Making melanoma therapy personal: an interview with Dr Keiran Smalley for Melanoma Management

Abstract

Dr Smalley earned his PhD in Pharmacology from the University of Cambridge, UK, in 2001. He worked as a post-doctoral fellow in the Oncology Department of University College London, the Institute of Cancer Research, Fulham Road and the Wistar Institute, PA, USA. Currently, Dr Smalley is a Professor in the Departments of Tumor Biology and Cutaneous Oncology at the Moffitt Cancer Center, FL, USA. He is also currently the Donald A Adam Endowed Chair in Melanoma Research and is the Director of the Melanoma and Skin Cancers Center of Excellence. The lab of Dr Smalley focuses upon the development of targeted therapy strategies for melanoma and is currently funded by the NCI, the pharmaceutical industry and a number of philanthropic sources. Dr Smalley's work is highly translational in nature and work from his lab has led to the initiation of a number of clinical trials. To date, Dr Smalley has published over 120 papers in top peer-reviewed journals including Cancer Research, Cancer Discovery, Cancer Cell, New England Journal of Medicine, the Proceedings of the National Academy of Sciences, the Lancet, Gastroenterology and Clinical Cancer Research. He currently sits on the editorial boards of Clinical Cancer Research, Biochemical Pharmacology, Drugs, Melanoma Research and the American Journal of Clinical Dermatology and is the Associate Editor of Pharmacological Research. Dr Smalley is a charter member of the Basic Mechanisms of Cancer Therapeutics Study Section for the NCI/NIH and has served on many other peer review panels for the Department of Defense, the state of Texas and numerous melanoma research foundations. He has also fulfilled advisory roles with the University of Pennsylvania, the University of Pittsburgh and a number of pharmaceutical companies. Dr Smalley has been a visiting professor at the University of Sao Paulo, Brazil in 2011 and in 2014 received a Science Without Borders Scholarship from the Brazilian Government.

Q How did your career lead you to working in melanoma?

My initial training was in pharmacology with the goal of eventually working in the pharmaceutical industry. At school, I always enjoyed both chemistry and biology and it was my goal to try and combine those two disciplines. During my undergraduate degree at the University of Bath, I was fortunate to have a one year internship at (what was then) Glaxo Research in Ware, Herts. At Glaxo I worked on an asthma project, looking at various beta-adrenergic agonists. I learned very quickly that industry was not for me; we had very little freedom to study what interested us and often long-lasting projects could be shut down overnight, with very little warning. I decided to further my training and went to Cambridge for my PhD. My internship with Glaxo helped me to gain a PhD studentship at the Glaxo Institute of Applied Pharmacology, which was at the time housed in the Cambridge University Department of Pharmacology. Again, I worked on G-protein-coupled receptor signaling, this time focusing upon somatostatin receptors. It was in Cambridge that I first learned about signaling and really got hooked on studying the MAP kinase pathway. After my PhD, I realized I wanted to do something a little more translational than endless drug screening and applied for a job with Professor Tim Eisen in the Department of Oncology at University College, London, UK. At the time Tim was interested in melanoma and hired me as a postdoc to work on α-melanocyte-stimulating hormone signaling. This was a great opportunity for me to branch out and I worked with Tim for over 3 years, eventually following him to the Institute of Cancer Research at Fulham Road. While there I was fortunate to work in the lab of Professor Chris Marshall, one of the heroes of the MAP kinase field. Eventually Tim realized his interests lay more as a clinical trialist and I took the opportunity to join the lab of Dr Meenhard Herlyn at the Wistar Institute in PA, USA.

Q Is there anyone that you have worked with that has influenced you along your career?

Probably my biggest influence has been Meenhard Herlyn. Meenhard really is the Godfather of melanoma research and he has been a towering presence in the field for many years. He really is a visionary thinker and has almost boundless energy. Meenhard taught me to think big and aim high, and it is through him I got to meet many great scientists. I was also fortunate to be at Wistar and part of the University of Pennsylvania melanoma group at a really revolutionary time for melanoma research.

Q What would you consider your biggest professional achievement to date?

My proudest achievements have been doing work that has directly influenced the life of melanoma patients. We have made some important contributions to understanding the role of signaling in melanoma progression and did some of the first work demonstrating that targeting BRAF and BRAF–MEK in combination could have real therapeutic benefit. Being a part of the story that led to the US FDA approval of BRAF and BRAF–MEK inhibitors has been very rewarding.

Q You are currently the Director of the Melanoma Research Center of Excellence, which brings together clinical and research scientists. How important is this multidisciplinary approach to tackling melanoma?

I think the real lesson of the melanoma revolution of the past 7 years is that great things can be achieved when scientists and clinicians collaborate effectively. While at Wistar, I worked very closely with Keith Flaherty on the science behind BRAF inhibition. This really paid off and helped deliver better treatments to patients with advanced melanoma. The clinicians often have really great insights that lead to important new hypotheses, and can greatly benefit from having scientific partners who can develop these ideas further. On the other side, I think the scientists have much to offer in terms of trial design and good correlative science. At Moffitt, we have been very successful in developing our clinical trials that come directly out of work going on in our labs. Our clinicians attend the lab meetings and the scientists go to tumor board. It is an exciting place to work. I think the interdisciplinary model is the future.

Q You recently published a paper on the management of leptomeningeal melanoma metastases in the era of immune and targeted therapy. How are targeted therapies being designed to combat this?

As we get better at controlling melanoma systemically, we are seeing more patients failing therapy in the brain and leptomeninges. Leptomeningeal-melanoma metastases are particularly devastating and are associated with a survival that is measured in weeks. Very little is known about this complication of advanced melanoma and the underlying biology is not well understood. At Moffitt, we are developing new research projects to define the therapeutic vulnerabilities of leptomeningeal-melanoma metastases and are in parallel developing new clinical trials to bring these discoveries to our patients. As you can imagine, there is a great deal of interest in evaluating immunotherapy in patients with leptomeningeal metastases. For a long time, it was thought that the CNS was an immune privileged site, so we still have a great deal to learn! An issue with developing clinical trials for leptomeningeal disease is the relatively low patient volume. We expect to overcome this through partnering with other high volume cancer centers and already have discussions with some of our collaborators around the country.

Q There have been a lot of recent developments in the field regarding combination immunotherapy. How crucial are the latest results in terms of patient care?

I think the advances made in the development of immunotherapy have been truly astounding. We routinely have cases now where patients are being cured through immunotherapy. For most of our patients, BRAF mutant or not, immune-checkpoint inhibitors will usually be the first-line therapy. Melanoma oncologists now have growing numbers of long-term follow-up patients. Even 2–3 years ago this was completely unheard of. We still have much to do though in this arena, these therapies are not without serious side effects and not everyone will respond to these treatments. We still don't entirely understand why this is. There is still some controversy over whether single agent anti-PD-1 checkpoint inhibitors are superior to the anti-PD-1/anti-CTAL-4 combination and whether this is worth the extra toxicity. I expect this issue will be resolved soon. It is also unclear what role immunotherapy will play in stage III melanoma patients in the adjuvant setting.

Q What major challenges does the field currently face? What opportunities do we need to capitalize on?

I think the clinical progress of the past 7 years has been so incredible. Things are now starting to slow down. We have hit a plateau. At this time, there are probably more slots on clinical trials (particularly for treatment-naive patients) than there are melanoma patients. It has been a unique time in the history of oncology in which the clinical results have outstripped our understanding of the basic science. I think we have some catching up to do here. There are a number of key areas that still need focus: better therapies need to be developed for patients with brain metastases, survival for these individuals is still quite short; we need to come up with optimized strategies for the FDA-approved therapies we currently have. Everything at the moment is given at the maximum tolerated doses, and this needs to be refined. There is also room to develop better dosing schedules, as continuous drug treatment may not be the answer; we also need to design rational strategies for combining immune therapy and targeted therapy. These combinations need to be driven by the science; at the moment the rationale for doing this is not well developed and I think opportunities are being missed.

Q Where do you see the field of melanoma research in 10 years?

Making predictions 10 years into the future is very difficult! I do not think 10 years ago, anyone would have dreamed that we would be where we are now in melanoma therapy, so predicting the next 10 years is not easy. If pushed, I would say that personalization of therapy could be the biggest area of progress. New methods will be developed to determine individualized therapy combinations at baseline. These sophisticated molecular analyses will be complimented by better pharmacodynamic assays so that patient responses can be tracked in real time, allowing relapse to be better predicted and new therapies added or dosing schedules altered before outright treatment failure. We will also need to develop new therapies that can target minimal residual disease or the dormant cancer cells that can hide for many years before eventually re-emerging. I think eventually melanoma will be managed as a chronic disease, requiring long-term surveillance.

I think the last few years have been quite revolutionary for the melanoma field, we really have set the tone for the development of both targeted therapy and immunotherapy for other cancers. Our challenge now is to keep the momentum going and to start delivering more cures to melanoma patients.