBM. The TrxR1-targeting drug Auranofin, FDA-approved for rheumatoid arthritis generated ROS and induced more cytotoxic effects in GBM cells displaying low expression of MGMT and TrXR1. We hypothesized that sunitinib-induced anti-proliferative effects might sensitize GBM cells to Auranofin. We showed that MGMT-negative GBM cells, which displayed lower levels of TrxR1, were more vulnerable to Auranofin than MGMT-positive cells. The ROS scavenger N-acetylcysteine (NAC) reverted the cytotoxicity of Auranofin suggesting ROS-mediated cytotoxic effects. Conversely, Sunitinib exhibited ROS-independent anti-proliferative effects in MGMT-positive cells. Remarkably, sequential treatment using sunitinib pre-treatment (2 hours) followed by Auranofin (24 hours) significantly decreased cell viability, clonogenicity, increased ROS, decreased TrXR1 and MGMT expression and sensitized MGMT-positive GBM cells resistant to Auranofin. NAC reverted these synergistic effects, suggesting ROS-mediated mechanism. Our study provides new insights into the modulation of the cellular redox homeostasis using sequential sunitinib and Auranofin. This will enable repurposing Auranofin and sunitinib, two drugs with a known safety profile for an effective therapeutic strategy for GBM patients.

Glioblastoma multiforme (GBM), the most common and advanced primary brain malignancy in adults remains an incurable disease, despite aggressive treatment with surgery, radiation therapy and chemoradiation using the alkylating agent, Temozolomide (TMZ). PRIMA-1MET (APR-246), a small molecule designed to restore mutant (mut)p53 function has been shown to affect cellular redox status through targeting thioredoxin reductase 1 (TrxR1) in wild-type (wt)p53 cancer cells. We have recently shown that PRIMA-1MET exerts cytotoxic effects status preferentially in GBM cell lines expressing low levels of the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT), known for its role in resistance to TMZ. We hypothesized that PRIMA-1MET mediates its growth inhibitory effects by modulating the redox balance and investigated the potential relationship between MGMT, redox balance and TrxR1. We show that PRIMA-1MET decreased TrxR1 expression levels preferentially in MGMT-low expressing isogenic GBM cell lines. Using pharmacological agents that modulate reactive oxygen species (ROS) levels i.e., ROS scavenger, N-acetylcysteine and ROS inducer, L-Buthionine-Sulfoximine, we show that PRIMA-1MET exerts its growth-inhibitory effects through increased ROS. Strikingly, we identified a novel positive relationship between MGMT and TrxR1, wherein high MGMT expression is associated with high expression of TrxR1 and low levels of ROS. Treatment with the MGMT inhibitor, O6-Benzylguanine, or the TrxR1-targeting FDA-approved drug Auranofin validated our findings. Interestingly, the latter exerted significantly more pronounced cytotoxic effects compared to PRIMA-1MET in GBM cell lines. Additional studies are warranted to assess PRIMA-1MET in combination with TrxR1-targeting therapies and propose repurposing of Auranofin as a novel strategy to improve the dismal outcome of patients with GBM.