Good afternoon, everyone. I'm Nicole Leber with Investor Relations at Lantern Pharma, and welcome to Lantern's Childhood Cancer Awareness Month Key Opinion Leader Webinar. September is Childhood Cancer Awareness Month, a month dedicated to supporting, empowering, and amplifying the voice of the childhood cancer community. According to the American Childhood Cancer Organization, childhood cancers are the number one cause of death by disease for children in the United States, with one out of six diagnosed children not surviving past five years of age. Additionally, despite advances in medicine, many childhood cancers remain incurable. As of 2020, only six new drugs have been developed to treat childhood cancers. For today's KOL webinar, you'll be listening to Dr. Peter Houghton, who has dedicated his career to improving our understanding of pediatric cancers and to the development of therapies that will improve survival outcomes for childhood cancer patients. He is currently a professor and principal investigator at the Greehey Children's Cancer Research Institute at the University of Texas Health Science Center at San Antonio, more commonly known as the GCCRI, which is one of only two institutes in the U.S. dedicated solely to pediatric cancer research. In today's webinar, you will hear Dr. Houghton talk about a wide range of topics surrounding pediatric cancer research, including the disparities and hurdles that currently exist in pediatric cancer research, drug development, and pediatric clinical trial design compared to adults. You'll also hear how his research group and researchers at the GCCRI are using state-of-the-art cancer models to advance pediatric drug development and find novel and less toxic treatments for childhood cancers. Finally, you will hear him discuss his research collaboration with Lantern and more about our drug candidates, LP-184 and LP-284 for pediatric cancers. He will also talk about exciting new preclinical results for LP-284 and how it has shown promise for the treatment of Ewing sarcoma, malignant rhabdoid tumors, and several other pediatric cancers. With that, I'll now turn the webinar over to Dr. Houghton for a more personal introduction to himself and to the Greehey Children's Cancer Research Institute at UT San Antonio. Yes, sure. I'm a molecular pharmacologist, so that basically means I study drugs at a mechanistic or molecular level. I received my PhD from the University of London in the United Kingdom at The Institute of Cancer Research, London. I joined St. Jude Children's Research Hospital as a postdoctoral fellow in 1977 and was Chair of the Department of Molecular Pharmacology and Co-leader of the Solid Malignancies Research Program at St. Jude from 1988 to 2009. Then I spent five years as Director for the Center for Childhood Cancer and Blood Diseases at Nationwide Children's Hospital in Columbus, Ohio. From 2014 to 2021, I was Director of the Greehey Children's Cancer Research Institute, which is part of UT Health San Antonio. The Greehey Children's Cancer Research Institute, or GCCRI, is the largest freestanding children's cancer research facility in Texas. It opened in 2004 with a $200 million endowment as part of the tobacco settlement. The Greehey is home to about 20 independent investigators, each of whom has a program focused on childhood cancer. Research programs focus on understanding very basic issues such as cancer-causing genes to more translational studies like mine, which aim to identify novel therapeutics. Greehey has state-of-the-art instrumentation. It is a great environment for students to train. Specifically, our lab focuses on understanding why tumors are either sensitive or resistant to drugs. We currently have funding from the NCI to study sarcomas, tumors of soft tissues, hepatoblastoma, which is a liver cancer, an embryonal tumor of the kidney called Wilms tumor, and specific types of brain tumors. What are the differences between pediatric cancers and adult cancers? Basically, children are diagnosed with a different spectrum of tumor types compared with adults. In adult patients, cancers are predominantly epithelial in origin. Carcinomas such as lung cancer, colorectal cancer, breast, and prostate cancers. These tumors are extremely rare in children. During the 32 years I was at St. Jude Children's Research Hospital, I think we had less than 10 patients with colorectal cancer. That shows how rare these tumors are. Distribution of pediatric cancers is about half are leukemias, cancers of the blood, one-quarter are brain tumors, and the remainder comprise mainly sarcomas, neuroblastoma, and kidney tumors. Even in older patients, adolescents and young adults, the so-called AYA group, cancers in this group differ from the same tumor types in adult patients. Overall, about 15,000 new cases of cancer are reported in the U.S. annually in patients under 21 years of age. Again, showing that these are rare cancers when you consider for lung cancer, it's about 150,000 patients a year. The five-year event-free survival for children is approximately 80%, and the overall survival is probably in excess of 70% now. However, outcomes differ by tumor type. It's now considered that 95% of children diagnosed with standard risk acute lymphoblastic leukemia, ALL, will be long-term survivors, whereas patients diagnosed with glioblastoma or diffuse intrinsic pontine glioma, both tumors of the brain, have quite dismal outcomes. Similarly, malignant rhabdoid tumor and most advanced solid tumors that have metastasized, that is they've spread from the primary site to multiple sites, that diagnosis will only have a 20%-30% long-term survival. Thus, although multimodality treatment consisting of surgery, radiation therapy, and intensive chemotherapy is curative in most children, patients with advanced cancers who fail on current therapies have poor outcomes. Clearly, we need better drugs that will benefit these children. Moving on to the next question. What are some of the major challenges in developing therapeutics for the treatment of pediatric cancers, specifically? Yeah. The major challenge is the very small numbers of patients that are diagnosed with each cancer type. For example, even the most prevalent cancer, leukemia, where there are about 3,000 patients diagnosed per year in the U.S. and Canada, there are 17 molecular subtypes. For solid tumors, the numbers are even smaller. For rhabdomyosarcoma, a cancer of the skeletal muscle lineage, there are perhaps 300, maybe 400 cases per year, and at least two distinct molecular subtypes. Even this is an underestimate of the true molecular diversity. For medulloblastoma, a cancer of the brain, there are maybe 200 or so new cases each year and at least four molecular subtypes, thus restricting testing of new targeted therapeutics. The other challenge is that for many of these cancers, initial therapy is highly effective, with a cure rate of around 70% of children and a five-year disease-free status of around 80%. Thus, testing new agents is done in a setting of disease relapse, where a patient may have done well for several years, but eventually the tumor cells become resistant to treatment and the cancer progresses. It's against these refractory patients that new drugs are tested, and not surprisingly, many drugs fail to show activity in this setting. When drugs make it out of preclinical development for pediatric cancers, can you speak to the challenges in running pediatric oncology clinical trials? Yeah. One of the greatest challenges in accurately translating preclinical results to clinical trials is that the drug exposures in preclinical models should be relevant to those that can be achieved in patients. For some drugs, this is difficult to model due to differences in metabolism and clearance of drug between species. Also, the schedule of drug treatment in patients may be different from drug scheduling used in models, and this can lead to differences in efficacy or anti-tumor activity. In general, initial testing in children is dictated by the dosage schedule used in adults and may not represent the optimal approach developed in preclinical testing. As I discussed above, phase I trials of new drugs in children often lag several years behind establishing a safe dose in adults. This lag time is in part because pharma does not necessarily see the benefit in developing a drug for a numerically rare disease, but also out of concern that the drug may cause adverse effects not observed in the adult population. There's very little evidence that drugs tested in pediatric patients have excessive toxicity compared to adults. However, in recognition of the apparent safety, many clinical trials have extended the age limit to include patients as young as 12 years of age at later stages during the drug escalation schema. Hopefully, this will facilitate more rapid development of novel agents for pediatric patients. How can pharmaceutical and biotech companies like Lantern help to address the disparities in drug development in pediatric cancer research? Well, clearly the pace of drug development for cancer drugs in children has been slow. From the perspective of pharma and biotech, this is relatively easy to understand. There's no market for the drug, if active, due to the rarity of childhood cancer. There's always a concern that an adverse event in a child could derail development of the drug. We're working closely with Lantern to evaluate LP-184 in multiple solid tumor PDX models. Our hope is that this novel agent will show strong anti-tumor activity at dose levels in mice that give clinically relevant drug exposures in children. Can you tell us about your research with Lantern and initial results in testing LP-284? Okay. In terms of sort of general approach, we've introduced single mouse testing as a rapid and economic approach to identify novel agents that have very good activity against different pediatric tumor models. The idea of single mouse testing is to look for drugs that cause marked tumor regressions in models economically, and this also allows us to look over a much greater range of tumor models or PDX models that represent molecular subtypes of pediatric cancers. The single mouse testing allows us to examine the sensitivity of many more PDX models than conventional testing does and allows us to encompass far greater molecular diversity that exists in the clinic. This initial screen shows that at the dosage schedule tested, the LP-284 causes tumor shrinkage in many models of sarcoma and other cancers. We've evaluated LP-284 against 10 Ewing sarcoma models. Ewing sarcoma is a tumor of bone and soft tissue that occurs largely in adolescents and young adults. It's driven by a gene fusion that leads to a hybrid or chimeric molecule, EWS-FLI, that is transcription factor that is the sole driver of these tumor types. Six of ten of these models had objective responses. That is, it caused tumor to shrink. In three models, there was a complete response, and the tumor disappeared, and that response was maintained for at least 100 days following a single cycle of LP-284 therapy. This is a very active agent in Ewing sarcoma. We've also examined two malignant rhabdoid tumors. These are tumors that arise largely in infants of two years of age or younger, and they're very aggressive tumors, and the outcome for these patients is extremely poor. In these two malignant rhabdoid tumors, LP-284 caused tumor shrinkage, and in one alveolar rhabdomyosarcoma, again, a fusion-driven type of tumor that has very bad prognosis, the mice remained tumor-free for over 100 days. Based on the promising preclinical results for LP-284 in your pediatric cancer models, what do you think the next steps are for its development for pediatric cancers? To identify models that are sensitive and not sensitive to LP-284. I think the next steps are to expand that screen to incorporate a greater diversity of tumors. The initial screen was very much biased towards Ewing sarcoma. I think we should look at other tumors, additional hepatoblastomas to see if they're consistently resistant. I think we now have something like 10 models there because that's the tumor where there really is an unmet need for new drugs because these kids do terribly. To expand the diversity of tumor types that we look at, I think that will also give us an opportunity to perhaps delve into the molecular characterization, the RNA-seq, the DNA sequencing work that has been done with all of these models to see if one can identify markers of response and non-response. I think that would be valuable. I think then the second stage is to take several of these models, maybe five models, where we show that the drug is very active at the dose and schedule we've used, and then to do a dose de-escalation study using more mice, so we can get statistical significance from the studies that define at what point we lose the ability to cause tumor shrinkage. Because that's going to be the critical issue to say, do we achieve drug exposures in patients that exceed this minimal effective dose in mice? In other words, can we achieve in children the drug exposures that actually cause tumor regressions in the preclinical models? I think they're the critical issues. From your experience testing other drugs, can you speak to the potential for LP-284 to progress into clinical trials? The drug is very clearly very active. I think what will determine its prioritization would be defining at what exposure in mice we lose activity or significant activity. That would be the critical issue. If one has pharmacokinetic data from the adult trials and can determine the pharmacokinetics in the preclinical animals such as the mouse, I think that's gonna give you a very good guide. You know, with this new generation of acylfulvene, there's clearly activity. I think the relative exposures mouse versus adult will be a very good guideline to say whether it's likely that this preclinical activity will translate into a clinical setting. I think the other aspect is we have a series of sarcomas where we've selected for acquired resistance to traditional vincristine, actinomycin D, cyclophosphamide, irinotecan therapy, and it would be nice to show at least some activity in those models because that's the challenge of going into a phase II setting is these patients have been fairly heavily pre-treated. I mean, both chemotherapy and radiation therapy, so they're bad actors, that's for sure. That is all the time we have for today. Thank you so much to Dr. Houghton and to all of you for tuning in. For more information, please visit our website at lanternpharma.com. Thank you, and have a great day.