By Chung Hee-hyung
A new class of “targeted” drug therapies was once praised as a physicians’ dream come true – medicine that only attacks cancerous cells without causing collateral damage to healthy tissues. When Gleevec was introduced in 2001, it was dubbed the “magic bullet” to combat leukemia by TIME magazine, and has prompted a steady stream of targeted cancer drugs. These brand-new drugs have revolutionized cancer treatment by enabling physicians for the first time to attack cancerous cells with precise surgical strikes.
But much of the initial enthusiasm has since abated and scientists caution that it would take an arduous path of trial and error before the full potential of these drugs can be exploited.
Cancer comes in countless forms, but it is essentially an uncontrolled growth of cells that spreads malignant tumors to other parts of the body until the person afflicted dies. Traditionally, when a cancer patient’s tumor has grown too large to be removed by surgery, chemotherapy becomes the only viable option. The hope was that the chemicals employed in chemotherapy would attack fast-dividing cancerous cells, thereby keeping the growth of the cancer in check.
Unfortunately, chemicals used in chemotherapy are unable to identify features that make cancers uniquely targetable. They tend to attack all fast-growing cells, whether they are cancerous or not. Even normal cells, such as those responsible for bone marrow or hair growth are targeted indiscriminately, explaining why patients experience nausea or hair loss while undergoing chemotherapy.
Target therapies try to cope with such collateral damage by focusing on specific molecules only involved in tumor growth and progression. Once molecules responsible for cancerous mutation are identified, research can find substances that specifically attack cancer-specific cells. If chemotherapy is akin to carpet bombing, target cancer drugs are the biological equivalent of smart bombs.
Some targeted drugs act as ‘inhibitors,’ suppressing the growth of malignant tumors. For instance, Gleevec selectively blocks the communicative pathway of tyrosine kinase, a protein that instructs cancerous cells to grow and divide indefinitely.
Other targeted drugs take a more direct approach and instruct the immune system to recognize and destroy tumors in a process known as apoptosis. Some therapies interfere with the growth of blood vessels in tumors. Deprived of its source of blood supply, the targeted tumors are unable to grow beyond a certain size.
Another therapy goes even further and delivers chemicals into cancerous cells directly. Shawn Douglas of Harvard University designed a nanoshell which is less than one billionth of a millimeter. It is packed with a payload of cancer-attacking chemicals too potent to be given independently. For guidance, it contains a molecule called an aptamer that only reacts to malignant tumors. When the aptamer identifies a target, it attaches itself to the cancerous cell and releases chemicals.
As promising as targeted drugs may sound, researchers caution that they are not panaceas. “For targeted drugs to work, a tumor should first and foremost contain an identifiable target,” said Choi Jin-hyuk, professor of Hemato-Oncology at Ajou University Hospital.
“Those targets, or ‘biomarkers,’ are quite narrow. For instance, the chemical Herceptin targets overactive HER2 genes found in breast cancer patients. Unfortunately, more than 80 percent of patients do not have overactive HER2s, and for them Herceptin is practically useless.”
For Crizotinib, developed to contain the growth of lung cancer, the record is even worse: only three percent of patients showed positive responses to the medicine. Their only hope is to wait until a new targeted drug comes out that might address whichever idiosyncratic genetic mutation they might have. Provided, of course, they manage to stay alive by such a time.
But the time it takes for a pharmaceutical company to come up with a solution is agonizingly long for terminal patients. The biomarker for leukemia - the Philadelphia chromosome- was discovered nearly three four decades ago, but it was only in 2001 that the Swiss drug maker Novartis introduced Gleevec to the market.
Moreover, not all cancers are equally conducive to targeted therapies. “Some cancers are more malignant than others,” said Kang Yun-gu of Asan Medical Center in Seoul. “For pancreatic or liver cancer, targeted drugs do not work very well. But they have a better record in treating breast cancer patients.”
Targeted drugs are not stand-alone treatments, either. They work best when combined with more conventional methods like chemotherapy, especially if a cancer is at an advanced stage. “If a patient is dying, you should use every weapon at your disposal,” said Kang.
The sobriquet “smart bomb” may prove to be a misnomer, because targeted drugs do not destroy cancer cells outright. Instead, they attack more indirectly by impairing cancerous cell division, thereby slowing down the tumor's speed of growth. Such treatment merely prolongs the life span of a patient, sometimes by no more than several months.
Even the “magic bullet” Gleevec simply has the effect of temporarily keeping the development of leukemia in check, although for a much longer period. During that time, patients have to look for a suitable donor for bone marrow transplantation to eventually cure the disease.
And chances are that these cells might develop resistance against their attackers as time goes by. “Tumors sometimes undergo genetic mutation,” said Chang Sun-young, professor of Pharmacology at Ajou University. “Once transformed, they are no longer genetically identical to their predecessors, and targeted drugs are unable to recognize them. As a result, the suppressed tumor might resume its growth.”
But even the limited effects of targeted drugs are meaningless if patients cannot afford them. In fact, the cost of most targeted drugs is prohibitively expensive. It costs five million won ($4,400) to take two dosages of Avastin, a targeted drug for colon cancer. That amounts to 60 million won a year, nearly 1.5 times the average annual household income. It is a price tag that patients cannot afford unless the drug is covered by insurance, in which case the price drops to one twentieth of the original. But the medicine is still under governmental review pending approval for insurance coverage.
“Drug makers should come up with a price tag that is affordable to patients,” said Ahn Ki-jong, head of Korea Organization for Patient Group. “The government, on its part, should give its stamp of approval at the earliest possible moment. For terminal patients, even several months of delay is a matter of life and death."