Cell specificity: Targeting cancer cells and nothing else

By Dr. Kevin Lan

The first chemotherapy drugs developed for human cancer were in many ways very crude instruments. Following Germany’s introduction of mustard gas as a tool for chemical warfare in World War I, it was discovered that many of its victims had loss of certain types of fast-dividing blood cells (myeloid and lymphoid) in their bodies. Reasoning that the agent somehow stopped the growth of these fast growing cell types in the human body, scientists at the United States Department of Defense wondered whether mustard gas could also work on other fast growing cells, such as human cancer cells. They went on to derive one of the first chemotherapies from nitrogen mustard, and successfully treated people with leukemia and lymphoma in clinical trials in 1942.

A few years later, Sidney Farber (an American Pathologist) was studying the effects of a vitamin called folic acid on kids diagnosed with acute lymphoblastic leukemia (ALL). While it was not fully appreciated at the time, Folic acid is actually an essential molecule for making DNA and to Dr. Farber’s horror, actually accelerated the growth of ALL cancers in children. Using this information however, he was able to work with other scientists to modify folic acid into a form that actually blocked its effect (so-called “antifolates”). This was important because it was one of the first cases of rational drug design, where scientists make new therapies based on knowledge of how molecules interact with their targets in the cell. Testing the antifolates in ALL patients, he was able to induce cancer remission, earning Dr. Farber the title of “father of modern chemotherapy”.

What was unfortunately common in these early cancer treatments (many of which are still used today) is that they acted on all fast-growing cell types in the human body non-discriminately. By creating massive damage to DNA, or targeting the process of cell division itself, early chemotherapies not only stopped the growth of cancer cells, but also affected many other cell types. As a result, these drugs had many harm side effects on patients, such as inducing hair loss, nausea, vomiting and problems in fertility and memory. Scientists also now know that not all cancer cells in a tumour are fast-dividing. Some cancer cells can lie dormant and escape chemotherapy, meaning that other strategies for targeting these cells are needed. A major topic in designing new treatments for cancer in the modern era has therefore been in cell specificity: How do we find new ways to target just cancer cells, while sparing the normal cells in the body?

A classic example for the newer type of cancer cell-specific drugs is called Herceptin, used to treat certain types of breast cancers. In the 1980s, scientists discovered that a gene called HER2/neu was produced in excess in about 25-30% of human breast cancers as well as ovarian cancers. Dr. Alex Ullrich, a scientist working at Genentech and Dr. Dennis Slamon, an oncologist working at UCLA then went on show that breast cancers with too much HER2/neu grew more aggressively and spread more quickly, suggesting that the HER2/neu has an important role in breast cancer growth. Later on, Dr. Slamon and his colleagues also showed that an antibody that can bind to HER2/neu, called Herceptin, could slow the growth of cancer cells grown in laboratory mice. Building on almost two decades of work, clinical trials in the 1990s showed that Herceptin also slowed the growth of breast cancer in human patients. Nowadays, doctors can evaluate patients’ tumours to see if they have an overproduction of HER2/neu and are therefore likely to depend on the protein for growth, and prescribe Herceptin for these patients to specifically target the abnormal cancer cells. As scientists learn more about different genetic mutations in cancer, the hope is to develop more drugs that specifically target these mutations. Terms that have been used to describe this strategy are personalized cancer medicine, or precision oncology.

Sometimes, new ideas for specific cancer therapies come from unexpected places. The Zika virus (ZIKV) is a type of virus spread by mosquitos. While it generally only results in mild symptoms, ZIKV has recently been linked to an epidemic of microcephaly, and brain malformations in babies because of its transmission from pregnant mothers. One reason why scientists believe that ZIKV causes brain defects is that it can specifically infect a type of cell called a neural progenitor cell (NPC)¹.These cells are very important for fetal brain development because they can divide to make the mature cell types of the brain, and the recent finding that ZIKV slows the growth of NPC cells provides a potential explanation for how ZIKV causes microcephaly. Interestingly, some cancer biologists believe that NPC-like cells exist in human brain tumours as well. Just like how NPC cells can make neurons in the normal brain, these NPC-like cells in brain tumours (called ‘brain tumour stem cells’) are thought to be responsible for generating and maintaining most of the other tumour cells. Recently, scientists have shown that ZIKV virus can specifically infect these brain tumour stem cells and slow their growth, and leaves normal surrounding neuronal cells unharmed². When scientists grew brain tumours in mice and infected them with the ZIKV virus, the growth of the tumours was also slowed leading to a longer survival of the mice. By engineering ZIKV into a harmless virus that can still infect brain tumour stem cells but does not cause any other adverse effects to surrounding healthy cells, it might be possible to use ZIKV as a future therapy for human brain cancers.

References

1. Tang, H. et al. Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth. Cell Stem Cell 18, 587-590, doi:10.1016/j.stem.2016.02.016 (2016).
2. Zhu, Z. et al. Zika virus has oncolytic activity against glioblastoma stem cells. J Exp Med, doi:10.1084/jem.20171093 (2017).