(This article is the outcome of a project collaboration between the Tang Prize Foundation and The Investigator Taiwan)
Chinese original by Kuan-Chun Lan and Yi-Hao Huang (interviewers and editors)
Reviewer: Wei-you Ji
Three renowned American scientists, Dr. Tony Hunter, Dr. Brian Druker, and Dr. John Mendelsohn were named the recipients of the 2018 Tang Prize in Biopharmaceutical Science on 19 June, for the discovery of protein phosphorylation at tyrosine residues and tyrosine kinases as oncogenes, leading to the clinical success of targeted cancer therapy. Noting that their research was built on a strong scientific foundation and has valuable practical applications, the Tang Prize selection committee hoped this award can serve as an acknowledgement of the significance of their achievements.
These three laureates set remarkable examples of how basic research can be translated into clinical applications. Through understanding the mechanism of cell signaling, scientists have been able to develop drugs to block the signal transduction pathways in cancer cells, depriving these cells of the nutrients they need so as to relieve the symptoms cancer patients may suffer from. Their contributions lie in opening a new chapter in the study of cancer biology, enabling research on oncogenes, on cell signaling and on targeted therapies to flourish, transforming our understanding of the mechanism of carcinogenesis, conveying a new vision for cancer treatment, and thus bringing enormous benefits to the whole humanity.
Dr. Tony Hunter was the first scientist to discover that tyrosine can also be phosphorylated, thereby overturning the previous knowledge that kinases would only attach phosphates to two amino acids, serine, and threonine. His subsequent experiments resulted in the confirmation that the oncogene v-Src is a tyrosine kinase, an ignition switch that controls cell growth. This seminal discovery not only raised the curtain on the scientific exploration of cell signaling pathways but also motivated scientists to make continuous efforts to develop tyrosine kinase inhibitors (TKIs), hoping that these drugs can improve the well-being of cancer patients.
Knowing very well how tyrosine kinases work, Dr. Brian Druker and Dr. John Mendelsohn were able to develop drugs to inhibit their activities. According to Dr. Druker, the chromosome translocation is present in 90% of patients with chronic myelogenous leukemia (CML). When the ABL oncogene located on chromosome 9 is translocated in its entirety to chromosome 22, a fusion gene called BCR-ABL is formed. The changed chromosome 22 with the fusion gene on it is called the Philadelphia chromosome. The BCR-ABL gene encodes a constitutively active tyrosine kinase, causing the bone marrow to malfunction and overproduce white blood cells. Dr. Druker’s research findings eventually gave birth to imatinib (Gleevec®), one of the first-generation TKIs used to treat CML. He also led the successful clinical trials of Gleevec, placing this drug in the vanguard of the development of tyrosine kinase-targeted therapy.
On the other hand, Dr. Mendelsohn examined the possibility of targeting cancer by blocking the signaling pathways activated by another protein tyrosine kinase, the epidermal growth factor receptor (EGFR). The phosphorylation of this receptor protein can lead to over-proliferation of cells and thus cause cancer. Advancing from the results of this basic research, Dr. Mendelsohn developed a monoclonal antibody, cetuximab (Erbitux®), to retard the growth of cancer cells. His effort to promote the clinical trials of cetuximab eventually won this drug approval from the US FDA for its treatment of colorectal as well as head and neck cancers.
After the announcement, a special correspondent from The Investigator Taiwan also conducted an exclusive interview with Prof. Hsing-Jien Kung, academician of Academia Sinica who introduced these three scientists in this press conference.
Q: How did the research on tyrosine kinases and its applications stand out among the works of other 2018 Tang Prize candidates in Biopharmaceutical Science?
A: We received quite a few submissions this time, 137 in total. So it was realty difficult to compare one with another. Actually the final 5 nominations on the shortlist all stood a good chance of winning the prize. In the end, we decided to award the prize to the research on tyrosine kinases and its applications mainly because it proved how basic science studies can have clinical benefits, which is especially true in the case of the drug developed to treat CML. For precision cancer medicine to fulfil its promise and cure patients is something very valuable. It took more than 20 years for targeted therapy to travel from medical research to clinical applications. Therefore, the selection committee thought this was an appropriate time to recognize the efforts these scientists have made to understand the basic mechanisms of cancer growth and to improve cancer treatment.
Q: In comparison with how effective Gleevec is in treating CML, why can’t other TKIs replicate its success when it comes to treating other types of cancer?
A: CML cancer cells have fewer genetic mutations, and since it is less heterogeneous, as long as we turn off the switch that controls certain mutant genes, the symptoms will disappear. However, other solid tumors, such as colorectal cancer, are very heterogeneous. The tumor cells can be formed by different mutations. Each patient is also very different. So we will need a combination therapy to treat a solid tumor like this.
Q: The clinical use of tyrosine kinase inhibitors has hit some bottlenecks, such as patients developing resistance to drugs. How should we address this problem?
A: One of the disadvantages of targeted therapy is that a drug is specifically developed to target one disease only, so when other cells also suffer genetic mutations, patients will display new symptoms. The general approach now is to use one targeted treatment to deal with one disease at a time. Later on, even when mutations occur in other cells, we can still use other TKIs to tackle them. In this way, cancer can be turned into a chronic disease that will not kill people within a short period of time.