Many new discoveries have been made that make us better understand what the biology of cancer is like. We know better than ever why cancer cells escape from the normal control of cell division, why some therapies work (or don’t), and what could be done to stop cancer from spreading or to treat it.

How far are we in the fight against cancer?
The latest advances in cancer research based on science - science article

Here at Sciencebriefss, we have covered much of the science news that have seen the light over the last months. While we have seen that there is reason to be hopeful that cancer might be treatable in the future, we have also observed that there are still many obstacles to overcome. Cancer cells have a couple of tricks up their sleeve to escape from current treatments, and sometimes treatment options need further refinements to become more efficient.

In this editorial, we will cover some examples of relevant studies to illustrate where cancer research stands at the beginning of 2019.

Promises and problems in immunotherapy

One sort of therapy that holds great promise is immunotherapy. Scientists James Allison (MD Anderson Cancer Center, Texas) and Tasuku Honjo (Kyoto University – Institute for Advanced Study in Japan) even got the Nobel Prize for the development of this therapy earlier this year.

Immunotherapy is based on removing the breaks on the immune system, especially those that limit the activity of T cells to prevent exaggerated immune responses. Two proteins that inhibit T cells are CTLA-4 and PD-1. CTLA-4 and PD-1 inhibitors are now being used to activate T cells to attack a wide variety of tumors.

The advantage of immunotherapy is that treatment makes use of the body’s own immune system. In theory, this should lead to very targeted responses without many of side effects usually seen with chemotherapy that attacks all dividing cell, including healthy ones, in the body.

While immunotherapy has thus entered the cancer mainstream, it mostly inhibits cancer development in the early phase of treatment, but then fails to completely stop it. This is because cancer cells remove particular variants of human leukocyte antigen (HLA) from their cell membrane so that the activated T cells cannot recognize anymore. Cancer cells thus escape from the immune system and continue to divide.

 

Another challenge for immunotherapy concerns the recent observation that T cells are not as picky in choosing their targets (cancer cells) as previously thought. T cell receptors appear to bind antigens (body-foreign or cancer cell protein fragments) that are quite different from each other. This might explain why activated T cells in immunotherapy at times attack healthy body cells instead of tumors.

Scientists think now that adjuvant drugs might be necessary to optimize immunotherapy further to reduce side effects and increase specificity and efficiency.

Tricky cancer cells

Cancer cells can be difficult to combat. In colon cancers, for example, tumors are composed of two different cancer cell types. While treatment is directed against one of the two cell types, the other one is not affected. Even more, the cell type under attack can switch to become the other cell type. Late colon cancers, i.e. after surgical removal of most of the tumor, are therefore often resistant to chemotherapy. Researchers will thus have to find new drugs, or a new combination of drugs, to obtain better treatment outcomes.

Cancer cells have thus a couple of mechanisms at their disposal to evade immunotherapy or chemotherapy. And if this doesn’t already create enough problems, sometimes the body itself gives the cancer cells a hand to survive. Bone marrow cells have been shown to protect cancer cells from a plant-derived anti-cancer agent called Parthenolide by the release of antioxidants. Parthenolide is used for the treatment of t-cell acute lymphoblastic leukemia in children and helps 85% of the patient to be cured. However, for the 15% that is not so lucky, it is important to take the role of healthy cells into account when developing new treatment options.

Tricky methods

Cancer diagnostics may not always be straightforward. This seems to be a rather urgent problem for prostate cancer screening. Researchers have found that testing men without cancer symptoms with a one-off PSA test does not save lives whatsoever.

 

This test detects some diseases that would be unlikely to cause any harm but also misses some aggressive and lethal prostate cancers. Better diagnostics for the detection of aggressive prostate cancer are thus required to be able to treat the disease early.

Moreover, one question that is central to any method to treat cancer is whether the drug applied actually reaches the cancer cells. The better a drug reaches the cancer cells in affected tissue, the better the outcome of the treatment is thought to be.

Researchers can now image single cancer cells in mouse tissue to determine whether drugs have reached these cells. It turned out that in mouse ovary cancer, there is a lot of variability between the numbers of cells reached within the same tumor and between tumors. This is important to know, as it could indicate which route of drug delivery should be chosen, or that other drugs should be considered to treat cancer.

While there are many encouraging developments in the field of cancer research, it is clear that cancer cells have their ways to escape from treatment. Also, some of the existing techniques need further optimization, and new approaches and more knowledge about cancers are necessary. Some interesting new avenues and findings have appeared recently that target precisely these problems in cancer research.

Latest insights into the biology of cancer

Cancer cells can release special vesicles

Cancer cells have been found to secrete very small particles that have been named “exomers”. These nanoparticles contain DNA, RNA, fats, and proteins. They can fuse with bone marrow and liver cells so that the exomer content enters these cells and changes their function and metabolism of drugs used in chemotherapy. This mechanism is now thought to underlie the reason why many cancer patients do not tolerate even small doses of drugs, due to toxicity.

Repairing DNA fast

A second major discovery is that breast cancer cells make use of fast mechanisms to repair damaged DNA. One of these mechanisms involves a a protein complex called Shieldin.

As its name implies, Shieldin shields the damaged DNA, so that the broken strands can be repaired. When Shieldin is intact, chemotherapy based on PARP-inhibitors and platinum-based drugs are effective for the treatment of breast cancer. However, when Shieldin is mutated, cancer cells make use of another method to repair DNA, and chemotherapy no longer works.

Cancer metabolism

Nitrogen is a building block of proteins, RNA, and DNA, and is therefore in high demand by cancer cells. Availability of nitrogen depends on metabolism in the liver, which, when disrupted, reduces the concentration of the nitrogenous waste product urea in some cancers.

 

This increases the availability of nitrogen for cancer cells, making them more aggressive but also more vulnerable to immunotherapy. Scientists think that measuring urea levels in the blood of cancer patients may predict whether immunotherapy might be successful or not, with lower levels predicting the best outcome.

Genetics and epigenetics play a role in tumor development

Recent lung cancer research has revealed that susceptibility to this disease is encoded on chromosome 15q25.1. There are two major cellular pathways that are controlled by this chromosome. One acts in the nervous system and is involved in nicotine addiction.

The other controls many key biological processes, such as the transport of nutrients and the immune system. This discovery links genetics with cancer and helps thus to understand why some smokers develop lung cancer and others do not.

Cancers are not always so clearly linked with chromosomes. For example, there are many and better risk factors known for breast cancers. These concern DNA methylations, chemical modification of the genes that do not change the gene itself. Chemical modification of genes is known as epigenetics and changes the way the genes are expressed. This may predispose certain individuals to breast cancer.

Role of bacteria in cancer

Finally, bacteria may protect us against cancer. This is been shown for example for skin cancer and liver cancer. In skin cancer, Staphylococcus epidermidis, part of the normal skin microbiome, prevents the disease from developing by secreting the chemical substance 6-HAP. While this has to date (December 2018) only been shown in mice, there is hope that the same applies to skin cancer in humans caused by overexposure to UV radiation from the sun.

A cancer-protective role for gut bacteria may come as a surprise, but scientists have managed to delineate the entire cascade from the microbiome in the intestines to immune responses against cancer in the liver. Again, this has been found only in mice, but some parallels have already been found in humans.

Briefly, bacteria control the metabolism of bile acids in the gut. Bile acids, in turn, control the expression of a signaling molecule of the immune system in liver capillaries, which boosts the immune system to fight cancer.

New approaches to treat cancer

Treatment based on the metabolism of cancers

New knowledge leads to new approaches to treat cancer. For example, scientists have found that cancer cells have high metabolic demands. The high demand for nitrogen that we described above is an example of this. Cancer cells’ exceptional high metabolic demand, to accommodate their need for continuous division, is on the radar for the development of new treatment options.

Increased metabolism requires extra oxygen consumption. Researchers have therefore turned to oxidative phosphorylation in a special form of lung cancer, and are now able to treat lung cancer with a newly developed drug that inhibits the oxidative phosphorylation pathway.

 

Another approach is to disrupt insulin signaling in lung tumors, which also interferes with cancer cell metabolism, and works very well in mice: tumors essentially disappear in 10 to 15 weeks of treatment.

In other cancers, conditions of low oxygen can arise, as these cancers grow faster than their oxygen consumption would permit. Cancer cells need to deal with this problem to sustain their high proliferation rate and appear to do so with the aid of a particular receptor called GPRC5A. Indeed, when the switching on of this receptor is prevented under low oxygen conditions, the cancer cells die. This has to date only been shown with cells in a dish in the laboratory, but scientists are optimistic that on the basis of this finding a new and safe cancer treatment may be developed in the future.

Cancer cell with lymphocytes under microscope
Cancer cell with lymphocytes under microscope - cancer science article

Strategies to fight cancer to prevent or during metastasis

One hallmark of many cancers is metastasis, i.e. spreading to other parts of the body. Scientists have developed a drug that stops this process. The drug binds to heat shock proteins that play a role in proper protein folding. Such inhibition of metastasis has not been addressed as much, as most treatment options concern themselves with killing cancer cells. Preventing metastasis is thus an important addition to the arsenal of treatments.

Also, researchers have managed to deliver mRNA molecules that code for tumor-suppressor genes, even when cancers are already in metastasis. Tumor-suppressor genes are often lost or damaged in cancerous tissue, and restoring them could thus provide a new way of treating cancers.

Attacking healthy and cancer cells

The typical goal of any cancer treatment is to destroy cancer cells only, leaving healthy cells intact. This is why chemotherapy has so many side effects, as it attacks any dividing cell in the body, not only the cancer cells. However, sometimes it is better to attack healthy cells as well, especially when healthy cells shield the cancers from the immune system.

Scientists have developed a new virus that targets both healthy and cancer cells locally, i.e. at the site of the tumor. This dual-action virus has already been successfully tested on mouse and human cancer tissues. When subsequent tests yield good results (cancer elimination and no side effects), scientists think that clinical testing in human patients can start in 2019.

Latest insights into the use of chemotherapy

As most of the promising developments to treat cancers are still in the preclinical phase, most current treatments rely on a combination of radiation and chemotherapy. This leads to a series of adverse effects, especially because both kill dividing healthy cells. To minimize this, scientists have developed a machine-learning algorithm to identify the minimum doses that are still effective for each of the 50 patients that were enrolled in the study. In detail, the algorithm found that treatment could be reduced by 25 to 50 percent while maintaining the same tumor-shrinking potential.

In the same vein, an analysis of 21 genes could provide a risk profile of breast cancer recurrence. It was found that as much as 69% of the patients can safely refrain from chemotherapy, without the outcome of their therapy and life expectancy being compromised.

Thus, while in the past the general treatment philosophy was to use maximum doses of radiation and chemical drugs, in a one-fits-all scenario, this has now shifted to the development of individual-based therapies, an example of personalized medicine.

Finally, clinical tests are already underway in which difficult to treat breast cancer are first targeted by chemotherapy, and then by immunotherapy. The chemotherapy treatment changes the appearance of cancer cells (it makes their membranes rougher) so that the immune system better recognizes and destroys them.

New and fast cancer detection methods

In an earlier editorial, we wrote that early detection of cancer is the best guarantee for a positive outcome of treatment. This view has not changed since. Researchers try to develop better tests for early diagnosis, or for an assessment of which treatment should be chosen.

For example, scientists have developed a pill that makes breast cancers light up under infrared light. This makes it easy to identify breast cancer reliably, although this has only been tested in animals. Furthermore, blood and urine tests are underway for the early detection of breast and lung cancer. Another blood test that is under development helps to decide which sort of therapy for the treatment of prostate cancer should be chosen, hormone therapy or chemotherapy. 

Where is cancer research going?

What we see is that there are currently four mainstream domains in cancer research: (1) biology of cancer, (2) developing new treatment strategies that are effective but with fewer side effects as current treatments, (3) improved diagnostics, and (4) a gradual shift to personalized medicine.

 

These four will continue to be pursued further in parallel by different research groups. There is no doubt that the treatment of cancers will improve in the years to come, but this will be a slow process due to the difficulties that have to be overcome: We have to beat the tricks cancer cells have to evade treatment, and to translate findings in animal models to human patients.


Stay up to date with the latest in science! Subscribe to our newsletter to receive weekly science news updates!