Targeted Therapy—Clinical Applications Yielded by Basic Research
2021.03.05
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Only through a deep understanding of cancer pathogenesis can we find the real target for treatment

By Hui-Chen Lin

We all dread hearing the word cancer. Fortunately, as cancer treatment continues to evolve, official reports in Taiwan which show cancer patients’ five-year survival rates from 2003 to 2007 and from 2013 to 2017 indicate that during these ten years, the overall survival rate has increased by nearly 10%. In the case of lung cancer, the survival rate has even grown by 15%. James Chih-Hsin Yang, director of National Taiwan University Cancer Center, is an expert on lung cancer and has led many clinical trials of cancer drugs. As far as he is concerned, the two reasons for the increase we saw in the survival rate are “early detection and targeted therapies that help prolong life for terminally-ill patients.” It has been more than 20 years since targeted therapy first came out. The therapy has proven to be effective in many types of cancer originally thought to be untreatable and thus elevated cancer treatment to a new level.

 

Before scientists were able to determine the molecular reactions that could turn normal cells cancerous, there was little certainty about whether the existing drugs and therapies would work, not to mention the severe side effects caused by the toxicity of these treatments. The goal of targeted therapy is to focus on certain molecules related to cancer cells as a way to develop drugs that specifically suppress the proliferation of these cells. But to find the right target requires a deeper understanding of cancer pathogenesis.  

 

Most of the targeted therapies we have now inhibit the activity of tyrosine kinases. These kinases are enzymes that regulate cell signaling. Starting from the cell surface, receptors respond to external stimuli and subsequently initiate a series of molecular signaling pathways in a cell. Signals are often passed on by phosphorylating tyrosine residues on one protein after the next by tyrosine kinases. These pathways are central to cell growth, migration, and death.  Unchecked cell growth that leads to cancer is usually due to defects in cell signaling. “Though there are many factors that regulate the growth of cancer cells, tyrosine kinases are the one scientists have better control of at the moment,” James Yang explained.

 

Tyrosine phosphorylation as well as the presence or abnormal functions of tyrosine kinases have a lot to do with cancer. The fundamental knowledge of this important connection was revealed through the experiments conducted during the 1970s and 80s by Tony Hunter of the Salk Institute. The work he did during that time inspired a plethora of related research and contributed to the development of a variety of cancer drugs. One class consists of small molecule inhibitors targeting mutated or malfunctioning tyrosine kinases, and the most groundbreaking of them all is imatinib (Gleevec®), developed by Brian Druker and used to treat chronical myeloid leukemia (CML). Academician of Taiwan’s Academia Sinica Mien-Chie Hung noted that before 1998, the only treatment for CML was bone-marrow transplant. But it would cause patients tremendous pain and their five-year survival rate was only 30%. Since Gleevec® was approved by the US Food and Drug Administration in 2001, the five-year survival rate of CML patients has gone up to 98%. “It’s almost as good as being cured,” Dr. Hung remarked.

 

There is an alternative strategy: develop antibodies that recognize receptor tyrosine kinases and then shut down their activities. One of the examples is cetuximab (Erbitux®), a drug targeting epidermal growth factor receptor (EGFR) that John Mendelsohn spent twenty years developing and is used to treat colorectal cancer as well as head and neck cancers. Mien-Chie Hung worked in the field of molecular cancer biology in the States for more than forty years and was able to witness this part of the history. He recalled that “when Mendelsohn first proposed this concept, he was met with numerous pushbacks and no pharmaceutical companies wanted to work with him.” However, as a visionary, Dr. Mendelsohn never gave up simply because his idea was not well-received, and his perseverance finally paid off. These three American scientists all worked on tyrosine kinases. Like runners in a relay race, they took turns to engage in different parts of this research on molecular targeted therapy and their achievements eventually earned them the 2018 Tang Prize in Biopharmaceutical Science.

Molecular biology has allowed scientists to uncover the face of cancer cells one step at a time, identify cancer-specific mechanisms with higher precision and therefore know how to suggest treatments that correspond to different types of cancer. In addition, inhibiting cancer cell activity rather than eliminating them by mass destruction means that targeted therapy can reach its goal of improving the quality of healthcare.  There is, nonetheless, a limit to what targeted therapy can do. It cannot target the more heterogeneous cells that compose a solid tumor. Instances of drug resistance also occur more often. Thus, to truly win the battle against cancer, we need more breakthroughs. Mien-Chi Hung believes that immunotherapy which activates a patient’s immune system to attack cancer cells may be where the hope lies in the future.

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1.Lin Hui-Zhen is a contributor for the Scientific American magazine. She obtained an MA degree from National Taiwan University’s Department of Animal Science and Technology, and has an MA degree in Science, Health & Environment Reporting from NYU’s Journalism Institute.
2. This article is the outcome of a project collaboration between the Tang Prize Foundation and the Scientific American. The opinions expressed here are the author’s own.
3. English translation by Wei-Hsin Lin.