Founder Stories: Jonathan Lim, Founder of Erasca and Ignyta

How do we erase cancer? I've outlined 5 revolutions that give us potential paths to being able to do this, and we've seen some miracles occur. But each one, on its own, in a vacuum, is insufficient. Everyone in this room has been touched by cancer. But I'm excited to be here today to tell you that there's reason for hope. The 5 revolutions to erase cancer will give you a sense of all of the different tools and approaches we have to fighting this devastating disease. I started out my career in surgery. I liked how surgeons combined their intellect with their hands to fix problems. I trained at Cornell Medical Center, New York Hospital, and Memorial Sloan Kettering Cancer Center, where I was involved in a number of complex surgeries to treat cancer. I also went abroad on 4 surgical missions to the Philippines and to Mexico, where I saw conditions that you would rarely see here in the United States. The pictures of the masses in these patients certainly are dramatic, but they also are benign, which means that they won't spread, and therefore are amenable to fixing by surgery. Surgery was extremely fulfilling as a career, but we were helping patients on a one-on-one basis. I wondered, what would it be like to be able to have impact on patients on a larger scale? Since then, I've had the privilege of serving as chairman, CEO, and co-founder of 6 companies that have developed 7 products that have been approved and launched globally in oncology, immunology, and drug delivery. I've also had the chance to work with some amazing people in the field. People like Patrick, whose life's mission was to cure cancer. He was the global head of oncology at Pfizer, and it was his teams who discovered drugs like axitinib and crizotinib, important cancer therapies in precision medicine. In 2013, Patrick and I worked on launching and building a company called Ignita, a precision medicine company in oncology. However, just a few months into his job as our chief scientific officer, he saw flashing lights. He was rushed to the hospital and diagnosed with a deadly form of brain cancer. Patrick received multidisciplinary treatment beginning with a 14-hour surgery. Unlike the patients in the Philippines whose tumors were benign, Patrick's was malignant. It had spread to other parts of his body, necessitating multiple surgical procedures, radiation therapy, and chemotherapy. Chemotherapy, as you know, does a terrific job of killing cancer cells. Unfortunately, it also hits healthy cells and leads to side effects. Tragically, Patrick's tumor was detected too late, and the treatments were insufficient. He passed away in 2016, just a few years after his initial diagnosis. I miss Patrick dearly and am committed to ensuring that his work lives on. And in fact, it is living on, because the work that we started on entrectinib at Ignita is now being continued by Roche, the world's largest oncology company. Patrick's treatment journey is part of the first revolution in cancer treatment. Surgery really came into vogue in the 1890s and then continued on with radiation therapy in the 1900s. And it wasn't until the 1940s when Dr. Sidney Farber pioneered the use of antifolate treatments for kids with childhood leukemia that saw dramatic results. Unfortunately, stories like Patrick's are far too common, which is one reason why my own personal prayer list of family and friends affected by this devastating disease number more than 40 people. Cancer is the second leading cause of death, responsible for nearly 10 million deaths globally every year. The best way to cure cancer is to identify and treat the tumor early before it has time to spread. Unfortunately, the statistics tell us that more than half of all patients present with advanced or late-stage disease. The problem with late-stage disease is it's very aggressive. It constantly mutates or changes. Which means we need additional revolutions to keep up. The second revolution is genomically targeted therapy, which really was birthed in the 1990s with the development and subsequent approval of Herceptin for breast cancer and Gleevec, which is an oral therapy for leukemia that was approved in 2001 and essentially launched the precision medicine revolution in oncology. My company, Erasca, named for our mission to erase cancer, is really proud to be a part of shaping this revolution. The way genomically targeted therapy works, unlike chemotherapy, is it targets the specific mutation that is driving the cancer cell and therefore kills the cancer cell while sparing the healthy cell. My own experience with targeted therapy was during my time as CEO at Ignita, where we had a patient named Mr. Z. He's a 46-year-old man who was on a business trip. He was running on a treadmill when he suddenly felt short of breath. He was diagnosed with advanced-stage lung cancer that had metastasized to his brain. In fact, he had 15 to 20 lesions. He underwent multiple lines of chemotherapy, including immunotherapy. All of that was to no avail. He grew progressively sicker and was admitted to the hospice, which is where end-of-life treatment is given. He had weeks left to live. Fortunately, he was given entrectinib, which targeted TREC, a very rare mutation that was driving his cancer. If you look at the CT scan of Mr. Z, Normally, the lung is black because it's full of air. You can see on his left lung, which is on your right-hand side, it's almost white. It's full of tumor. After one month of treatment on entrectinib, which is an oral capsule given daily, his lung cleared very dramatically. In fact, at this point, Mr. Z felt so good that he got out of bed and consumed an entire bag of Oreo cookies. 10 months later, you can see his lung was much better, and more importantly, the 15 to 20 lesions in his brain completely disappeared. For a patient like Mr. Z to have advanced-stage lung cancer metastatic to the brain and to go from that to complete recovery That's nothing short of a miracle, and that would not have been possible 5 to 10 years ago without the right targeted therapy. Visiting Mr. Z and his family in his home in Needham, Massachusetts, was truly one of the highlights of my career. And there's reason for more hope. You've undoubtedly read the exciting news about cancer immunotherapy. Cancer immunotherapy is a broad field that includes checkpoint inhibitors that release the brakes on the immune system, CAR-T cell therapy, which harvests immune cells from patients' blood, engineers them to better fight tumors, especially liquid tumors these days, cancer vaccines, which boost patients' immune systems and allow them to better recognize antigens to destroy the tumor cells in a personalized fashion. I'm going to talk a little bit more about the checkpoint inhibitors, which are very relevant to solid tumor therapy. Cancer cells secrete factors that create this barrier that basically puts the brakes on immune cells like our T cells. The way checkpoint inhibitors like Keytruda work is that they release the brakes that allow the T cells to better kill the tumor while preserving the healthy cells. The most famous example of this working is in former President Jimmy Carter, who in August of 2015 announced that his metastatic melanoma had spread to his liver and his brain. He underwent radiation therapy followed by Keytruda, a checkpoint inhibitor, and later that year was free of cancer. President Carter just turned 95 earlier this year, yet another miracle of modern cancer therapy. On a population level, the goal of any cancer treatment is to enable patients to be able to survive to the 5-year mark, because by reaching that mark, they essentially have the potential to be cured. For a patient with metastatic melanoma like President Carter, about 10 years ago, very few patients would have reached this 5-year mark. The data here show you that with checkpoint inhibitors, as many as a third of patients reach that important 5-year mark. That's incredible progress just in the last decade. But we still have more work to be done in terms of finding the right biomarkers and combinations of agents to get that number closer to 100%. Checkpoint inhibitors have since been approved in multiple solid tumor types outside of metastatic melanoma. And the story holds true where you have a minority of patients that reach that 5-year mark, what we call the long tail of survival. But still, the majority of patients unfortunately don't respond to immunotherapy. So as exciting as progress is in the second and third revolutions of cancer treatment, there are pros and cons in terms of response rates and durability of response. So the question is, is there a missing link? I believe the missing link is extrachromosomal DNA, or ecDNA. Which represents a brand-new way in understanding how cancer behaves. Dr. Paul Michel and other scientists at UCSD observed that cancer behaves in a way that cannot be explained solely by looking at DNA on our chromosomes. So they looked where no one else was looking, and they found these extrachromosomal circles, what they called ecDNA, that basically independently replicate, almost like plasmids in bacteria. And these circles can drive the growth, proliferation, resistance and recurrence of different cancers. And this phenomenon is found in more than 50% of all solid tumor types. This is crazy stuff, but it's pervasive. What you're looking at here on the left is normal cell division. On the right-hand side, these are cancer cells that are dividing much more rapidly and out of control. This phenomenon can be driven by these ecDNA circles that drive amplification. So the question is, can we exploit the unique enzymatic vulnerabilities of these circles to further kill cancer and complement current standards of care? Well, if we're successful, this would truly represent a fourth revolution in cancer treatment and could be used to complement existing chemotherapeutic, targeted therapy and cancer immunotherapy approaches to erase cancer. And now I want to leave you with a thought. This is Hippocrates, the Greek physician who might have had the answer to treating cancer over 2,000 years ago. One word: food. We've been talking a lot about high-tech approaches to treating cancer. Looking forward into the future, could this low-tech approach represent yet another approach to treating and erasing cancer? Well, I believe that nutrition is a critical component of the fifth revolution in cancer treatment. Think about it. We eat 3, sometimes more meals a day, so the foods that we eat can be as impactful to our health as the drugs that we take. Here's an example of a 42-year-old woman with advanced-stage lymphoma. Her CT scan shows that before treatment, her lymph nodes were significantly enlarged. After a 21-day water-only fast, You can see that her lymph nodes shrank pretty dramatically. She then transitioned over to a whole food, plant-based lifestyle, and 3 years later, her PET scan remained all clear. Now, this is a miraculous outcome, but it's an N-of-1 data point. So clearly, more studies need to be done, especially with randomized controlled studies, because this is a very complex field. But there are exciting frontiers. Cancer is a disease of uncontrolled growth. Certain hormones, like insulin or insulin growth factor, have been associated with cancer growth. There's been different plant-based, calorie-restricted diets that have been explored, as well as targeting the glucose-glutamine dependency of tumor cells while boosting the metabolic efficiency of healthy cells that have also been explored. But there's also some high-tech approaches. For instance, we are just scratching the surface of our understanding of the microbiome, which is the sum total of genetic material in microorganisms like bacteria and fungi and viruses that live in and on our bodies. The microbiome is hugely impacted by the drugs that we take and the foods that we eat. So clearly, this warrants further study. So this brings me full circle to the original question, which is, how do we erase cancer? I've outlined 5 revolutions that give us potential paths to being able to do this. And we've seen some miracles occur. But each one, on its own, in a vacuum, is insufficient. The ability to integrate most or all of these revolutions with the patient at the center in a personalized fashion— this is what gives me hope that we will be able to one day erase cancer. Thank you very much.