On a visit to Brazil, the scientific director for LICR and one of the most cited researchers in the field of oncology spoke about advances in cancer treatment and the development of tools that in his view enable physicians to detect tumors very early on (photo: Léo Ramos Chaves/Pesquisa FAPESP)
Published on 12/02/2022
By Karina Toledo | Agência FAPESP and Ricardo Zorzetto | Pesquisa FAPESP – Chi Van Dang, a Vietnamese-American oncologist and currently Scientific Director of the Ludwig Institute for Cancer Research (LICR) in New York, is optimistic about the future of cancer treatment. In his view, advances in recent years such as the development of tools for early detection will enable physicians to identify tumors at a very initial stage and eliminate them before they develop. “I think we’re going to start curing more and more patients in the next decade. That’s why I have such an enthusiastic and positive outlook,” he said in November during his first visit to Brazil.
Dang became internationally famous for helping to elucidate how alterations in the functioning of genes in the MYC family lead cells to use a different energy pathway from usual, favoring the development of tumors. A little over a decade ago, his laboratory was the first to show that tumor cells containing mutated or aberrantly behaving MYC genes produce energy by means of fermentation. In healthy cells, energy is produced preferentially through respiration, which consumes oxygen. Fermentation is used only in the absence of oxygen. This metabolic alteration is known as the Warburg effect. It was discovered by German physician and physiologist Otto Heinrich Warburg (1883-1970), who was awarded the 1931 Nobel Prize in Medicine or Physiology. Although fermentation is a less efficient energy production pathway, it allows cells to accumulate ingredients for multiplication more easily. Research by Dang and his group tended to confirm the hypothesis that tumor cells may become dependent on this pathway for generating energy and specific nutrients, which could be targeted by cancer drugs. Some proposals for treatment based on this idea are at different stages of testing in humans.
Dang was born in Saigon, now Ho Chi Minh City but then the capital of South Vietnam. He was one of ten children. His father was S. Vietnam’s first neurosurgeon and Dean of Saigon University’s Medical School. Dang moved to the United States in 1967, during the Vietnam War. He graduated in chemistry from the University of Michigan and earned a PhD in chemistry from Georgetown University in 1978. In 1982 he received his M.D. from Johns Hopkins University, where he is now Bloomberg Distinguished Professor of Cancer Medicine.
He visited São Paulo in November to participate in an event commemorating the twentieth anniversary of completion of the FAPESP Genome Project. The anniversary was actually in 2020, but the commemorations were postponed because of the pandemic. The project sequenced the genome of Xylella fastidiosa, the bacterium that causes citrus variegated chlorosis, known to Brazilian orange growers as amarelinho because it causes yellowing of leaf tissue due to lack of chlorophyll. The disease was then ravaging orange groves in São Paulo state. The initiative enabled several Brazilian research groups to acquire expertise in genome sequencing and led to the Human Cancer Genome Project, which was conducted in partnership with LICR and sequenced genes expressed in high-incidence tumors in Brazil. At the event, which marked the end of the cycle commemorating FAPESP’s sixtieth anniversary, Dang paid tribute to physician and biochemist Ricardo Renzo Brentani (1937-2011), creator and first director of LICR’s Brazilian arm. Brentani was CEO of FAPESP from 2004 until his death in 2011.
Dang gave an interview to Agência FAPESP and Pesquisa FAPESP magazine on November 22. A slightly abridged transcript follows.
Agência FAPESP – When you became editor-in-chief of the journal Cancer Research in 2018, you wrote that we could begin to use the word “cure” without trepidation and with substantial hope that our science will deliver this promise. What makes you so confident that we will find a cure for cancer?
Chi Van Dang – As physicians and oncologists, we stayed away from the word cure for many years. I think the Human Cancer Genome Project really provided the roadmap for cancer biology and cancer medicine. The evolution of what we’ve learned over the last few decades has been tremendous. New drugs have been made from the Genome Project. I used to take care of patients with chronic myelogenous leukemia. We didn’t have very good therapy. Now you can take a pill. People aren’t quite cured, but they can live with the disease. Over the last five to ten years, we’ve witnessed the progress of immunotherapy, where I think we can use the word cure. We’re deploying our immune system to really fight against cancer. That’s a revolution everyone is focusing on from all different fields, whether chemotherapy, radiotherapy or surgery. I think we’re going to start curing more and more patients in the next decade. That’s why I have such an enthusiastic and positive outlook.
AF – In terms of prevention and treatment, do you believe in a cancer-free future?
Dang – I think we can indeed envision a cancer-free future. With early detection of tumors using the latest tools, such as liquid biopsy, taking your blood, for example, we’ll be able to intercept before cancer can develop. In that sense, I think we will have a cancer-free world in the foreseeable future, again because of all the technologies from the Genome Project that enable us to detect cancer very early on. Now there are companies that are basically providing this. I think this whole area is going to evolve in the next five to ten years, to the point where instead of going to your doctor for a regular checkup, you give a blood sample and they call you back in saying there’s a signal here, we need to chase down where the cancer is and get rid of it now.
AF – What are the next challenges to be faced in cancer research?
Dang – I look at it as opportunities. We can talk about challenges in terms of questions we want to answer. There are a number of areas where we still don’t quite understand the immuno-oncology, why some patients respond very well, while others really don’t respond. We need to move the needle there. One area of great opportunity is to understand not only our genome but also the role of the microbiome. This is where bacteria, viruses, and fungi actually play a role. They’re intimately part of us. Our health depends on the microbiome. In the next decade, there will be more and more studies that identify what it is about these organisms that we can manipulate to prevent or even treat cancer, to get cancer to respond more. There are some remarkable things that I’d probably think were science fiction if I’d read about them in the scientific literature 20 years ago. An example is stool transplants. How is it possible that you can provide immunotherapy to patients who do and don’t respond, and you do stool transplant from those who do respond to those who don’t, and they now respond? It sounds like science fiction but it’s reality now. There are many more things. For example, what about diet and how does our diet affect cancer development or treatment? Again, the microbiome may play a role – what we eat, how the bacteria metabolize the chemicals in our diet, and how it affects us by making us more inflammatory or anti-cancer. From a public health standpoint, hopefully we can advise people not just to stop smoking but to eat certain kinds of food.
AF – How has your work on tumor cell metabolism helped to fight cancer?
Dang – Back in the late 1990s, we found a link between cancer genes and cell metabolism. That’s what got us into cancer metabolism. I would say the challenge over the last 20 years has been finding the “sweet spot” to target metabolism and cause tumors to regress without harming the body. I think the main lesson we’ve learned in the past five to ten years is that whatever the target is, we need to harm the cancer cells but spare the immune system. So this whole area of immunometabolism is emerging out of cancer metabolism. Some colleagues and I published a paper this year showing that choline [vitamin B8] in your diet can be converted into a chemical by the bacteria in your gut and this chemical gets converted further into another chemical in the liver that activates your immune system. In an animal setting, we can now get a much better response to immunotherapy by creating more inflammatory conditions through both metabolism and the microbiome. Companies have emerged out of the landscape we established. One in particular makes the drug for IDH mutations in acute myelogenous leukemia. It’s FDA-approved. It’s a metabolic drug. People are responding and it’s providing them with longer survival.
AF – Why is it so difficult to find drugs that act on cancer cells but not normal cells?
Dang – Metabolism is used by all cells. The question is whether the cancer cells are more vulnerable to certain metabolic pathways than, say, the T cells that fight against cancer. There’s one angle to this, based on some of the studies we’ve done on glutamine metabolism, which some cancer cells rely on [glutamine is an amino acid that is used in the biosynthesis of proteins and can be an alternative to glucose in energy production]. It turns out that inhibiting this pathway in cancer cells actually stimulates the immune system. So that might be a sweet spot. There’s a company that’s developing a drug based on this concept. They’re in Phase I studies. We’ll see what happens. We hope it’s a sweet spot, but maybe it’s not the only one.
AF – There’s no silver bullet for cancer. We need many because cancer is many different diseases.
Dang – You’re absolutely right. The public usually think cancer is a single disease, but there are more than 200 different types of cancer. Even targeted therapies, which act on specific proteins whose functions are altered in cancer, work only against certain types of cancer, against a subset of cancers that have that particular mutation. What we’re dealing with is extremely complex. We hope cancer research can boil it down to some simple principles that can be exploited across multiple types of cancer. Immunotherapy is one area that has been proven to work for several different cancers. I hope and believe that the microbiome is another such opportunity. We need a cassette with multiple silver bullets, and we’ll get there.
AF – You’ve just been to see ICESP, the São Paulo State Cancer Institute. What can you say about cancer research in Brazil? How do you think Brazil can help address the challenges you’ve mentioned?
Dang – I was extremely impressed with the very high level of research that’s embedded in this public hospital. It also has a clinical trials unit that seeks to deliver Phase I trials to patients. I saw the cleverness of Brazilian scientists in exploiting what you do best. This is also illustrated by FAPESP’s Genome Project, which we’re now celebrating. The opportunity of focusing on specific problems, which the group is doing, will be key. I love following what they’re doing, to see the impact that I know will come along. As in all places, if one has more resources and very talented people, you can make more impact. What I can say to the government here is that research is important. As I say in the US, invest more and you’ll get more return on your investment.
AF – You’re a proponent of chronotherapy. Could you explain what it is and what is the evidence to support it?
Dang – Chronotherapy has been around for a couple of decades. As you know, we have a wake and sleep cycle because of the solar cycle of day and night. It turns out that many of our cells, if not almost all of them, have molecular clocks that synchronize individual cells with our daily activities. When we sleep, the cells rest. When we’re awake, they’re active. Some of the clues to the importance of the circadian rhythm to health come from studies of people who work night shift. These studies have been done with tens of thousands of individuals, especially women in a nursing study. What you find is that women who work nights have a higher risk of breast cancer. The question is why. We think the reason is desynchrony between your sleep and wake cycle and your cells’ internal clocks. This can create chaos, if you will, where you start seeing more inflammation, and we know inflammation can help trigger cancer. Some of the key experiments that have been done are fascinating. For example, if you take mice, which are more active at night, and just switch their food from night to day, they get more obese even with the same calories. They’re simply eating at the wrong time. This teaches us that the circadian clock is important. Coming back to the question of what chronotherapy is, the belief is that normal cells undergo regulated circadian rhythms – active and inactive – and cancer cells may have lost the clock, so they’re desynchronized. If you look at the medical literature on radiation therapy for cancer, it turns out that patients treated in the afternoon fare less well than patients treated in the morning. The same with chronotherapy using drugs. There’s a clinical trial that suggests that for colon cancer, you also see a benefit if you give a certain type of chemotherapy in the morning versus the afternoon. I think this is more about sparing normal tissue from the side effects of the therapy than the cancer cells being vulnerable. Ideally, the cancer cells would always be vulnerable, but you would know when to spare the normal cells from the side effects. This was also reported recently for immunotherapy. Patients who received the treatment in the morning or afternoon had different outcomes. It’s very interesting, but we don’t completely understand yet why it’s the case. Something in the immune system behaves very differently in the morning than in the afternoon.
AF – Is there a best time for treatment?
Dang – It depends on the treatment and on the tumor. Certain types of cancer retain their clock. We really need to understand this whole area a lot better.
AF – Are you studying the clocks of different tumors at your lab?
Dang – Yes. This is an area of interest for us right now. I like areas that aren’t crowded. There aren’t many people working on this at the moment.
AF – Are your studies in animal models?
Dang – In animal models. I’m hoping to take them to humans as quickly as possible, now that I’m part of the Johns Hopkins cancer center and working with clinical colleagues.
AF – You mentioned cancer-related lifestyle factors like diet and sleep. Are they as important as genetics?
Dang – Environmental factors clearly play a role. Studies in the US that use ZIP codes to group participants by the area where they live have shown higher cancer rates because of environmental exposure depending on where people live. Clearly, there’s much more to know about how pollutants, diet or secondary smoking can contribute to the risk of cancer.
AF – What fascinates you about cancer research?
Dang – One of the challenging thoughts I have almost daily is that collectively we have such great intellects around the world to tackle cancer, which, as already noted, isn’t one disease but hundreds of diseases. What fascinates me is how we can use our intellect to take a complex problem and boil it down to enough simplicity that we can make a difference in people’s lives. Every day I try to think of different things. We can always do more of the same, but we need to be imaginative and say maybe this is a missing link. That’s why I got into circadian rhythm and diet. They may seem to be on the periphery, but we need to understand all these factors and try to move the needle. I’m also fascinated by the big role played by microbes in our health. That’s going to be a gold mine. Our work at my lab is slowly getting to that as well. We’re looking at microbial metabolism.
AF – What advice would you give Brazilian students who are interested in cancer research?
Dang – My advice first and foremost would be: figure out what your passion is, what drives you. This is going to be the big factor for success. Second, I’d advise them to study the literature in order to understand the questions that haven’t been answered yet. That might be the missing link where you could make a difference. It’s okay to do some incremental stuff when you’re training, but when you go out on your own, find the question by understanding the literature. Find out where the gaps are and try to fill those gaps. Explore areas that are emerging or that people haven’t thought about.
AF – FAPESP and Ludwig Institute made a great contribution to science with the Cancer Genome Project. Would a project of this kind be possible in future? In what areas?
Dang – FAPESP and Ludwig have really made an impact, not only here but around the world, with the transcriptome analysis of cancer, for example. I look forward to a continuing partnership. Having ideas from different corners of the world is very important. No single place is going to solve such a big problem. We’re discussing and exploring the possibilities.
AF – Could you give us a spoiler? What are the key problems?
Dang – Infectious disease has always been a big thing, in Brazil, in particular, and I know there are people working on the microbiome. Could that be a connection between microbial science, cancer and immunology? We could think together. Maybe we won’t go to that scale, but we could start with fellows, students or trainees, who can work together on combined projects and explore the space where the opportunities really are, and the willingness. Then, perhaps, we could commit to a big project.
Source: https://agencia.fapesp.br/40229
