 My name is Dr Stephanie Virger. I'm a senior lecturer at the University of Northumbria in Newcastle-upon Tyne in the United Kingdom. Pretty soon I'll introduce you to my PhD student, Gina Abdelhal, who is a student in my lab working with another student and she's the first author of the review published in 2020, which is entitled Reversing Oncogenic Transformation with Iron Collation. And as I say, I'll introduce Gina pretty soon who will talk to you about her research area, what she's found, her key findings in the review we hope to achieve in the lab in the future. So my work, to take a little bit step back and talk about where I'm coming from, supports the primary goal of anti-cancer drugs and so by that I mean to selectively interact with molecules essential for cancer cell survival. In that vein, I have extensive background in cancer drug discovery. I have extensive experience in preclinical evaluation of novel therapeutics with DNA repair inhibitors. And lots of my research has been looking at those drugs as potential to be used with combination with current cancer therapies or a standalone therapies in their own right. I've supported anti-cancer drug discovery projects in many different ways, for example, by investigating their interactive effects of proteins involved in sensing and responding to DNA damage, by developing and validating pharmacodynamic biomarkers, agents progressing to clinical trials, and also by evaluating enzyme inhibitors designed to exploit underlying molecular defects in a range of human cancers. But overall, the key focus of my research has always been proof of principal testing of preclinical lead compounds. And as I say, this will lead into discussing both the review and the work that Gina is currently doing. The work that I've done evaluating agents progressing to clinical trials and in helping to develop biomarkers has contributed towards, for example, the successful introduction of poly-ADP ribose polymerase, or let's call them PARP inhibitors, into patients. And most recently in 2019, Rucaparib, which is a first class PARP inhibitor that I was involved in the in vitro testing of, was announced by Clovis Oncology to be made available for women. So the major research achievements that I've had, first of all, as a young PhD student, was to show the identification of a competition as well as a cooperation between two particular DNA repair enzymes. So poly-ADP ribose polymerase that I've already introduced, and another enzyme called DNA-dependent protein kinase. And what this work did was further the understanding that we see when we have overlapping and competing pathways in cancer cell signalling. And in particular, it highlighted the potential for combination therapies that can be used to treat cancer. I was also involved in demonstrating for the first time that enzyme PARP1 has a role in DNA double-strand break repair. And I have to admit this data was received with a lot of apprehension at first, and made a huge amount of evidence that PARP was mainly only involved in basic decision repair. This observation was recognised widely as needing further investigation. And many studies did actually swiftly build on that work that I had done. And from there, this led to the important identification of a backup role for PARP in homologous recombinational repair. And showing this homologous recombinational repair defective tumours were far more sensitive to PARP inhibitors than those that were not defective. And thus the role for stand-alone therapy with PARP inhibitors, particularly in these bracket-efficient breast and ovarian tumours, was born. One of the other things that I've been involved in demonstrating a very controversial role for PARP1 and another enzyme, a taxiotel angiectasia mutated ATM, the way in which they mediate cell survival by a nuclear factor capybi, and not through the widely purported DNA repair pathways that everybody was publishing on. And the reason I mention that is because, although it was met with great scepticism at the time, and it's only recently become a field of study and an approach to mediate cancer therapy, why the reason that work was so important was that it highlighted the need for a molecular understanding of aberrant singling pathways in cancer in order for targeted cancer therapy to work. So, where am I now? Well, currently I have a number of collaborations with synthetic chemists, both at Nathumbria University and Newcastle University. And here at Nathumbria University, we're exploring the underlying biological mechanisms of novel therapeutics, both alone and in combination with some of those repair inhibitors that I've mentioned. And this portfolio of research that I have includes exploring the LAT1 transporter as a novel mode of entry for ion colatus to enable selective targeting of those tumours that actually overexpress this transporter. And the data that we're going to be talking about today is being generated by three PhD students, two of whom are currently in the lab, and one of those students is Gina Abdelal, who will come on and speak to you further about this in a moment. And Gina and my other PhD student, Andrew Carter, are furthering the work of a chemistry PhD student, but we're trained up in some of the key techniques needed to accrue data quickly. So, just to give a very brief overview of where we were at at the point of the review being published before Gina takes over our initial discovery of these hydroxypyridinone-based colatus, which are LAT1 substrates. We were able to demonstrate their cytotoxic activity and selectivity for cancer cells over healthy cells in melanoma. So the original model was in melanoma. Ongoing preliminary work by myself and Gina has identified activity against a variety of other cancerous cell lines, including prostate cancer. And some of that preliminary data within our group is showing that a more aggressive PC3 cell line is more sensitive than a less aggressive DU145 cell line. So demonstrating that these compounds can have profound effects on cell survival and death. Being a little bit more specific then, we have published on melanoma and shown that the lead compound we have, SK4, has the ability to, one, promote increased generation of reactive oxygen species. Two, activate both intrinsic and extrinsic apoptosis. And finally, they're also able to induce perturbations in cell cycle and induce growth arrest. So what I'm going to do now is pause here and change author across to Gina to talk a little bit more in detail. I'm Gina Abdel, and I'm a third year PhD student at Dr Berger's lab at Northumbria University in the UK. I will give a brief overview of the review that we have published together and some of the background behind it. So iron colladers are a set of cancer drugs which strip cells of their iron content, with some also inducing reactive oxygen species. And the rationale behind their use is cancer therapy is cancer cells usually have a higher level of iron compared to normal cells. Usually because cancers upregulate their iron import proteins such as transferrin and downregulate their iron export proteins. And this accumulation of iron is what helps support cancer cell growth and metabolism as many enzymes in the cells are iron dependent. DNA synthesis, for example, is reliant on ribonucleotide reductase, which produces DNTPs. And this enzyme uses iron as a cofactor, and this is the rate limiting step of DNA synthesis. Therefore, iron can be a major driver of cell proliferation and different tumor types may accumulate iron or be addicted to iron. Iron colladers are an effective agent against many tumor types because it's a universal trait, and that makes them a tumor agnostic therapy, even with P53 mutant cancers. Our review entitled Reversing oncogenic transformation with iron collation investigated the mechanistic side of iron colladers and related them to the hallmarks of cancer. Iron colladers have been shown to reverse some of the hallmarks of cancer through a cell signalling protein called NDRG1. Essentially, when cells are treated with iron colladers in vitro, NDRG1 is upregulated through which many oncogenic signalling pathways are inhibited, such as WIMP, PI3K and EGFR signalling. However, NDRG1's role as a tumor suppressor is still controversial. As some studies suggest more of an oncogenic sort of role, in some patient samples you see an upregulation of NDRG1 being associated with poor prognosis and for others high NDRG1 means good prognosis. So there's still some controversy there. In triple negative breast cancer cells, iron collation actually induced an upregulation of PI3K signalling and induced transfer and expression. This made those triple negative breast cancer cells accumulate more iron, so there's still room for debate on NDRG1's exact role and it may not be consistent across all cancer types. Additionally, iron colladers can induce apoptosis, autophagy and also ear stress. We've also seen that when you combine iron colladers with PARP inhibition there is an increase in sensitivity in BRCA positive cell lines which would normally be resistant to the PARP inhibitors. So what I would really like to see next is more focus on clinical trials that use iron colladers in combination with chemotherapeutic drugs or possibly other anti cancer agents. We've seen a mixed bag of results with clinical trials with iron colladers. There's been a lack of response in some cases as well as resistance and some side effects. Potentially I would really like to see more focus on making iron colladers more selective. There are some studies that have shown if you encapsulate an iron collator in nanoparticles it makes them slightly more selective and effective against cancer cells. At the moment I am working alongside another PhD student Andrew Carter who Dr Vogher has mentioned and I'm working on investigating the effects of SK4 which is based on l-memozine and has a moiety that allows entry through the amino acid transporter LAT1. SK4 is aimed at targeting LAT1 over expressing tumors making it selectively cytotoxic potentially in clinic. OK, so I just want to really say thank you to everybody who has been involved in this research with SK4 which is an iron collator with the LAT1 moiety attached to it which we hope to be far more selective for cancer cells than perhaps some of the other iron collators that are out there at the moment. So I'd like to say thank you to David Tatard who is our synthetic chemist who has designed, synthesised and worked really hard to produce enough compound for us to test. And then our previous PhD student Satiris Kiriaku and his supervisor Mihailas Panagiotidis for all of their work underpinning a lot of the pilot data in melanoma that has enabled us to continue to look at this in more depth in other cell lines and then go on to look at the mechanisms. So yes, I want to thank all those that have been involved. Thank you.