1.Why is cancer so hard to treat When I was growing up, cancer and AIDS were the most horrible disease terms. If you ask me, which one will be attacked first, cancer or AIDS? My answer is definitely AIDS. Why is cancer so hard to get rid of? In my opinion, there are three main reasons. The first reason is that cancer is an “endogenous disease”: the cancer cells are part of the patient’s body. For “exogenous diseases”, such as bacterial infections, we have antibiotics. The reason why antibiotics work well is that they are only toxic to bacteria and have no effect on human cells, so they can be used in very high concentrations to kill all the bacteria and leave the patient intact. It’s not as easy to fix cancer. Cancer cells are still human cells even though they have turned bad. So to fix them, it is almost a hook to kill a thousand enemies and lose 800, which is the “side effects” we often hear. For example, traditional chemotherapy drugs can kill fast-growing cells, which is certainly useful for cancer cells, but unfortunately, there are many normal cells in our body that are also growing fast, such as the hair follicle cells under the scalp. Hair follicle cells are vital to hair growth, and while chemotherapy drugs kill cancer cells, they also kill hair follicle cells, which is why hair falls out in chemotherapy patients. Hematopoietic stem cells, which are responsible for blood production and maintaining the immune system, are also killed, so chemotherapy patients have a very weak immune system and are highly susceptible to infection. The epithelial cells of the digestive tract are also killed, so the patient has severe diarrhea, no appetite, etc., etc. Such severe side effects leave the doctor with a constant trade-off, or even “compromise”, between curing the cancer and keeping the patient basically alive. That is why the concentration of all chemotherapy drugs must be strictly controlled and cannot be used all the time, but must come one course of treatment at a time. If chemotherapy drugs could be used consistently in high doses like antibiotics, the cancer would have been cured long ago. This is the main reason why I think AIDS will be overcome before cancer, after all, AIDS is an “exogenous disease” caused by the HIV virus. The second reason why cancer is so difficult is that cancer is not a single disease, but a combination of thousands and thousands of diseases. There are no two identical leaves in the world, and there are no two identical cancers in the world. Lung cancer, for example, is the new number one killer among cancers in China, with a 465% increase in incidence over 30 years. China now has nearly 600,000 lung cancer patients each year, and the United States has 160,000. People often ask me: Are there any new drugs for lung cancer in the United States? I say: Yes, but only for a very small percentage of patients. For example, Novartis’ newest anti-lung cancer drug, Ceritinib, was just approved by the FDA last week, and it works very well for about 1% of lung cancers. But why is it that the new drug we have been studying for so long is only effective in 1% of patients? Lung cancer is simply classified by pathology into small cell lung cancer and non-small cell lung cancer. Is that the only two types of lung cancer? No, it is not. We know that cancer is caused by genetic mutations, and the number of mutated genes in each cancer is more than one and varies widely. A recent systematic genetic sequencing study showed that the average number of mutations in lung cancer patients was close to 5,000 per person! The random combination of so many variables results in each patient being a little different. These 600,000+ lung cancer patients in China are actually more like 600,000 different diseases. Of course, this is not to say that we need 600,000 different drugs for lung cancer. Because out of 5,000 mutations, there are only a few mutations that are critical, and by capturing those few key genes, we can potentially develop more effective drugs. But in any case, the new drugs developed by pharmaceutical companies, even if they are panacea, can not cure all lung cancer patients. Going back to the question earlier, why is Novartis’ new drug Ceritinib effective in only 1% of lung cancer patients? Because Ceritinib targets the mutated ALK gene, and only about 1% of lung cancer patients have ALK gene mutation. (This drug is not yet available in China, but is currently in clinical trials in China, and we expect that in the near future, Chinese patients with ALK mutation lung cancer will be able to use this drug). Because of the diversity of cancers, drug companies are almost destined to develop drugs for only a small number of patients at a time, and the development cost of each new drug is 10 years + $2 billion! Such a large investment of time and money leads to slow progress, and it is a long way to go, if not a long way to go, to conquer all cancers. The third is the mutation resistance of cancer. This is common to both cancer and AIDS and is a headache for everyone. It is also the fundamental reason why we have not yet conquered AIDS. You’ve probably heard of superbugs. Before the advent of antibiotics, Staphylococcus aureus infections were deadly, such as sepsis. But after the advent of penicillin, S. aureus wimped out. But the evolution of living things is unbelievably amazing, and because we misused penicillin, at the point where it killed 99.999999% of the bacteria, one or both of them suddenly evolved resistance and they were no longer afraid of penicillin. So man invented other antibiotics, like vancomycin. But now there is already a Staphylococcus aureus that is resistant to both penicillin and vancomycin, which is a superbug. Biological evolution is a double-edged sword. Nature has given us this ability to adapt to different environments, but cancer cells not only retain the basic evolutionary ability, but they are stronger, and in response to the drugs we give them, the cancer cells are constantly changing and finding ways to evade the effects of the drugs. When Ceritinib was in clinical trials, it was found that many cancer cells discarded the mutated ALK gene after a few months of treatment and produced new mutations to help the cancer grow. Such a fast evolutionary rate always makes me sigh at the smallness of human beings in front of the natural world. 2. What causes cancer What is the most important factor that causes cancer? Genes? Pollution? Diet? Smoking? None of them. The most relevant factor to the incidence of cancer is age! In 2013, China published its first annual report on tumors, from which it is clear that firstly, the incidence of cancer increases exponentially after the age of 40 for both men and women; secondly, older men are more likely to get cancer than women, mainly prostate cancer. Most of the cancers we are familiar with: lung cancer, liver cancer, stomach cancer, rectal cancer, etc. are all diseases of the elderly! Children can get leukemia, but when have you ever heard of children getting lung cancer or liver cancer? As the average life expectancy of human beings increases, it is inevitable that the probability of getting cancer is getting higher and higher. Why do flies rarely get cancer? Because they live a very short life and die before they get cancer. Our pet dogs and cats can get cancer because their life span can be more than 10 years, which is equivalent to 70~100 years for human, so the probability of getting cancer is not low. So do other factors have anything to do with it? There must be. Cancer occurs because of genetic mutations. There are more than 20,000 genes in our body, and there are more than 100 genes that are directly related to cancer. Then why and when do genes mutate? Mutations occur when cells divide, and they occur every time a cell divides, but most mutations are not in key genes, so cancer is still a small probability event. When do cells divide? When they grow or repair tissue. My own mathematical formula is: probability of cancer (p) = number of cell divisions (a) X number of mutations per division (b) X probability that the mutated gene is oncogenic (e) In this formula, e is the same for everyone, but the key is the a and b factors. I think many causes related to cancer can be deduced and explained by this formula: (1) The older you are, the more times cells need to divide, so the elderly are more prone to cancer than the young. (2) The more damage the body’s organs suffer, the more they need to be repaired. Tissue repair is done by cell division, so the number of cell divisions increases. Therefore, long-term organ damage and repeated repair of tissues are likely to induce cancer. Sun exposure damages skin cells, so the number of sunburns is directly related to skin cancer; smoking or heavy air pollution damages lung cells, so long-term smoking is prone to lung cancer; eating irritating and contaminated food damages the epidermal cells of the digestive tract, so long-term eating of heavy spicy and contaminated food increases the occurrence of esophageal, stomach, colon and rectal cancers; chronic hepatitis B virus damages liver cells, so hepatitis B virus The chronic hepatitis B virus damages liver cells, so hepatitis B virus carriers are prone to liver cancer, and so on and so forth. (3) The number of mutations produced by each cell division is different for each person. Some people are born with some genetic mutations, which do not directly cause cancer, but can increase the number of mutations per cell division. Last year, the famous Hollywood actress Angelina Jolie (Angelina Jolie) was born with the mutation. Jolie (Angelina Jolie) wrote an article in the New York Times last year about the preventive removal of both breasts to prevent breast cancer. The story was a global sensation. The reason for her decision was that both her family and herself carry the BRAC1 gene mutation, which causes her cells to divide 100 times more than normal, so many women in her family, including her mother, get breast cancer early, and she personally is estimated to have an 87% chance of getting breast cancer and a 50% chance of getting ovarian cancer. Her move was a bit impulsive to me from a scientific point of view at the time because there was no guarantee that other parts (especially the ovaries) would not become cancerous, but I was still incredibly impressed by her courage. When I heard later that Julie was going to have her ovaries removed, I could only think of one word: “brave”. Probability of cancer (p) = number of cell divisions (a) X number of mutations per division (b) X probability that the mutated gene is an oncogene (e) You may want to find out the factors you are interested in and see if this formula really applies. 3.Why children get cancer Usually, cancer is a disease of old age, and the incidence of all kinds of cancers plummets as we get older. But there are exceptions to everything. We should have heard many stories of young people, children and even babies getting cancer, especially leukemia in our life, why is this? Cancer is caused by mutations, and it takes time to accumulate mutations caused by acquired factors, and it is impossible for cancer to be caused by purely acquired factors within a few years. Therefore, it is certain that a baby or a child of a few years old must have a congenital factor to get cancer: either the parents inherited the cancer-causing gene, or the fetus developed a mutation during pregnancy for various reasons. An important task of bioassay technology now is to detect congenital mutations as early as possible in the pregnancy process, so that parents can at least choose whether to abort the baby if it proves to have a serious genetic disease. The maturity of genetic testing technology and the recognition of oncogenes has led me to believe that whether parents carry cancer-causing mutations should become a routine part of preconception medical examinations. Testing for mutations that occur during pregnancy is relatively much more difficult, mainly because it is difficult to obtain samples during fetal development. Traditional tests such as Down syndrome screening also rely on amniocentesis, which is a procedure that also carries some risk to fetal development. A lot of people are working on puncture-free testing technology, which is a huge market that is believed to be breaking through within a few years. But no matter how advanced the testing technology is, a headache will always exist: even if the fetus is known to have a genetic mutation, due to the complexity of the organism, it may not be 100% cancerous, and the parents will be faced with a very difficult choice with no right answer. Should they risk having the baby or continue to wait for the next healthy baby? It is believed that with the maturity and widespread use of genetic testing technology, this question will become increasingly prominent. There are now approximately 500,000 children worldwide with various types of cancer, and cancer is the number one killer of children’s deaths. The most common childhood cancer is leukemia, accounting for nearly 40% , which is why we keep hearing stories of children with leukemia requiring bone marrow donation. This is followed by neurological tumors, then bone and various soft tissue tumors. The approach used to treat pediatric tumors is also surgery + chemotherapy + radiation therapy. In contrast to adult cancers, chemotherapy and radiation therapy are often surprisingly effective for pediatric cancers, and many pediatric patients are able to be cured by conventional chemoradiotherapy even when bone marrow transplantation is not considered to cure leukemia. The reasons for this may be complex. First: childhood cancers tend to have few mutations, so the likelihood of cancer resistance is low; second, unlike conventional thinking, children often receive more doses of chemotherapy and radiation than adults relative to their body weight, due to the fact that children have stronger tissue repair capabilities and can tolerate stronger side effects from chemotherapy and radiation. Both of these are important factors in the much higher cure rate of childhood cancers than adult tumors. However, there are gains and losses. While high-dose chemotherapy and radiotherapy can cure tumors, they can also cause a variety of long-term and serious side effects in children: neurodevelopmental deficits, mental retardation, depression and suicidality, infertility, and so on. Therefore, there is an urgent need to develop drugs for pediatric cancer. Unfortunately, compared to our investment in adult cancers, research on pediatric cancers is lagging far behind. The underlying reason is due to the low number of childhood cancers. This leads, on the one hand, to an insufficient number of samples and therefore fewer laboratories for basic to medical translational research. More importantly, because of the small number of patients, big pharmaceutical companies are often reluctant to invest human and financial resources in research specifically on pediatric cancer, both because clinical trials are difficult to conduct and because even if a drug is made, it will not pay for itself. Finally, because there are few pediatric cancer patients around, society does not pay enough attention to this disease, and there is not enough pressure on the government. I have become involved in childhood cancer research in recent years, and I have had a lot of contact with people from all walks of life, and I feel a lot of emotions. Last week I went to a conference on rhabdomyosarcoma in Cold Spring Harbor, Long Island, sponsored by a couple who lost their son to the disease last year. There are only about 400 cases of rhabdomyosarcoma a year in the entire United States, mostly in children. With so few patients, the survival rate for this disease has not changed in the last 30 years! The couple was very wealthy and used the most expensive drugs at the best oncology hospitals in the United States, but remained deeply desperate during the treatment process. So after the death of their son, they set up a fund to raise awareness of these “rare diseases” in the community. At the meeting, I met with them and several other parents of patients, and heard several doctors tell their patients’ stories, from happy stories of healing to sad stories of misfortune. I feel that only by seeing such examples firsthand can researchers know their mission and responsibility. Together with these research and clinical friends, we have established an advocacy charity for rhabdomyosarcoma. It contains all the content we can find related to rhabdomyosarcoma, and all scientific articles and advances are updated all the time, and there are monthly online lectures by scientific and clinical experts. Families of patients can also share and encourage each other. In China, research on rhabdomyosarcoma is even more scarce, as many doctors have never seen this tumor before, so many people end up not knowing what they have. During free time, the important web pages on the website are translated into Chinese for the convenience of doctors and patients in China. In the face of childhood cancer, on the one hand, there is the helplessness of patients’ families, on the other hand, there is the lack of scientific research resources and the stagnation of drug development. It is strongly urged to increase the attention to this direction, and only when the society and public opinion push the government to act, it is possible to force drug companies to make more investment. I hope that one day no child will be beaten by cancer again!