Josep Maria Llovet

«I try to transfer my research findings and knowledge to patients». Josep Maria Llovet describes his job in these words. He is one of the main world experts in liver cancer. «I have one foot on each side», as the different jobs he carries out prove: ICREA (Catalan Institution for Research and Advanced Studies) research professor in the August Pi i Sunyer Biomedical Research Institute (IDIBAPS), which is part of the Clinical Hospital of Barcelona, full professor of Medicine and director of the Liver Cancer Program in the Mount Sinai School of Medicine in New York, and president of the International Liver Cancer Association (ILCA).

We met at the CCCB (Centre for Contemporary Culture of Barcelona), where professor Llovet is the first guest of a conference cycle to raise awareness on ICREA grants research. Llovet uses knowledge coming from molecular biology in his descent into the hell that is cancer. Carcinogenic cells have lost track of the baton that guided their harmonic dance of birth, growth and death. Mutations that alter this regulation –such as the ones related to apoptosis or cell suicide– relate to a wide variety of cancers. Identifying these mutations and turning them into therapeutic targets is one of the goals of his research. In his conference, Llovet highlights the variety of molecular alterations that are being identified, and how it inevitably boosts development of customized treatment for every cancer sub-type. Each new drug focuses in a very particular type of cancer affecting a small percentage of cases. Effectiveness depends precisely on achieving, slowly but surely, this degree of definition towards the disease.

Is cancer research improving comprehension of what life is?
To understand cancer, we have to understand the normal functioning of a cell, and cells are the architecture of life. In cancer, cells function in an abnormal way, and when we investigate it, we can indirectly gain better understanding of cell functions.

Should cancer be understood as one illness, or more as an umbrella term encompassing a great range of illnesses?
It refers to a great variety of illnesses and, thanks to genome research, we are abandoning an anatomical pathology or histology classification for a better, more complete one, developed from the molecular point of view. What was previously known as colon cancer is now known to include many sub-types. The same applies to breast cancer, in which we distinguish six different sub-types. Or liver cancer, now divided into five different classes.

And thanks to that classification we can think of more specific and effective treatment?
Some drugs do not work with everyone; they only affect, for example, 10% of patients. In a trial, we have to select some biomarkers and those individuals with a certain alteration, and then we can see the benefits. For instance, we have 1.8 million new patients of lung cancer every year. If we find an alteration affecting 3% of them and it may be treated, like the ALK fusion responding to crizotinib, it may seem like a limited percentage, but there are actually thousands of people who can benefit from it.

Which were your main contributions to liver cancer research up until now?
With liver cancer, we made three main breakthroughs. A clinical advance (that is, not exactly research) was the creation of the Barcelona classification [Barcelona Clinic Liver Cancer (BCLC), a world reference system to classify patients with hepatocellular carcinoma according to prognosis stage]. It is applied all over the world and we are very proud of it. In the second place, two treatments: chemoembolization [chemotherapy applied directly to the hepatic artery so it does not affect the rest of the body so aggressively] and Sorafenib1, which is the only molecular therapy for liver cancer. We lead those treatments and they are used everywhere. Chemoembolization is used in 20% of the cases of intermediate stage patients; Sorafenib, in 40% of advanced stage patients. In the third place, I am devoting most of my time right now to the identification of new therapeutic targets for drugs. We found different important signalling pathways. Akt/mTOR pathways [a pathway regulating apoptosis or cell suicide that can suffer a mutation during cancer boosting the creation of cells], or the EGFR – Ras – MAPK pathway. These discoveries are going into clinical trial now.

Then, the aim is to research cancer in the molecular and genetic level.
Our work tries to link basic breakthroughs in molecular biology to clinical treatment. I have one foot on each side. I try to transfer my research findings and knowledge to patients. For instance, we found out that 5% of patients of liver cancer have RAS mutation [Ras proteins and genes are molecular switches and regulators and take part in many processes; their mutation in malignant tumours causes a decrease in apoptosis or cell suicide]. We are now testing a drug in a phase clinical trial. We have to do a 400-patient screening in order to include twenty of them with the mutation. We give them the drug. Patients who did not respond to anything before, can respond up to a 50%. That would be extraordinary.

I guess the study of the human genome has also allowed many breakthroughs.
Indeed. For example, we discovered an amplification in the area 11q of the genome. There is a gene there, FGF19 [in gene amplification an DNA fragment is replicated several times instead of one, as usually]. We are studying 8% of the patients with that amplification. We are in conversations with two companies to narrow down the patients to identify that 8%. Once we manage to do it, we will give them an antibody against that oncogene. That is my obsession for the next five years. The same was done in breast cancer with the amplification of gene HER2 [a gene producing breast cell receptor proteins that control the way those cells grow, divide and repair]. Tumours are addicted to a mutation. If you block it, they become separated and die, or the response rate is 50% higher. Is like in The Matrix: when the avatars were disconnected, they dropped dead.

Your active collaboration with the pharmaceutical industry in the creation of drugs is also noteworthy.
I was the main researcher in the Sorafenib trial that led to the approval of the drug. I was the main researcher in another drug called Brivanib [brivanib alaninate prevents the creation of new blood vessels, necessary for tumours to grow]. We are working with world leading companies.

How is a new drug developed?
The European Medicine Agency (EMA) or the Food and Drug Administration (FDA) ask for exceptional requirements concerning effectiveness and safety. They do not want to approve anything that is not effective. They need to be sure so they ask for trials with up to 1,500 patients and the cost to produce a new drug greatly exceeds 500 million euro. The way the approval system is currently organised, only 10 out of 1,000 drugs discovered pass the clinical stage. The rest falls during the pre-clinical or experimental stages. And out of those ten, only one drug succeeds. That means only a thousandth of suggested drugs reaches the patients. The amount of funding you need to reach success is extraordinary and the industry needs to make it profitable. That is just good judgement.

«The way it is, the industry is absolutely necessary for the discovery, development and approval of new drugs»

4-79-josep-maria-llovetJordi Play

6-79-josep-maria-llovetJordi Play

«I try to transfer my research findings and knowledge to patients»

And how is this process financed?
In the clinical stage, there are the first phases –1 and 2– and phase 3 –the main study it needs to be approved– and between 700 and 1,500 patients are included in it. There is no public institution able to fund that. Trials done in North-American public networks are loss making, and it is very difficult for them to fulfil the task. Only the industry has the capacity and resources to carry out phase 3. Many study centres can design new drugs, and make pre-clinical studies or the early phases. There are also small industries called biotech that, after discovering a new drug, can carry out phases 1 and 2. When we get to the advanced phases of clinical studies the cost is so high that the inventors of the molecule have to sell the patent. The industry is interested in buying and developing it themselves. The way it is, the industry is absolutely necessary for the discovery, development and approval of new drugs.

You explained in your conference that liver cancer is a poor country disease. Does that affect research?
Liver cancer is a poor country disease, like China, Mongolia, Central African Republic, Uganda and South Africa. Prevalence there is astonishing. Liver cancer is the fifth cancer in the world in number of cases, and the second cause of death. The impact in public health is extraordinary. However, from the point of view of research, we are ten years behind if we compare it with lung or breast cancer, for instance. There are different reasons for that. In the first place, governments just started financing liver cancer research in the last years. The NHI, which is the number one knowledge generator in the world, did not have a special program for liver cancer until 2005. And from 2007 on, the European Commission has a similar program, too. That is so because incidence of this cancer in the United States and Europe was very low compared to the big killers: lung, breast, colon or prostate cancers. On the other hand, stomach and liver cancer have a bigger effect in the rest of the world.

And how could poor countries benefit from the discoveries we already have?
Special programs for the poorest countries, like some African countries, must be created. That is what I would like to happen with liver cancer. These patients will not have access to the drugs. I would like the companies –whom I recognise have a capital role because that kind of research would not be possible without them– to consider also special programs for the Third World.

Many alternative therapies appeared around cancer. What is your opinion on them?
It is a known situation. We are academicians. We apply the scientific method, governed by rigorous rules and criteria. One cannot claim a drug is better because a patient felt better. We need a design, clear objectives, a low risk ensuring the drug works in up to 95% of the cases. That is, the risk of a false positive is lower than 5%. If you do not apply the scientific method, doctors like Ryke Geerd Hamer [who suggested an alternative therapy for cancer and was condemned by justice] can say: «that works just fine for me». But how do I know? How do I measure it? Without the scientific method it is very difficult to know if what they claim is true or not. Scientists are sceptics. We have to be convinced that something is true; that whatever this person is using cures or helps. The world of oncology and cancer patients is subscribed to para-academic medicine. Sometimes medicine does not have the solution. If a patient went through surgery, radiotherapy, chemotherapy and molecular therapy and nothing worked, at some point the doctor must talk to him –one of the hardest things– and tell him he will be given three final supports: psychological support, nutritional support and pain therapy. But we cannot give them any more drugs to improve life expectancy because everything failed. Some people and organisations take advantage of that and offer hope for the ill, and people need hope. That is something we need to live with.

You explain in your talks how genetic incidence of cancer is very low, around 5%, and the fact that the illness is more related to lifestyle.
We have to personalise cancer to cancer. In the recent case of actress Angelina Jolie and breast cancer, she is a patient with family precedents, but that is only 5% of breast cancer patients, and from them 20% will have that specific mutation. It is a small percentage, not at all comparable to the effect of tobacco. Tobacco causes 30% of cancers: larynx, pharynx, lung, pancreas or bladder, and is a co-factor of liver cancer. Another factor is diet. A fibre-rich diet prevents colon cancer, and a diet without fibre predisposes to it. Pollution can also cause a type of cancer, as can sunlight. There are many factors.

You also talked about virus and bacteria causing cancer.
Infections are responsible for 20% of cancers. They are very important, like Helicobacter pylori [coiled bacteria that live in the human stomach]. Nowadays, a two-drug treatment can remove these bacteria that cause stomach cancer. It is treatable. B virus can also be prevented with vaccines. Concerning C virus, we have an 80% response with triple therapies. The same thing happens with human papilloma virus.

There are opportunists such as the nun and doctor Teresa Forcades, very publicised in the Catalan television channel TV3, who became very famous, among other things, for not getting the vaccine for the human papilloma virus.
The general recommendation is to prevent infection of the virus because it produces cervical cancer, and we recently discovered it raises the probability for pharynx cancer. As the number of cases increases, the recommendation is to eradicate the virus, and vaccination is the only way. Treatment is not enough. This also applies to B virus. There is no vaccine for C virus, unfortunately, but the virus can be removed. Those cancers can be treated fighting the infections that cause them.

1. First and –up until now– only drug to treat liver cancer. A great investment–made by Bayer– and more than five years of research led by Josep Maria Llovet and Jordi Broix from the Clinical Hospital in Barcelona, in collaboration with Mount Sinai School and more than 120 centres around the world, were necessary. Sorafenib acts blocking the proliferation of tumour cells and prevents new blood vessels from being formed. (Go back)

«Liver cancer is a poor country disease, like China, Mongolia, Central African Republic, Uganda and South Africa. Prevalence there is astonishing»

© Mètode 2013 - 79. Online only. Pathfinders in Science - Autumn 2013
Journalist, Barcelona.