Why is cancer so difficult to cure?
By Mark Wanner
Recent advances in cancer research have revealed much more about just how complex cancer is and how difficult it is to completely cure. It can be sobering to confront the challenges ahead. Day by day researchers better understand why my cancer is not your cancer, and one-size-fits-all therapies seem less and less realistic.
So is the cancer research picture bleak? Far from it! Targeted therapies will yield huge gains, with fewer severe side effects, compared to the sledgehammer chemotherapeutic and radiation approaches—which kill almost all quickly dividing cells—currently serving as the standard of care. It just helps to be realistic about progress and accept that success is unlikely to yield “cures” for cancer, at least not in the near future. Nonetheless, it is likely to provide far better prognoses for a large number of cancer patients in the near future.
For a better handle on where we are now, what challenges remain to be overcome, and what progress may be around the corner, here are a few key biological concepts, how they relate to cancer, and research at the NCI-designated Jackson Laboratory Cancer Center that is increasing our understanding of each concept and, in some cases, is identifying new therapeutic targets.
Cancer cells, even within the same tumor, are heterogeneous—that is, differences exist between the individual cells. The consequences of this fact started coming into focus only a few years ago, when researchers showed that cells collected from four different regions of the same tumor were in fact quite different. Further studies have reinforced this finding, and cancer cell heterogeneity is now widely recognized. Given that biopsies are typically taken from a single spot within a tumor, this fact has serious implications for improving diagnostics and therapies. It also indicates that any one targeted therapy is highly unlikely to eliminate all cancer cells by itself.
Research at JAX
The recently established Single Cell Genomics Center at JAX Genomic Medicine, led by Paul Robson, Ph.D., provides a powerful new platform for investigating cancer. There are many possible applications, but it’s easy to see that focusing on one cell at a time provides a way to identify, characterize and better understand the effects of cellular differences. Single-cell sequencing can track how mutations spread through tumors and make them genetically heterogeneous. The technology also provides the opportunity to uncover molecules that control cell-to-cell communication between the many cell types that reside within a tumor, identifying potential drug targets. And it has the potential to reveal cell types that are rare or otherwise difficult to study but are important to cancer growth and survival.
Cancer cells grow and divide with extreme rapidity and must endure a certain amount of stress and damage to their DNA. Fast-growing cancers depend on a fine balance between DNA damage and repair, but genetic changes add up over time, and the result is like evolution at warp speed, where growth-promoting mutations lead to even more rapid expansion. This contributes to the heterogeneity discussed above. It also means the cancer you find today may differ from the one you try to treat in the weeks and months to come. With modern sequencing and analysis, it’s now possible to track cancer cell evolution and begin to predict the changes before they occur. Nonetheless, it’s much harder to hit a moving target than a stationary one, and even a highly effective, precisely targeted combination of therapies may not succeed if enough cancer cells survive initial treatment and further evolve.
Research at JAX
Adjunct Professor Kevin Mills, Ph.D., has identified a natural system in immune cells that provides a promising therapy target that also short circuits cancer cell evolution. In immune cells, a protein known as AID creates widespread DNA damage to generate the antibody response needed to fight off a diverse array of bacteria and other pathogens. Another system repairs the DNA, including “off-target” damage in other areas of the genome. AID is usually not active in other cells, but in some cancers—Mills estimates 40 percent—it becomes overactive and causes widespread DNA damage and rapid cancer cell evolution. These AID-positive cancers, in turn, become “addicted” to the repair mechanism, depending on it to survive. Mills discovered that blocking repair in these cancers not only leads to catastrophic levels of DNA damage and death, it also prevents the cancers from evolving and recurring. At Cyteir Therapeutics, a company he co-founded based on his research at JAX, he is now working with compounds that block DNA repair in AID-positive cancer cells, killing them without harming other tissues. Mills hopes that they will benefit cancer patients within the next decade.
Structural variants (SVs) include duplications, deletions, inversions and insertions of stretches of DNA, changes in the genome that don’t change the sequence per se but can have significant consequences. While most SVs are hard to detect and details about them are just beginning to emerge, the role of a particular structural variant in cancer has been known for a very long time. Researchers discovered the famous Philadelphia chromosome, which gives rise to chronic myeloid leukemia (CML), in 1960. SVs add to the list of genetic changes that can tip the balance toward cancerous growth through overexpression of duplicated oncogenic (cancer-causing) genes, underexpression of deleted cancer suppressor genes and other insertions/translocations giving rise to oncogenic proteins.
Research at JAX
Although it can be relatively easy to find structural variants that involve long segments of DNA, such as the Philadelphia chromosome, many elude standard sequencing and analysis methods. JAX-Genomic Medicine Scientific Director and Professor Charles Lee, Ph.D., helped pioneer structural variant research and discovered that such variants are common in healthy people. Lee’s recent work in gastric cancer, which currently has a poor prognosis, revealed that a significant percentage of patient tumors had additional copies of a gene, BCL2L1, that prevents cells from self-destructing. Thus, even in conditions that would normally initiate the self-destruct process, a cell will continue to grow and divide and be very susceptible to turning cancerous. Lee also found that a drug that inhibits BCL2L1 function in cancer cells. It allowed the self-destruct process to reactivate, leading to cell death, making it a promising new therapeutic target for gastric cancer.
Immune system evasion
Cancer cells, although different in many ways from other cells in the body, are known to evade our immune system or suppress key elements of the usual immune response. In some cases aggressive cytotoxic (killer) T cells—the immune cells that locate and kill invading pathogens—actually infiltrate tumors. For some reason, however, they soon halt their attack through a combination of cell-to-cell signaling and an influx of T regulator cells, a different type of immune cells that suppress the immune response. Other research found that a chemical compound is sometimes added to cancer cell DNA and suppresses the activity of certain genes, making the cells much less likely to be targeted by the immune system. By controlling the activity of these genes, cancer is able to hide in plain sight within the body and avoid an immune response.
Research at JAX
Cancer immunotherapy, using the body’s own immune system to target and destroy cancer cells, is one of the most exciting fields in biomedical research. The excitement is merited, and there have been spectacular successes in human patients, albeit in small, preliminary studies. And many challenges remain. JAX Professor Karolina Palucka, M.D., Ph.D., is working to better understand the complex interplay between the human immune system and cancer. To do this, she is developing a special mouse system that provides an experimental model using both human tumor tissue and human immune cells. She is also investigating how to increase response to a class of drugs—checkpoint inhibitors—that block immune cell inhibition and promote cancer cell destruction. One method is to enhance the expansion or activation of killer T cells through cancer vaccines. It’s a delicate balance, as overstimulation can lead to toxic side effects, but careful manipulation can yield an extremely effective cancer-destroying response.
Cancer remains a difficult disease to treat, but the emerging therapies are increasingly effective. As we pass the mid-decade point, it is interesting to speculate what we will be able to do when we stand on the threshold of 2020. What therapies will be available that seem far out of reach today? While outright cures will likely remain elusive, we may be poised at the brink of an important step or even leap forward in our ability to treat cancer nonetheless. Cancer’s complexity will not go away, but our ability to understand and manipulate cancer cells—as well as suppress and kill them—will accelerate year by year.