 Hello everybody. My name is Aditya Kulkarni and I'm a senior research scientist at Lantern Pharma. I would like to thank the Oncotar Get Journal and its associated publishing house for the opportunity to present our cancer drug development research activities on this platform. I've been a biopharmaceutical scientist, manager and inventor combining over 12 years of research experience with a vision to direct drug candidates from the bench to the bedside. I'm a biochemist by training having applied it in the fields of cancer biology and small molecule drug development. One of my areas of interest involve identification and validation of biomarkers of drug response and resistance and at Lantern Pharma I've been fortunate to have explored and contributed to several areas of drug development. Lantern Pharma is a clinical stage oncology focused by a pharma company leveraging artificial intelligence methodologies to generate gene signatures predictive of response in patients to its pipeline of genomically targeted therapeutics. Using this precision medicine approach Lantern Pharma aims to potentially deliver best in class outcomes using the method of targeting drugs to patients whose genomic profile is going to identify them as having the highest probability of benefiting from a given drug. Now Lantern Pharma is having four drug candidates in development all in various cancer types having unique and unmet clinical needs. One of these is LP184 which has a very interesting history as well as a unique anti-cancer activity profile which brings me to the topic of our publication. The title of the paper which I am going to be describing in today's session is LP184 retains nanomolar potency in non-small cell lung cancer carrying otherwise therapy refractory mutations and as the lead author on this study I'll make sure to break down the title for everybody to appreciate. Our paper is essentially describing the activity of LP184 Lantern Pharma's lead preclinical drug candidate in a wide range of preclinical models of lung cancer specifically non-small cell lung cancer which accounts for 85 to 90 percent of the total lung cancer incidence. LP184 belongs to a class of compounds called acylphalvein agents which further can be categorized as DNA damaging agents. In this paper we also identify genetic correlates and determinants of LP184 sensitivity that will facilitate further biomarker development during during clinical translation and allow additional personalization of therapeutic options for future treatment of non-small cell lung cancer. With this I'd like to talk about a bit of a history of the research leading up to this paper. Our company name Lantern Pharma actually comes from the lantern mushroom that naturally produces a fungal toxin called eludin. The first identified examples of eludins were isolated from the lantern mushroom at the New York Botanical Garden in the 1950s. Eludins were then extensively studied for their cytotoxicity in various tumor types in cell lines as well as xenograft models. However frequent animal deaths associated with high eludin toxicity restricted their use as potential anti-cancer agents. In an effort to obtain cytotoxic compounds with favorable anti-cancer properties, in an effort to obtain compounds with favorable anti-cancer properties, acylphalveins were derived as semi-synthetic analogs from eludins. And this class of compounds with the core structure of acylphalveins and their analogs were much milder cytotoxins than their natural precursors eludins and exhibited favorable tumor specificities. Now I want to point out four highlights that emerged from this early generation of acylphalvein molecules. Number one is the retention of sensitivity of acylphalvein molecules in multi-drug resistant cancer cells that were otherwise resistant to commonly used chemotherapy agents such as cisplatin, doxorubicin and ironotecan. The second highlight is that acylphalveins are uniquely tumor targeting while sparing normal or non-tumor cells. The third highlight is that acylphalveins show heightened activity in cancer cells with compromised DNA repair capacities. And the fourth highlight which is the most remarkable is that acylphalveins are pro-drugs that are activated by prostaglandin reductase I or PTGR I which is an oxidoreductase enzyme and has now been established as a fundamental driver of tumor sensitivity and appears to be a unique and stringent efficacy biomarker for this class of compounds. High level of interest in this profile of acylphalvein bioactivity and mode of action further triggered the development of new synthetic strategies to produce newer generations of acylphalveins and their analogs. We identified LP184 as a next generation acylphalvein analog with highly improved and favorable therapeutic window potency and a validated role of PTGR I in its cytotoxicity along with preliminary hints of synthetic lethal relationship with DNA damage repair defects. It isn't surprising that certain mutations in oncogenes and tumor suppressor genes underlie non-small cell lung cancer likely by acting as drivers of tumor genesis or metastasis or therapy resistance at some point in the disease and treatment progression. But what is surprising is that if we consider just four genes, two oncogenes KRAS and KEEP1 and two tumor suppressor genes CP53 and STIC11, these combined account for more than 40% of non-small cell lung cancer cases. And it is not surprising that alterations in tumor suppressors or oncogenes underlie non-small cell lung cancer likely by driving tumor genesis, metastasis or treatment resistance at some point during the disease and treatment progression. What is surprising is that if we consider a handful of these tumor suppressor or oncogenes, namely KEEP1 and KRAS that are famous oncogenes and TP53 and STK11 that are tumor suppressors, these four genes account for more than 40% of non-small cell lung cancer cases. And there are hardly any therapies that are effective in patients having mutations in these genes. Furthermore, it's important to note that the signaling pathways and interaction networks in which these genes operate are non-overlapping or non-redundant and hence it's very difficult to develop any single class of agents to target non-small cell lung cancer having alterations in these genes. And we believe that LP184 could really have a big impact potentially in these molecular subsets that appear to be very segregated. I wish to talk about the most notable features of our work published in this paper and that can be summarized in six points. One is that LP184 is effective in vitro, not only in 2D models and in primary non-small cell lung cancer models, but also in 3D models of metastatic lung cancer models, especially brain metastasis originating from primary non-small cell lung cancer. And this is especially relevant for application in brain metastasis since we also found that LP184 crosses the blood-brain barrier in an in vitro model of multicellular human blood-brain barrier. The second feature of our work is that LP184 sensitivity correlates positively with transcript levels of PTGR1 in the panel of cell lines tested. This supports the hypothesis that PTGR1 is very important for the cytotoxicity of this compound. The third highlight from our work is that LP184 activity actually turned out to be independent of mutations in the four genes that I mentioned previously, K1, KRAS, STK11 and TP53. When we compared cell line subgroups with and without mutations in these genes, there was no statistically significant difference in the IC50s across the cell lines. LP184 retained in vitro activity even in the presence of deleterious mutations in these genes that would otherwise be associated with chemotherapy resistance in non-small cell lung cancer. The fourth highlight from our work is that LP184 turned out to be up to 3,000 times more potent than commonly prescribed chemotherapy agents such as cisplatin, toxorubicin, genocytobine and oxalipatin. The fifth highlight from our work was that LP184 dose ranges that were safe and tolerable were identified in vivo in the mouse model along with demonstration of anti-tumor efficacy in the xenograft mouse model of non-small cell lung cancer. And the sixth highlight from our work, which is the most clinically relevant, is that elevated PTGR1 co-occurs with mutated KEEP1 in clinical samples upon retrospective analysis from clinical databases. Non-small cell lung cancer especially is one of the very few cancer types in which the response biomarker PTGR1 that underlies LP184 activation actually correlates very significantly with the molecular drivers of the disease that are often mutated and even undruggable, for example KEEP1. Here we see a clear overlap between the drug activity and the area of unmet need in non-small cell lung cancer. And this also makes sense mechanistically considering the regulatory relationships between components of the KEEP1-NRF2-PTGR1 axis. When we have wild type KEEP1 in cancer cells, represses NRF2 and does not induce PTGR1 above basal levels. However when KEEP1 is mutated as seen in up to 20% of lung cancer patients, it does not repress NRF2 which is then free to translocate to the nucleus and induce its target genes including PTGR1. So there you see how KEEP1 mutation could really drive the upregulation of PTGR1 which in turn would sensitize the tumor cell to LP184. Now I'd like to talk a bit about what we would like to do next, what's in progress and where we would like to see our research being taken. We find that LP184 is a promising small molecule with activity in multiple solid tumor types. Here we continue to identify patient derived models that correspond to the clinical and molecular niches that LP184 is predicted to be effective in. We'd really like to see translation of our cell line based in vitro and in vivo work to a demonstration of efficacy and safety in patient derived models be it ex vivo 3D models, fresh tumor biopsies or xenografts not only in non-small cell lung cancer but in other solid tumor types where strong rationale exists to pursue the development of LP184. Predominantly undruggable non-small cell lung cancer is associated with either KEEP1 or KRAS mutations that account for 25% of lung cancer patients and there are very few therapeutic options that are only recently emerging to address these patients. Further, there are also uncharacterized or non-detectable mutations or alterations occurring in up to 35% of non-small cell lung cancer patients. Now when we compared overall survival and time-to-treatment failure within two subgroups of patients, KEEP1 mutated and KEEP1 wild type receiving the same standard platinum doublet chemotherapy, the KEEP1 mutant patients perform much worse. Their outcomes are much inferior to the KEEP1 wild type patients. Also KEEP1 mutant patients are more likely to undergo metastasis. So we'd like to really propose LP184 as a treatment option in three different areas. One as an option for KEEP1 mutated lung cancer, two as an alternative to cisplatin in patients that are ineligible to receive platinum based therapies and three as a combination with radiation therapy as part of the palliative care for late-stage cancer patients. There are other areas also that we envision LP184 entering the clinic and those include DNA damage repaired efficient solid tumors such as pancreatic cancers having defects in the homologous recombination pathway or the nucleotide excision repair pathway. Furthermore, since we have preliminary hints that LP184 crosses the blood-brain barrier and shows in vivo antitumor effects in aggressive brain tumors in mouse models, it also becomes a promising candidate for CNS tumors as well as brain metastasis. And at the end I would like to extend acknowledgments to the entire Lantern team of my colleagues, supervisors and executives as well as our partners at ReproCell without whose support this work would not have been possible. Thank you.