In 2005, I was miserable. I have spent more than five years in my Ph.D. study. Experiments were always full of too many factors beyond my control. The thesis committees were not convinced by my ideas. My track of publication or applying for research grants is just bad. I believed that I did not fit for a PI job, nor wanted to be one. I called my cousin, who had a stellar career in R&D of big pharma, to get his advice for my next step. He told me to do postdoc research anyway. Very luckily, I received an offer from Dr. Glenn Merlino at the National Cancer Institute, NIH. He is a super knowledgeable and open-minded mentor. I can honestly discuss the negative results with him and design studies with the craziest ideas.

In Glenn’s laboratory, he believed that the best way to understand human melanoma is to replicate it in mice. In the following years, my colleague Raza Zaidi was collaborating with Ed DeFabo and Francis Noonan to study how melanocytes responded to UV irradiation, the well recognized etiological factor of melanoma. They found that UV activated melanocytes through inflammation. I was busy genetically engineering mice, trying to generate human-like melanoma and using them to test therapies. During this process, I received the best training in preclinical study from top experts in the field, especially Dr. Melinda Hollingshead (Developmental Therapeutic Program, NCI) and Dr. Terry Van Dyke (Center for Advanced Preclinical Research [CAPR], NCI). However, melanoma research in those years was kind of depressing. It was an extreme disease: either it could be cured at the early stage by a simple surgery, or the patients at the late stage would be told only a few months remaining for them because the disease was resistant to every available therapies at that time. I was not sure if our studies in the biology of melanoma did matter or not. I struggled publishing my work in elite journals. Even worse, I tried to get a job in my home country but everyone there told me that GEM was either too expensive or irrelevant to human disease. I became very anxious about the future of my research career.

Meanwhile, the hope was in the making and coming. By the mid-90s, Dr. James P. Allison and others hypothesized that blocking CTLA-4, an immune "checkpoint", could release T cells from restrained status, allowing them to attack tumors. The immune checkpoint blockade (ICB) therapy successfully eradicated tumors in mouse studies. In the early 2000s, the first humanized anti-CTLA-4 (ipilimumab) was tested in phase I clinical trials in multiple cancer centers, including NCI. The results demonstrated the efficacy of the drug. About the same time, Stratton et al. discovered that mutated BRAF gene could be a drug target for melanoma. Prototype BRAF-inhibitory compounds were found to inhibit growth of melanoma cells in culture dishes and in mice. The first targeted drug for BRAF-mutated melanoma (vemurafenib) was developed and ready for clinical trials. In the following decade, ipilimumab and vemurafenib were tested in clinical trials for treating patients with metastatic melanoma. 

From 2010 to 2011, the results of clinical trials of ipilimumab and vemurafenib were published. Ipilimumab increased the five-year survival rate of patients with metastatic melanoma to 10%. I could not believe what I read from the paper- a small but significant fraction of patients survived late-stage metastatic melanoma for more than five years? Compared to the hopelessness previously, it looked like a miracle! Vemurafenib also gave impressive results: 50%-80% response rate, and prolonged survival. A photo showed that the metastatic melanoma nodules all over a patient’s body vanished after vemurafenib treatment. It went viral in many media reports and internet posts. Following these successes, therapies against new targets, including  immune checkpoints PD-1 and PD-L1 and BRAF downstream gene, MEK, were developed and tested in clinical studies. In a few years, the five year survival rate of patients with late-stage melanoma has increased to about 50%. It was beyond oncologists’ wildest dream even five years ago. For sure, these breakthroughs did not mean that we have won the war against melanoma. Oncologists quickly understood the limitations of these new therapies. For example, about half of the late-stage melanoma patients do not respond to immune checkpoint inhibitors. For targeted therapies, after initial remission following treatment, the melanoma would come back in one year. Nevertheless, for the first time in the history of cancer therapy, we had effective weapons to fight back melanoma.

Kerrie Marie came to our laboratory from the UK in 2014 for her postdoctoral research. She studied how melanoma cells learned from embryonic melanocytes to switch identity, so they can escape from immunity. After two years, Eva Perez Guijarro joined us from Spain for her postdoctoral research. Around that time, I have generated various mouse models of melanoma by combining different genes, so we worked together to test their responses to immunotherapy in an attempt to identify gene combinations that caused resistance. Meanwhile, many new technologies emerged during those years, leading to the accumulation of cancer data at light speed. We understood melanoma more than any time before. I was very optimistic that melanoma would become a curable disease soon. 

In the summer of 2020, we all worked from home while waiting for this pandemic to end. On a regular evening, I received a message from my collaborator Zoe at CAPR, asking me to call her immediately. As soon as the call was connected, I heard her crying. She told me that Alan, the mouse technician in her team, was experiencing melanoma recurrence. He was diagnosed with metastatic melanoma about two years ago. The tumors went away after treatment with anti-PD-1 immunotherapy, and everyone thought he was cured. Now the disease has attacked again.

Alan was a gentle, soft-spoken family man. During those years of my collaboration with CAPR, I worked with him quite often. He was a caring father, always talking about his three-year-old son and where they spent time together over the weekend. During a mouse study, the technicians have to come into the facility to run the procedures regardless of the weekend, holidays, or bad weather. I remembered that, in a meeting, Zoe said that their technicians came to the facility during consecutive days of big snow, "they did not skip any dosing", she told us with gratitude and professional pride. Alan was one of the two technicians who took care of mice in that study.  

I was very shocked. However, I thought there was hope. We knew the best melanoma experts and clinicians in the best cancer centers. We know the trials of new therapies are ongoing. We knew melanoma could respond to the new combination therapies. There must be some way. A renowned oncologist offered his help as soon as Glenn and I reached out to him. I called Alan to tell him all the optimistic things happening now. He was so fragile and spoke  only "OK" or "right" with difficulty. When we finished the 10-minute talk, I really believed that he would get ready to fight for another round and win. 

After three days, Zoe emailed me that Alan passed away. I was so saddened and felt totally crushed. How could I be so ignorant- there are the other half of patients of metastatic melanoma who do not respond to any kind of therapies? How dare I give any patient false hope? 

With all the progress we have now for melanoma treatment, Alan reminded us that so much work lies ahead before we find a cure for every patient. It’s like hitting the thick stone wall between humans and the cure relentlessly. Starting from making dents, to chipping inches, hammer by hammer, we will crash a hole on that wall, and eventually demolish the wall.

Therefore, I want to write down all that happened during this fight. It began in the 19th century, when physicians noted a link between sun exposure and skin cancer, and early 20th-century animal experiments provided further evidence.