Recent advances in cancer research
Cancer occurs when abnormal cells divide in an uncontrolled way. Some cancers may eventually spread into other tissues.
There are more than 200 different types of cancer.
1 in 2 people in the UK will get cancer in their lifetime.
https://www.cancerresearchuk.org/about-cancer/what-is-cancer
The 2018 Nobel Prize in Medicine celebrated two breakthrough scientific discoveries that used mice,“revolutionized cancer treatment”, and “fundamentally changed the way we view how cancer can be managed”. The researchers found ways to boost the immune system to recognise and attack cancerous cells, a technique known as immunotherapy which can be effective for as many as a fifth of cancer patients.
Immunotherapy joins three more traditional therapeutic approaches in the fight against cancer. Surgery has been practised for at least 3,000 years, although for much of that time the treatment was generally more deadly than the disease. Radiation therapy is more recent, of course, although surprisingly not as recent as we sometimes assume, beginning in 1899, only three years after the discovery of X-rays. Chemotherapy, emerges later and as an accidental off-shoot of chemical warfare research in 1946 when it was found that mustard gas derivatives were effective at killing off cancer cells.
Huge advances have been made in such traditional approaches to the treatment of cancer, especially in recent years, but they all have a common limitation, they are all therapies of brute force, attacking cancer but with significant collateral damage to healthy cells. While, these ‘cut, burn and poison’ techniques are effective to some degree in about half of cancer cases that still leaves us with more than 9 million untreatable cases of cancer worldwide annually, according to the World Health Organization’s international agency for research on cancer. It is a startling figure and highlights the pressing need for continuing research to improve available treatments and to find new ones.
Preventing cancer through diet and lifestyle
Once again, in 2018, the media was filled with lifestyle and diet advice that promised to protect us from cancer and other diseases. Some of this advice did have a scientific basis, but very often the evidence was unclear and sometimes contradictory. So are there solutions to the fight against cancer on our plate? And if we are having conventional treatments for cancer, can our diet support our therapy?
The answer is, sometimes at least, yes. Boosting the power of some cancer drugs could be achieved by modifying what you eat, according to two recent studies in mice. The first found that supplementing the mouse diet with the amino acid histidine made a chemotherapy called methotrexate more effective against leukaemia cells. Histidine, which is particularly rich in foods like meat and beans, can be given as a nutritional supplement. The second study found that using diet to influence insulin levels can make another set of cancer drugs — those that target a protein called PI3K — more effective. As the evidence in mice suggests that the food that patients eat could influence how well their cancer drugs work both research teams now aim to find out if this approach works in people with cancer through clinical trials.
Scientists also believe they have discovered why some vegetables - including cabbage, broccoli and kale - can reduce the risk of bowel cancers. That cruciferous veg is good for the gut has been known for a while but a detailed explanation has been elusive. The team at the Francis Crick Institute found anti-cancer chemicals were produced as the vegetables were digested. Indole-3-carbinol, which is produced by chewing such vegetables, is modified by stomach acid as it continues its journey through the digestive system. In the lower bowel, it can change the behaviour of stem cells, which regenerate the bowel lining, and of immune cells that control inflammation. The study showed diets high in indole-3-carbinol protected the mice from cancer, even those whose genes put them at very high risk of the disease.
And this is not the only example. Aa type of sugar found in cranberries, mannose, is able to disrupt tumour growth and could provide an “entirely new” way to enhance chemotherapy, a study has found. Indeed, sugars act like switches and control-knobs that decide where and when a cell’s biological machines, proteins and lipids, do their jobs. A cancer tumour’s insatiable need for glucose to fuel its rapid growth can be exploited by giving an alternative sugar, mannose, which it cannot process as easily. Trials in mice with pancreatic, lung and skin cancers found that mannose significantly slowed the growth of tumours without causing side-effects.
Using sugars as immune therapies
A few companies are venturing across a new frontier—glycobiology, the science of the sugars that stud the surface of cells - to develop anti-cancer drugs. In 2018, a Massachusetts startup, unveiled new data from experiments in rodents on a profoundly different set of checkpoint blockers that target sugars. These experimental drugs work by interfering with complex sugars called glycans that coat the surface of tumour cells and let them pass unnoticed by the otherwise vigilant immune system – an under appreciated mechanism of immune evasion.
Another team focussed on a particular glycan, sialic acid, that is sensed by a family of surface proteins found mostly on innate immune cells but also on activated T cells at tumour sites. These proteins, called Siglecs, act as molecular brakes. When Siglecs bind to sialic acids, coating the surface of a tumour, the immune cell is inactivated. The researchers designed a therapeutic molecule that inhibits all Siglecs by trimming sialic acids off the tumour cell. By removing sialic acids from glycans on the surface of tumour cells in mice, the drug reveals their real identity to immune cells leading to the death of the unveiled cancerous cells.
Tweaking the immune system
Many new therapies attempt to empower the already present immune system to recognize and attack cancerous cells. Several current trials are looking at ways to block a molecule called CD47, which is present on many tumour cells and helps them evade the immune system by giving off a “don’t eat me” signal. But antibodies against this molecule lead not only to death of tumour cells but also to destruction of other cells that have CD47 on their surface such as red blood cells.
American scientists have developed a spray-on gel to use around the cancer surgery wound in mice. This contains antibodies against CD47, as well as a chemical that makes the tissue less acidic. Lowering acidity is a method of revving up immune cells called macrophages, these have been shown to slow the regrowth of tumours after surgery. The targeted delivery means nearby immune cells start killing cancer cells, both at the wound and elsewhere in the body, but don’t cause a potentially harmful body-wide immune reaction. The team’s next step is further trials in larger animals.
Other potential immune boosting strategies that have shown promise in the last year include virus-based therapies that have been shown to prevent cancer from recurring in mice. Cancer tumours can sometimes camouflage themselves by hijacking healthy cells called fibroblasts which are used as a sort of life-support that is invisible to the immune system. Researchers working with mice showed how for the first time viruses could be used to target the healthy fibroblast cells to unmask the cancer without causing any toxic reactions in healthy tissue. This study was published around the same time that the pharmaceutical giant Johnson & Johnson announced (on 2 May, 2018) that it would pay up to US$1 billion to acquire a company that makes cancer-killing viruses.
Elsewhere, therapies using specially altered T cells have been getting attention. T cells are an important part of the immune system but they can be adapted to make them specifically target cancer. The adapted cells, known as CarT cells, have been shown to be effective against lymphoma and leukaemia and three CarT based treatments have already received U.S. FDA approval while hundreds of trials are scheduled to test them against other malignancies.
Following the success of CarT cell therapies, researchers have equipped other immune cells - natural killer cells and macrophages – with the same type of cancer-homing receptors. These cells, called CAR natural killer (CAR NK) cells, could be safer, faster to produce, and cheaper, and they may work in situations where T cells falter according to studies in mice.
There are also drugs that are helping stimulate the immune system to attack cancer cells. In 2018, US scientists designed a type of drug known as a ‘spramolecule’ that helps the body to destroy and eat cancerous cells by boosting the action of white blood cells and interfering with the ability of cancer cells to hide from them. Tests in mice showed the therapy worked for aggressive breast and skin tumours.
The Holy Grail of cancer drugs?
Around half of all human cancer cases are related to a DNA mutation which prevents the body switching off rapid cell division in the usual way. A drug that could target the defects in the molecular pathway caused by this mutation has long been the Holy Grail of cancer researchers, but may now be within reach. Recent experiments with lung, skin, colon and pancreatic cancer cells have found that a recently discovered drug could drastically slow cell division, with similar effects seen in tests in animals.
This isn’t the only drug to have switched use. Scottish researchers recently found that an existing cancer treatment could be used for a common form of lung cancer for which there is currently no specific treatment available. The treatment was able to block cell growth in the formation of KRAS-driven lung cancers in mice and raises hope for many patients.
Benefits of the drug treasure hunt are not only directed to humans. New research from the University of Cambridge identified key anti-cancer drugs which could be trialled as a treatment for the very rare transmissible cancers, which are threatening Tasmanian devils with extinction. The team studied the genetic and physical features of DFT1 tumours in Tasmanian devils, and compared the lineages with each other and with human cancers. In doing so, they identified the important role of receptor tyrosine kinases (RTKs) in sustaining growth and survival of DFT cancers. Drugs targeting RTKs have already been developed for human cancer and the researchers showed that these drugs efficiently stopped the growth of Tasmanian devil cancer cells growing in the lab. Anti-cancer drugs that are already in use in humans may offer a chance to assist with conservation efforts for this iconic animal.
Fundamental research leads to therapeutic discoveries and personalised medicine
Solutions to fighting cancers can come from the most unusual places. Elephants have a very low rate of cancer and researchers think they have uncovered their secret weapon. This phenomenon can be explained in part by a so-called zombie gene. In the face of DNA damage, elephant cells fire up the activity of the zombie gene LIF6 to kill cells, thereby destroying any cancer-causing genetic defects. The LIFT6 gene product is controlled by TP53, a tumour suppressor. When the researchers overexpressed LIF6 in elephant cells, the cells underwent apoptosis (programmed cell-death). The same thing happened with they introduced the gene to Chinese hamster ovary cells, indicating that LIF6 has a role in elephants’ defence against DNA damage.
But researchers don’t necessarily have to look every far to find new strategies for the cancer problem. In 2018, for example, a group of American researchers described in mouse models of cancer and the peripheral blood of patients with solid tumours, cancerous cells that fuse with immune cells. These hybrid cells give the tumour an advantage, allowing it to spread more readily, promoting heterogeneity and possibly metastasis. In the human cancer patients, the presence of these circulating hybrid cancer cells correlated with more advanced disease and poorer survival compared with patients who did not have detectable hybrids in their blood. These could become a new therapeutic target for the years to come.
This isn’t the only study of 2018 trying to beat resisting metastatic cancers in the body by looking at how they function. A group of researchers from Cambridge identified a protein complex that might explain why some cancer patients treated with the revolutionary new anti-cancer drugs known as PARP inhibitors develop resistance to their medication. They confirmed their results in mice transplanted with human breast cancer biopsies with the BRAC1 mutation. Improving our knowledge of these DNA repair networks and how they interact, could help better predict the responsiveness of an individual patient’s tumour to specific therapies like PARP inhibitors, and ultimately personalise cancer therapy to achieve the maximum benefit.
And indeed, personalized cancer treatments have been on the rise over the past decade thanks to patient-derived xenografts (PDX) animal models. A sample of cancer cells can be removed from the patient and grown for a while in cell-culture. Then these cells can be injected into a mouse, usually just under the skin on the flank of the animal. Here they grow to make a visible, measurable tumour and as they grow, the animal can be dosed with potential chemotherapies.
PDX mice have recently exploded in popularity in cancer research laboratories and are beginning to supplant other techniques for modelling cancer in research and drug development, such as mice implanted with cancer cell lines. Although scientists have been transplanting human cancers into mice for more than 50 years, these models are linked to a single patient and help identify the particularities of their cancer. They help to carry out experiments on human tumours that would be impractical in people, such as testing new drugs and identifying factors that predict a good response to treatment. Because the models use fresh human tumour fragments rather than cells grown in a Petri dish, researchers have long hoped that PDXs would model tumour behaviour more accurately, and perhaps even help to guide treatment decisions for patients.
They also allow researchers to explore the vast variety of human tumours. PDXFinder, a catalogue launched earlier this year, lists more than 1,900 types of PDX mouse. However, PDX models are not perfect, — and scientists are beginning to recognize their shortcomings and complexities. The tumours can diverge from the original sample, for example, and the models cannot be used to test immunotherapies. Now, biologists are scrutinizing PDX mice and looking for creative ways to cope with the challenges. The real question is how predictive are these models going to turn out to be? One solution that researchers are looking at is creating mice with tumour and immune cells from the same person, to help evaluate the immune reactions of the patients.
From bench to bedside and back again
This sample of the scientific work into understanding cancer and developing treatments on the basis of that new understanding from just one year illustrates the massive human endeavour that is going into reducing the toll cancer takes. Research with animals remains a vital part of that work.
Last edited: 29 July 2022 13:49
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