Of the 7.35 world population in 2015, 26.99 million people died, and of these, 3.94 million people died of cancer, i.e., 1 in every 7 deaths worldwide was due to cancer. If we try to understand the risk factors, we would see that tobacco use accounts for almost 33% contribution towards cancer incidences. In fact, the maximum number of deaths from cancer were from trachea, bronchus and lung cancers and about 17 types of cancer would arise from the use of tobacco, including bladder cancer. It is very clear that almost 1/3rd of cancer can be eradicated in the next decade by completely turning one’s back from tobacco use, but then we humans were never known to be prudent.
Obesity, a disease characterized by overweight and metabolical disorders, contributes towards another ten types of cancer, about 20% of total incidences. Infectious agents like human papilloma virus (HPV), Helicobacter pylori and Hepatitis C are known to cause around 15% of cancers, ranging from cervical to lower gastric to liver, respectively. Similar to these diverse contribution towards cancer incidence, is the diversity of different cancers and their treatments. However, all such diverse cancers can still be classified into three broadly common parts; viz., Initiation, Progression and Metastasis, which eventually leads to death. The patient or hosts repair system failure is attributed to the cause, whereas the failure of the immune system is responsible for the progression, and metastasis of cancer cells.
If one has to explain the initiation of cancer to somebody who is not versed with advanced biology, then it would be fair to say that the cause is almost always some genetic mutation. This can be in the form of an oncogene, that is analogous to a “stuck accelerator in an automobile”, or a tumor suppressor gene analogous to a “dysfunctional brake in an automobile” and both eventually leading to car accident and death. There are stability genes or caretaker genes, that were supposed to ensure the car had no defect, akin to an inept mechanic, but had failed to do so. Such genetic defects or mutations can be either germline, that is they were there when the car was originally made or somatic, which means they developed during the life of the car.
In a scientist’s language, such defects or mutations that are responsible for cancer initiation are mostly in signalling (PI3K/AKT/mTOR/PTEN, Ras Pathway) or developmental pathways (Wnt / Notch / Hedgehog). Mutations in PI3K, Ras etc acts like a dysfunctional accelerator, whereas mutations in p53, Rb etc acts as a dysfunctional brake. Mutations in repair enzymes bring up the repertoire of inept mechanic genes (PARP).
Further mutations in such signalling pathways accentuate the progression of the disease. The tumor microenvironment also plays a very key role in this. Unconditional growth is the trademark of any cancer and that would require a lot of building blocks, i.e. raw materials for all the anabolic processes. This in turn uses up a lot of energy and creates an environment that is low in oxygen, which in scientific terms is known as hypoxia. Also, in order to feed all the newly growing cells, blood needs to access them, just like a basic infrastructure of roads are required before building highrises. Such a process of new blood vessel formation or angiogenesis is another key driver for cancer progression. The body, being very smart, also believes in recycling it’s junk and making the most out of it, a process known as autophagy, where it breaks down lipids, proteins etc, into building blocks which are further used in the synthesis of new proteins and macromolecules.
The last nail in the coffin is marked when the cancer metastasizes. This is a process by which a cancer cell, abandons all the other cancer cells and enters into a voyage for the unknown, foregoing all cell-cell interaction (epithelial mesenchymal transition), penetrating tissues and entering blood vessels (extravasation), journeying through the blood, evading all immune cells and finally anchoring into some other land, some other tissue. If that land is too foreign, the cell dies, and that is the case 99.9 % of times, but there are rare instances, when such a cell finds nourishment in the foreign “soil” and acts as a “seed” to give rise to a tumor tree. This highly inefficient and adventurous journey of cancer cells, known as metastasis, kills 90% of cancer patients.
Therefore it is imperative that battling this menace or three legged giant called cancer, one has to target all its three legs; for cancer can run even on one single leg, and when it is necessary can even outgrow a fourth leg called immunosuppression, by which it efficiently bypasses the body’s immune system. Since the nineteenth century, traditional radiotherapy has only targeted the road on which the giant has been running, thus delaying its sprint but eventually unable to stop the home run. After the 1940’s, chemotherapy was introduced, and definitely showed more success. However it killed a lot of innocent spectators and by standers and only hurt cancer, unable to kill it. Then, since the late nineties came the era of targeted therapy which addressed for the first time one of the limbs of cancer, severely handicapping it.
This series of article will discuss how different targeted therapy drugs have combated cancer, how cancer have eventually had the last laugh, if not always, most of the time. It’s been a cat and mouse game, but make no mistake, it’s no Tom and Jerry, and people are still dying; and by 2030 it is estimated that total cancer deaths would reach 13.2 million.