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Chi Van Dang: An optimistic view of oncology

Scientific director of the Ludwig Institute for Cancer Research talks about the challenges and perspectives of the field

Dang, one of the most cited scientists in oncology, during a visit to São Paulo

Léo Ramos Chaves / Revista Pesquisa FAPESP

Chi Van Dang, an American physician born in Vietnam and current scientific director of Ludwig Institute for Cancer Research (LICR) in New York, is optimistic about the future of oncology. He believes that treatment advances made in recent years and the development of new tools for early detection will make it easier to identify tumors at a very early stage and eliminate them before they develop. “In the next decade we will start to cure more and more patients. That’s why I have such an enthusiastic and positive outlook,” he said during his first visit to Brazil in November.

Dang explained that changes in how genes in the Myc family function cause cells to adopt a different energy production pathway: fermentation, instead of respiration. Although fermentation is a less efficient way to produce energy, it allows cells to more easily accumulate the ingredients they need to multiply.

Work by Dang’s group supported the hypothesis that tumor cells may become dependent on this pathway to generate energy and specific nutrients, which could be potential new targets for cancer drugs. There are treatment proposals based on this idea at varying stages of human testing.

Born in Saigon (now called Ho Chi Minh City), formerly the capital of South Vietnam, Dang moved to the USA in 1967 during the Vietnam War. He earned a degree in chemistry from the University of Michigan and a medical degree from Johns Hopkins University, where he is now a professor. In November, he visited São Paulo for the celebration of the twentieth anniversary of the FAPESP Genome Program, which was originally set to take place in 2020 but was postponed because of the pandemic. The project sequenced the genome of the bacterium Xylella fastidiosa, which causes citrus variegated chlorosis (CVC), a disease that affects orange trees in São Paulo.

While he was here, Dang gave an interview to Agência FAPESP and Pesquisa FAPESP, which you can read below.

When you became editor in chief of the Cancer Research magazine in 2018, you wrote that “we can begin to use the word ‘cure’ without trepidation and with substantial hope that our science will deliver this promise.” What makes you so confident?
Doctors and oncologists tend to avoid using the word cure. I think the Human Cancer Genome Project really provided the roadmap for cancer biology and medicine. And the progress we have made in terms of our knowledge over recent decades has been tremendous. New drugs were developed thanks to the Genome Project. When I cared for patients with chronic myelogenous leukemia in the past, there were no good treatments available. Now, they can take a pill and live with the disease. In the last five to 10 years, we have witnessed major advances in immunotherapy. I really think we can use the word cure when we talk about preparing our immune system to fight against cancer. In the next decade we will start to cure more and more patients. That’s why I have a very enthusiastic and positive outlook.

In terms of prevention and treatment, do you believe in a cancer-free future?
We can envision a future without cancer. Early tumor detection using the latest tools, such as liquid biopsies of blood samples, should make it possible to diagnose the problem early enough to prevent the cancer from developing. So yes, because of the technologies now able to identify cancer so early, I think the world will be cancer-free in the foreseeable future. Companies are making this possible. This area is likely to evolve over the next five to 10 years to the point where instead of going to the doctor for a regular checkup, a person can just give a blood sample and wait for the lab to test it and tell them “there’s a signal here, we need to trace where the cancer is and get rid of it.”

What are the next challenges to overcome in cancer research?
There are a number of subjects that we still don’t understand very well, such as immuno-oncology. Why do some patients respond well to the treatment but others don’t? Another important topic is the role of our microbiome. Bacteria, viruses, and fungi are part of us. Our health depends on our microbiome. In the next decade there will be more and more studies attempting to identify how we can manipulate these microorganisms to prevent or even treat cancer, or to make cancer respond better to other therapies. One of the most notable recent achievements—and one that I would probably have thought was science fiction if I had read about it in the medical literature 20 years ago—is fecal transplantation. It is possible to make patients who have previously failed to respond to immunotherapy respond to it by transplanting the microbiome of people for whom immunotherapy works into them. This is already reality. There are many factors related to diet and how it affects the development or treatment of cancer that need to be studied. And again, the microbiome might play a role there.

How has your work on tumor cell metabolism been helping to fight cancer?
In the late 1990s, we found a link between cancer-associated genes and cell metabolism. This led us to cancer metabolism. Over the past 20 years, the challenge has been to find the ideal point for interfering with the metabolism to trigger tumor regression without harming the rest of the organism. What we’ve learned is that whatever the target, we need to impact it in a way that harms the tumor cells and spares the immune system. Some colleagues and I published a paper this year showing that choline [vitamin B8] in the diet can be converted by bacteria in the gut into a chemical that is then converted in the liver into a compound that activates the immune system. Thus, in tests on animals, we were able to obtain a better response to immunotherapy by creating more inflammatory conditions. Companies were founded based on the scenario we created. There is even an FDA-approved drug to treat acute myeloid leukemia that affects the metabolism of tumor cells and is giving patients greater chances of survival.

Why is it so difficult to find drugs that impact cancer cells without affecting normal cells?
Several metabolic pathways are shared by the two cell types. The question is whether cancer cells are more vulnerable to interference via certain metabolic pathways than, say, cancer-fighting T cells. There is one study based on some of our research on the metabolism of glutamine [an amino acid that can be used as an alternative to glucose for energy production], which some cancer cells rely on. In this case, inhibiting this pathway in cancer cells stimulates the immune system. This could be an ideal point of interference. And there is a drug candidate being developed by a company, currently in phase 1 clinical trials. Let’s see what happens. We hope this is an ideal target, but it may not be the only one.

In cancer research, we always hope to arrive at simple principles that can be exploited in various tumor types

There is no silver bullet for cancer. We need lots of different silver bullets, because cancer is actually many different diseases.
People often think that cancer is one single disease, but there are over 200 types. Even targeted therapies, designed to affect specific proteins whose functioning is altered by the cancer, only work against certain types of cancer that contain the genetic alteration that cause the protein to malfunction. So we’re dealing with a high level of complexity. In cancer research, we always hope to arrive at simple principles that can be exploited in various tumor types. Immunotherapy, for example, works against different types of cancer. I believe and hope that the microbiome is another such opportunity. What we need is a gun with several silver bullets. We will get there.

You are an advocate of chronotherapy. Could you explain what it is and the evidence supporting it?
Chronotherapy has been around for a few decades now. As we know, people go through a cycle of being awake and being asleep because of the solar cycle of day and night. Many—if not all—of our cells have molecular clocks that synchronize their functions with our daily activities. When we sleep, our cells rest. When we are awake, they are active. Studies involving tens of thousands of night-shift workers, mostly women, suggest that the circadian rhythm is important to health. The results showed that people who work night shifts are at a higher risk of developing breast cancer. The question is: why? It’s quite possible that it is related to a lack of synchrony between the person’s sleep-wake cycle and the internal clocks of their cells. This leads to inflammation, which can trigger cancer. The medical literature on radiotherapy for cancer shows that patients treated in the afternoon respond differently to those treated in the morning. The same is true with drugs. I think it has more to do with the fact that healthy tissue is spared than tumor cells being more vulnerable. This has also recently been reported for immunotherapy. We still don’t really understand why.

In general, is there a better time to provide the treatment?
It depends on the treatment type and the tumor. Certain cancers follow the clock more than others. We really need to understand this area better.

Do you study the internal clocks of different tumors in your lab?
Yes, this is one of our areas of interest now. I like fields of study that aren’t too crowded, and there aren’t many people working on it right now.

Are these animal studies?
That’s right, we are currently using animal models. But I hope to move on to humans as soon as possible now that I’m part of the Cancer Center at Johns Hopkins University and working with clinical colleagues.

You mentioned several lifestyle factors related to cancer, such as diet and sleep. Are they as important as genetics?
Environmental factors clearly play a role. There have been studies in the USA that look at the participants’ zip code. Depending where a person lives, their risk of getting cancer is higher due to environmental exposure. There is so much we don’t yet know about how environmental pollutants, diet, or secondary smoking contribute to cancer risk.

FAPESP and the Ludwig Institute made an important contribution to science with the Cancer Genome Project. Would a similar partnership be possible in the future? In which area?
FAPESP and Ludwig really made a big impact, not only here, but all over the world with their analysis of the cancer transcriptome. I look forward to this partnership continuing. Gathering ideas from different corners of the world is really important. No one place is going to solve such a big problem alone. We are discussing possibilities.

Could you tell us anything about what the biggest problems are?
Infectious diseases have always been a major problem in Brazil and there are people working with the microbiome. There could be a connection between microbial science, cancer, and immunology. We can all think together. Maybe we could start with research fellows or scholarship holders working together on joint projects and exploring the opportunities, and then committing to a big project.