Today we interview Dr Suso J. Platero, whose research is probing the frontiers of next-generation sequencing, transcriptional profiling, and proteomics in the validation of biomarkers for lung cancers. In his 2009 book, Molecular Pathology in Drug Discovery and Development, Dr Platero makes the case for clinicians and researchers working together to produce biomarkers and therapeutic agents simultaneously, resulting in their understanding of pathophysiology, identification of specific subsets of patients, and improved physician acumen in drug selection and titration during the management of head and lung cancers.
PMO: Thank you for meeting with us today. We are very interested to hear the perspective of the researcher in the quest to personalize oncology care. To begin, can you please provide a brief chronology of your research path?
Dr Platero: I received my bachelor of science degree from the University of Pittsburgh. Then, I completed a master’s degree at Columbia University School of Medicine in the field of integrated molecular biology, molecular biophysics, and cell biology. I received my PhD at St Louis University Medical School in classical genetics. That led to a postdoctoral research position at the Fred Hutchinson Cancer Research Center, where I focused on cell division and the components that were important in forming a centromere, the part of the chromosome related to mitotic and meiotic segregation. There, I developed new technologies in measuring DNA and RNA. In the early 2000s, I began my work in the industry with Becton Dickinson, following up on work that was generated by Millennium Pharmaceuticals in transcriptional profiling data and converting it into assays that were later developed into diagnostic products.
I have also worked for Bristol-Myers Squibb [BMS] and now Janssen, a Johnson & Johnson company, and my work has focused on the discovery of biomarkers, their application in clinical trials, and their development as companion diagnostics.
PMO: How would you summarize your research goals?
Dr Platero: Our goal is to determine how drugs work, what makes them effective, and identify the right patients for each drug. We do this by using markers to match patients to the right therapy to increase the probability of response, not only because most of the drugs we work with in oncology are very toxic, but to ensure those patients derive the most benefit from our drugs. We want to move our technologies from the realm of research and put them in a clinical setting to help identify the right subset of patients while keeping the toxicity to a minimum and the benefits to a maximum.
PMO: Can you describe the course of your work and to what extent it is translated into clinical practice?
Dr Platero: All our work is geared toward ensuring applicability to the clinic. We start with the basic research questions, and we try to develop those assays for clinical utility and implement them in clinical trials. Let me give you an example. We began work about 6 years ago on a compound that is an FGFR [fibroblast growth factor receptor] inhibitor. We took about 250 cell lines, treated them with one of the early compounds, and we differentiated those cell lines that were sensitive to the compound versus the ones that were resistant. We figured out that sensitivity was due to the presence in those cell lines of chromosomal abnormalities in the FGFRs. We then developed several assays that are able to measure mutations, amplifications, or translocations of the FGFRs. With that knowledge, we started a phase 1 clinical trial. The results were consistent with what we expected-we started to see patients on trial responding to this drug, and they had the specific molecular profile that we anticipated. We are now refining tests for the phase 2 trials with the knowledge we acquire from the phase 1 setting. This process will help enrich the phase 2 clinical trial with patients who will have higher efficacy to the compound. In this way, we eliminate patients who may not get benefit from this compound, and they can look for other options for their treatment. Thus, we’re using the biomarkers to drive higher sensitivity and hopefully faster clinical trials.
PMO: This is the perfect personalized medicine premise—the fulfillment of the goal of personalized medicine.
Dr Platero: That’s exactly what we’re attempting to do here in my group. As you can see, we started from a research question, researched ideas with experimental compounds, and now we’re in clinical trials. It requires a lot of time and effort as well as great collaboration between companies and departments within the companies to make this a reality.
PMO: We’d like your thoughts on the ability to respond and adapt to unforeseen situations in clinical trials.
Dr Platero: A perfect example of our ability to adapt happened during the phase 1 clinical trial I just described. We started to see responses in patients who were not necessarily expected to respond. We paused, looked back at our research and were able to identify that these patients have a different aberration that we were not looking for originally. Then we went back to the lab to develop a new test that captures these other patients too. So now we have several tests that we have put into a multiplex assay that will assist us in identifying all of these patients who may respond to this drug.
PMO: How is this altering the landscape of new drug discovery and development?
Dr Platero: From the pharmacological development point of view, we are making the trials faster, we’re making the trials smaller, and we’re updating our methods of developing compounds. Remember when we used to do clinical development with pharmacology? We’d just take a population and expose them to drugs that were pretty toxic. Now we are able to select patients who have the best chance of responding. This will increase our efficacy and speed in clinical development.
PMO: Can you speak to the evolution of tumors and how this impacts your clinical trials?
Dr Platero: This is a fairly new concept. Once a patient undergoes a therapy, the tumors can be quite different after therapy; therefore, we may need to change treatment for those patients. Rebiopsying of tumors is becoming more of the standard of care, especially in the university hospital setting, because we understand that tumors evolve over time and that evolution is due to the pressure we’re exerting on the tumor by treating with different drugs. It’s also worth pointing out that patients tend to be willing to rebiopsy because the procedure involves minimal surgery-small core biopsies or incision biopsies. They are willing if it helps the management of their disease.
As we move on and more drugs are approved and we gain better understanding of genomics and the tumors’ evolution, we will be in a better position to give the right dose to the right patient at the right time.
PMO: There is a lot of discussion about the promising future of immunotherapy in oncology. What is your experience in this field?
Dr Platero: Immunotherapy is certainly a fascinating topic and an area where we will see an incredible explosion of new drugs being tested. I am actually working now with immune checkpoints and vaccines in clinical trials. I also worked at BMS during the early development of ipilimumab and saw how these treatments take the brakes off the immune system. I think the role of pathologists is fundamental within immuno-oncology to look at these tumors before and after dosing to determine what types of immune cells infiltrate the tumor cells.
Recent advances in immunotherapy provide a great opportunity and a new area of research to effectively integrate concepts of sequencing, histology, pathology, and immunology to improve our ability to treat patients.
PMO: Can you expand on the concept of “releasing the brakes” of the immune system?
Dr Platero: I think there is going to be an incredible interplay between the tumor genetic composition and the ability of the immune system to mount an attack on the tumor. In that sense, we have to identify not only what the target is within the tumor that is sensitive to specific drugs but also look at the tumor’s genetic components and determine if it has the ability to elicit a response from the immune system. After a tumor has been attacked by the immune system, it tries to evade it by releasing factors and deploying receptors with the purpose of escaping immunosurveillance. Releasing the brakes means going after those factors and letting the immune system continually attack and destroy the tumors.
I would argue that this is going to lead to a greater desire on the part of researchers to understand the molecular characteristics of the tumors themselves on a different level than we have ever studied before.
PMO: It would appear that immunotherapies, targeted therapies, and the diagnostics that go with them is stimulating an appreciation for the pathophysiology itself. This is a much richer environment and culture of medicine as a result of a personalized approach to care.
Dr Platero: Absolutely. We currently have several drugs in our arsenal for which we know that patients with specific mutations have a better chance for response. Tomorrow, we will give more tools to oncologists so they can look at the genomics, histology, and pathophysiology of that tumor and start thinking about how to treat it in a historical way; not in a way that says “I want to give you this drug, and I hope it will work.” I think as a consequence of this new knowledge, because we have a more personalized way of attacking tumors, the patients will benefit tremendously.
PMO: What is the level of understanding by each of the members of the cancer management team, and how can they sharpen their knowledge of next-generation sequencing, transcriptional profiling, and proteomics?
Dr Platero: Oncologists need to have access to resources of researchers and pathologists. From the point of view of developing these new drugs, we work in teams, each one bringing an expertise in a specific area. I’m there trying to understand what assays we can apply to the early drug development. At the same time, we have a team of people working on the pharmacologic characteristics of the drug, chemists making the compounds, biologists making antibodies, and clinical teams deriving the trials. We all come together to make personalized medicine a reality.
PMO: Can you elaborate on the approach to bringing a drug to market?
Dr Platero: There are several strategies to bringing drugs to market. We’re looking at different companies to see what drugs they have. Do they fit in our portfolio? Can we license them and shortcut the process? Normally, if we develop the drug internally, the process is long and starts by making the drug and testing it in vitro and in vivo. We then test to see if the drug is toxic, and we start the clinical trials. Upon successful completion of clinical trials, the drug is approved. Only about 10% of drugs that enter clinical trials will be successfully developed.
Those kinds of ideas are more a strategic view of how we bring new drugs to the market. Obviously, because of my role in discovering these biomarkers, one of the things we want to do is not only bringing the drug to market but bringing with it a companion diagnostic.
That is the great thing about working at Janssen Pharmaceuticals. We have a diagnostic company, so we can work with them to make sure that by the time this drug is approved, we have a test to identify the best candidates for patients. If the test is positive, put the patient on the drug. That way you don’t give drugs to patients who will not benefit from them.
PMO: Effective diagnostics is the key to effective drug administration.
Dr Platero: Absolutely. You have to find the right people. If you don’t find the right people, your drug will lose effectiveness. If we’re able to present a specific population of patients with a 40% to 50% response rate, the FDA is more likely to approve that drug. At the end of the day, we want drugs that are approvable and that will benefit the patients we treat.
PMO: As you’re saying, good medicine is inextricably tied to drug commercialization. Drug commercialization means you’re doing the right thing in the development of that drug. It’s a win/win.
Dr Platero: I think you can hear in my voice that I’m very excited about that prospect. Personalized medicine is here to stay, and I think it’s going to make an incredible impact on the lives of people. With personalized medicine we can bring the right drug to the right patient at the right time, and we can do that in a faster way than ever before. That’s what gets me out of bed when we see the impact we’re having on patients and the lives of people that we’re touching.
PMO: Thank you for your time today. And best of luck to you in your endeavors.
Dr Platero: Thank you.