Why haven’t we been able to find a cure for cancer yet?

It’s a question that spontaneously arises whenever we hear of someone dying of cancer. The discovery of antibiotics and the invention of vaccines drastically reduced the number of deaths due to bacterial and viral diseases, respectively. These innovations, together with the general improvement of healthcare conditions, led to a significant extention of the average life, revealing that in old age (in most cases) we are susceptible to different types of cancer.

But let’s see a few numbers in detail. After the cardio-circulatory system-related deaths (ischemic heart disease and stroke), cancer is the second leading cause of death worldwide, with 9.6 million deaths in 2018 (Top 5: lung cancer: 1.76 million deaths; colorectal: 862 000 deaths; stomach: 783 000 dead; liver: 782 000 dead; breast: 627 000 dead). One in six deaths is due to a tumor, but the distribution is not homogeneous: about 70% of cancer deaths occur in low- and middle-income countries. Furthermore, although we are far from defining a cure for cancer, mortality has dropped dramatically. For example, in 2015, deaths from cancer in the US decreased by 26% compared to 1991, which means having averted 2.4 million deaths in the specified timeframe.

 

What are tumors?

A tumor arises when a cell of the organism undergoes a process of transformation, passing through a pre-cancerous stage to the stage of malignancy. A tumor cell begins to proliferate in an uncontrolled manner, ignoring signals that the body sends them to stop. It is therefore a different kind of disease than bacterial and viral infections.

Tumor causative factors can be grouped into: physical agents (ultraviolet and ionizing radiation), chemical agents (asbestos, cigarette smoke, etc.) and biological agents, such as viruses, bacteria and parasites (papillomavirus can cause cervical cancer; combined hepatitis B and C are related to liver cancer; helicobacter pilori can cause stomach cancer; schistomatosis, caused by a parasite belonging to the phylum of platyhelminths, can cause bladder cancer).

These agents cause a mutation, known as driver mutation (or guide mutation), after which the process of malignant transformation begins. I will explain this process in another post, while now I will return to the original question:

 

If we know all these things, why haven’t we been able to find a cure for cancer yet?

For several reasons. First of all, because there are hundreds of different types of cancer, and you can not treat them all the same way. When we need to repair something at home, we choose tools depending on the damage. Or would anyone fix the leaky faucet with nails and hammer? There are hundreds of different types of cells in the human body, and each of these can give rise to a different type of cancer. Different illness, different care.

 

Received, there are hundreds of types of cancer. And cannot they be treated one at the time?

Sure. In fact some tumors are treatable, with a high percentage of remission, like chronic myelogenous leukemia and acute lymphoblastic leukemia. But here the complicated part begins, which is at the root of the issue:

 

How do cancer cells differ from healthy cells?

Here we are at the heart of the matter. How do mutations in DNA lead to tumor transformation? To give an exhaustive answer and make it understandable, I need to spend a few lines explaining a couple of notions of cell biology.

The genome consists of a coding part and a non-coding part, which alternate in all the chromosomes. The coding part consists of genes, while the non-coding part includes regulatory regions and others to be defined. Genes (approximately 20,000 in the human genome) code for proteins and each gene corresponds to a protein. Proteins are the effectors of all functions in the cell. To make an example, we can say that each gene represents a command in an instruction booklet, and the physical actions of the person who executes these commands are proteins. Some proteins are constantly present in the cell (like proteins that give it the “shape”), while others are produced only when necessary (like the insulin that is produced when glucose level increases in the blood), and then they are degraded. Furthermore, not all 20,000 genes are active, which means that we do not have all the 20,000 kinds of proteins expressed in each cell. Some genes are universal and their proteins are omnipresent, while others are specific for the cell type (insulin is produced only by the pancreatic beta cells). It is difficult to estimate, but approximately 10 000 genes are expressed on average in a cell.

Is that it? Not really. Here come two more levels of complexity: splicing and post-translational modifications. In short, genes are not linear sequences of DNA, but they are made up of coding DNA segments (exons) separated by non-coding segments (introns) and the protein is translated only by exons. Based on the input received at the time of translation, the protein is generated by jumping or including one exon rather than another (the gene with more exons is titin, which contains 312, in second place is nebulin with 150 exons, while in third position we find nesprin 1 with 146 exons). This process is called splicing, and it makes us understand that there are different versions of the same protein, even if usually one is predominant. What are post-translational modifications instead? After the protein is translated from the gene, it can be further modified with some “details” (even dozens) that can affect its function (better not to go into the details of this, because I should write an entire chapter about it).

At this level of complexity, we have understood that a protein exists in different versions of splicing and with various post-translational modifications, which exponentially increase the complexity within the cell. Professor Bernhard Küster from the University of Munich said that it would not be an exaggeration to hypothesize the presence of 100,000 different proteins, or even more, in a cell.

So here we come to the answer we were looking for. It is not possible to find a cure for cancer because it would serve a different therapy for each different mutation that causes a specific tumor. A mutation can affect a coding region of a gene, or a specific splicing site, or alter a post-translational modification, or be in a region with regulatory function on a protein (which would be expressed without mutations, but at a too high or too low level, altering cellular processes in which it is involved).

One consideration to keep in mind is that usually a mutation is not associated with a type of tumor. The same mutation can determine the onset of one type of tumor rather than another, depending on the type of cell in which it occurs.

 

How are cancer-driver mutations identified?

By sequencing patients’ DNA. Recently, DNA sequencing techniques have improved dramatically, but we are far from offering DNA sequencing as a basic diagnostic tool, even if this seems to be the chosen path. A major problem is represented by the fact that DNA sequence varies significantly from individual to individual. This is called genetic variability, a very normal phenomenon that makes us different from one another. In this way it becomes difficult to determine which variation, among the thousands identified with sequencing, is responsible for the tumor. To do this, population studies are needed to analyze data from dozens of patients, but these are long, expensive studies without obvious success.

 

So why are some tumors curable?

A few paragraphs above I mentioned acute lymphoblastic leukemia and chronic myeloid leukemia as examples of curable tumors. This is because the mutation that characterizes them has been identified several years ago. It is a translocation between chromosomes 9 and 22 (which means that these two chromosomes exchange a piece of DNA), which leads to the production of a chimeric protein (the two break points break two genes that are fused together after the translocation occurs). This mutant protein has been the target of numerous studies that have led to the definition of an extremely specific drug to inhibit it. The advantage is represented by the fact that this chimeric protein is expressed only by tumor cells, so the drug has no effect on healthy cells.

Unfortunately, in the majority of cases, the driver mutation does not generate such massive consequences like chimeric proteins. Therefore it is extremely difficult to create drugs able to inhibit specifically the mutated protein in the tumor and not the healthy counterpart in all the other cells.

We can conclude that, in addition to the problem of detecting the driver mutation of the tumor, there is the second problem – once the mutation has been discovered – to create a drug that is specific enough to hit only the tumor cells. The lack of specificity is the reason why chemotherapies cause so many side effects in patients.

 

Is the future really so black?

No. As already written, cancer mortality decreases constantly. This happens because we are collecting more and more information about tumors, testing new potential drugs, offering more efficient diagnostic services (remember that early diagnosis is the first step to defeat a tumor), doing more prevention (stop smoking, do not exaggerate with alcohol, do exercise, eat more fruits and vegetables and limit red meat).

Thanks to the new information gathered with DNA sequencing, nowadays we are starting to consider a tumor classification based on the type of driver mutation, rather than on the organ they hit: in fact, if I have to fix a hole in the wall, I use plaster and a spatula, regardless of whether the hole is in the kitchen rather than in the bedroom. The possibility of treating different types of tumors with the same driver mutation using a unique drug is becoming real.

In conclusion we can say that the future is brighter than the present, at least concerning scientific research.

 

Sources:

https://www.cancer.org/latest-news/facts-and-figures-2018-rate-of-deaths-from-cancer-continues-decline.html

http://www.who.int/news-room/fact-sheets/detail/cancer

https://www.wikipedia.org/

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