(This article is the ourcome of a project collaboration between the Tang Prize Foundation and Pan Sci Taiwan.)
Chinese original by Chi-Chien Lee, Hung Lo and the Editorial Board of Pan Sci Taiwan
From the ancient Egyptian medical texts written on papyrus papers to the mummified skeletal remains of Peruvian Inca, there exists tangible evidence showing how human beings were plagued by cancer. Even in the modern world where medical technology advances every minute, cancer is still the leading cause of death in Taiwan, leaving us wonder whether we will ever find a treatment effective enough to end mankind’s centuries-old battle with this medical nightmare.
Before imatinib, the star of targeted cancer drugs, was approved by the US Food and Drug Administration (US FDA) in 2001, the mainstays of treatments would be surgery, radiotherapy and chemotherapy. However, not only are these treatments unable to identify and attack specific types of cancer cells, but in most cases, they also cause devastating side effects. That makes Dr. Tony Hunter, Dr. Brian J. Druker and Dr. John Mendelsohn the worthy winners of the 2018 Tang Prize in Biopharmaceutical Science, for their research efforts ushered in a whole new era in the history of cancer treatment, the era of targeted cancer therapies.
What is the mechanism of these miracle therapies and how were they developed?
Tyrosine phosphorylation, a discovery that paved the way for the development of targeted therapies
“It is an amazing feeling to be the first person to know something right.”—Dr. Tony Hunter, from his 2017 interview.
Let’s start from the beginning. In the 1980s when Dr. Hunter was working on his biomedical research, scientists could only name two amino acids that can be phosphorylated, i.e. threonine and serine. “Phosphorylation is the chemical addition of a phosphoryl group (PO32- ) to an organic molecule.”[1] It is an important biochemical process that can affect cell signaling or even the function of proteins. And this is where Dr. Hunter came into the scene. When studying the protein kinase of the tumor-inducing polyomavirus, he serendipitously discovered the third amino acid the phosphoryl group was added to, namely tyrosine. This in turn “led to the fortuitous observation that”[2] the transforming protein of Rous sarcoma virus was also a tyrosine kinase. These findings suggested that tyrosine phosphorylation could trigger cancer cells to divide and grow. As a result, they opened the door to the development of targeted cancer therapies as we see today.
So why do the chemical activities of protein kinases have such profound impact on our body? To answer this question, we need to take a long, hard look at intercellular communications. When a cell receives an external signal, this signal will then be propagated from one protein to another until it reaches the nucleus of that cell. The transmission of signals “plays a key role in diverse biological processes,”[3] such as DNA replication, cell growth, cell division and cellular metabolism. This process is known as “intracellular signal transduction.” We can liken it to a relay race and every molecule to a runner. Messages have to be transmitted from one molecule to another in order to instruct all kinds of cell behaviors.
The human kinome comprises a variety of tyrosine kinases. They are the first legs in this relay race because they will change the structure of their downstream proteins (by adding a phosphate group to an amino acid, an organic compound proteins are made of). Therefore, they “are important mediators of this signal transduction process, leading to cell proliferation, differentiation, migration, metabolism and programmed cell death.”[4] Moreover, all receptor tyrosine kinases (RTKs) consist of “intracellular receptors…found on the inside of the cell” and “cell-surface receptors…that bind to ligands on the outside surface of the cell.”[5] When a receptor tyrosine kinase is overexpressed or when tyrosine phosphatases (“a group of enzymes that remove phosphate from tyrosine residues and thereby are the major means of terminating RTK signal.”[6]) cannot carry out their main function, there is a likelihood of the overproduction of cells and even the formation of tumors.
Once we know the pathogenesis of certain types of cancer, as long as we can find a way to inhibit the malfunctioning tyrosine kinases, maybe we will be able to control the growth of cancer cells—this is the principle behind targeted cancer therapies.
The birth of a medical star: imatinib
Standing on Dr. Hunter’s shoulders, Dr. Druker drew applause for the development of imatinib, the first tyrosine kinase inhibitor (TKI) drug for the treatment of chronic myelogenous leukemia (CML).
Though as early as 1845, there were already published clinical descriptions of CML, it was not until 1985 that scientists can point to chromosome translocation as the main culprit of this specific human malignant disorder. Subsequent research showed this translocation is responsible for the formation of the BCR-ABL fusion gene inside CML patients’ bodies. Even before this chromosomal abnormality takes place, the ABL1 protein is already oncogenic because it is a tyrosine kinase that acts like an on-off switch for the proliferation of white blood cells. When the switch gets stuck in the on position, the cells will grow incessantly and leukemia occurs.
Therefore, in theory, if we can fix this switch, we can stop the bone marrow from rapidly producing abnormal white blood cells. Technically, it means to make a molecule that can occupy the ATP-binding site, disrupting its work and blocking the BCR-ABL signal transduction pathways. Then we will be able to prevent the progression of leukemia. In reality, however, things are more complicated than we imagine. This molecular drug has to complete a series of clinical trials to prove that while eliminating cancer cells, it won’t cause too many unfortunate side effects.
In the first few years when Dr. Druker’s experiment just got off the ground, the prognosis of CML patients was quite gloomy. About 25% to 50% of them would die within one year. His practical experience as a clinician made him brave all kinds of obstacles and pledge to find a real effective treatment. Trial after trial conducted by two pharmaceutical companies finally led to the birth of the first generation drug, imatinib (Gleevec ®), from which today’s CML patients benefit greatly as their survival rate is almost the same as those with other diseases.
Cetuximab, an antibody that treats cancer
As mentioned above, a receptor tyrosine kinase has two ends, and while imatinib is used to inhibit the activities of the intracellular receptors, Dr. John Mendelsohn’s main contribution is to develop an antibody that targets the cell-surface receptors.
In the 1950s, scientists had already found out that the epidermal growth factor (EGF) can drive cell growth. The EGF itself doesn’t enter cells. It relies on the epidermal growth factor receptor (EGFR) located on the cell surface to do the job. The EGFR is also a tyrosine kinase, conveying messages by phosphorylating the downstream signaling molecules. Something in Dr. Mendelsohn's research that is similar to Dr. Druker’s is that any aberrant tyrosine kinase behavior, in this case the overexpression or mutation of the EGFR, could lead to excessive growth of cells and eventually to malignancies.
A receptor is like a small mailbox on the cell membrane that is designated to receive messages from certain molecules. Let’s cite the EGFR as an example. “When growth factor ligands bind to their receptors, the receptors pair up and act as kinases,” relaying signals from one molecule to another and triggering a series of phosphorylation events that will “promote cell growth and division.”[7]
If we want to stunt the growth of cancer cells, how should we tackle such a huge number of the EGFR mailboxes? One effective way is to flood them with similar junk mails until they overflow.
It’s about time an antibody that can identify specific molecules on the cell surface entered the arena of immunotherapy. In the early 1980s, immunotherapy wasn’t recognized as a possible treatment for cancer. Thanks to the efforts made by Dr. John Mendelsohn and his colleague, cetuximab (Erbitux®), an antibody which binds to the extracellular domain of the overexpressed EGFR and inhibit its activation, was finally approved by the US FDA in 2004, after many successful clinical trials. It became an important targeted therapy drug for the treatment of colorectal cancer and head and neck cancer (including cancers of the mouth, nose, throat, larynx, sinuses, or salivary glands.) Many research works have since ensued to unlock the potential of antibodies as tyrosine kinase inhibitor drugs.
Notes: Schematic representation of how cetuximab mediates its antitumor activity. The antibody binding to epidermal growth factor receptor (EGFR) prevents receptor dimerization, leading to inhibition of receptor function as shown. Cetuximab binding also fosters receptor internalization and promote antibody-dependent cell cytotoxicity.
Source: Patil, N., Abba, M., & Allgayer, H. (2012)
An ongoing replay race for unraveling the mystery of life
Signal transduction is a complex relay of messages between various molecules, and human beings are running a real marathon to fully understand the etiology of cancer and how to cure it. Our hats off to many scientists who have devoted their lives to cancer research. Because of them, every link in the intricate biological mechanism of our body can be gradually discovered and deciphered. This long race began when Dr. Hunter stumbled across tyrosine phosphorylation, showed the Src oncoprotein is a tyrosine kinase and laid the foundation for the vibrant culture of research on targeted cancer therapies. The second leg was the development of imatinib, the first TKI drug, which, kudos to Dr. Brian Druker, was approved by the US FDA in 2001. Then we entered the third leg when in 2004, cetuximab, the first EGFR monoclonal antibody targeting colorectal cancer and the result of Dr. John Mendelsohn’s painstaking research, also got the nod from the US FDA. Finally dawn started to break over the landscape of cancer treatment. Not only has the number of people dedicating themselves to the development of targeted therapies gone up ever since, but the types of both the drugs and cancer they can treat have also increased steadily.
Though mankind’s war with cancer is still going on, what lies ahead is no longer sheer darkness of despair. As long as we embrace the spirit of a true scientist, embodied by these three laureates, stand firm despite all the confusions and obstructions, never give up in the face of constant failures, and fully apply ourselves to our quest for the answers to the most important questions, the day will finally come, when we can claim victory over this mortal enemy that has tormented humanity for centuries.
References:
Druker, B. J. (2009). “Perspectives on the Development of Imatinib and the Future of Cancer Research.” Nature Medicine, 15(10), 1149.
Helmenstine, Anne Marie (2019) “What Is Phosphorylation and How Does It Work?”
https://www.thoughtco.com/phosphorylation-definition-4140732
Hunter, Tony. (2015), “Discovering the First Tyrosine Kinase.” Proceedings of the National Academy of Science 112(26):7877-82.
Khan Academy. “Ligands and Receptors.” https://www.khanacademy.org/science/biology/cell-signaling/mechanisms-of-cell-signaling/a/signal-perception
Khan Academy. “Signal Relay Pathways.” https://www.khanacademy.org/science/biology/cell-signaling/mechanisms-of-cell-signaling/a/intracellular-signal-transduction
Manash K. Paul & Anup K. Mukhopadhyay. (2004). “Tyrosine Kinase-Role and Significance in Cancer.” International Journal of Medical Sciences, 2004; 1(2):101-115, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1074718/
O'Dwyer, M. E., & Druker, B. J. (2000). “STI571: An Inhibitor of the BCR-ABL Tyrosine Kinase for the Treatment of Chronic Myelogenous Leukemia.” The Lancet Oncology, 1(4), 207-211.
Patil, N., Abba, M., & Allgayer, H. (2012). “Cetuximab and Biomarkers in Non-Small-Cell Lung Carcinoma.” Biologics: Targets & Therapy, 6, 221.
Zhong, Yao & Igor Stagljar. (2017). “Multiple Functions of Protein Phosphatases in Receptor Tyrosine Signaling Revealed by Interactome Analysis.” Mol Cell Oncol, 2017, 4(3):e1297101, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462513/
Notes:
[1] Anne Marie Helmenstine, “What Is Phosphorylation and How Does It Work?”
[2] Tony Hunter, “Discovering the First Tyrosine Kinase.”
[3] Paul, MK and Mukhopadhyay AK, “Tyrosine Kinase-Role and Significance in Cancer.”
[4] Paul, MK and Mukhopadhyay AK, “Tyrosine Kinase-Role and Significance in Cancer.”
[5] Khan Academy, “Ligands & Receptors."
[6] Yao Zhong and Stagljar Igor, “Multiple Functions of Protein Phosphatases in Receptor Tyrosine Signaling Revealed by Interactome Analysis.”
[7] Khan Academy, “Signal Relay Pathways.”
