Image: Professor Joshua Schiffman pictured with an elephant. Credit: University of Utah
Darwinian evolution has influenced and inspired the rapidly growing field of evolutionary medicine that uses evolution to approach the diagnosis, treatment, and prevention of human diseases.
For the sixth annual Darwin Lecture the ICR’s Professor Sir Mel Greaves, who hosts the lecture, invited Professor Joshua Schiffman to speak from the Huntsman Cancer Institute at the University of Utah and Peel Therapeutics. The first clinician scientist to deliver the lecture, Professor Schiffman is developing an evolutionary medicine approach to treat children with cancer.
Taking the concepts of evolution and translating them in the real world for patients
Cancer treatment has traditionally aimed to wipe out a patient’s tumour with a very aggressive approach. Research, influenced by Darwinian theory, is changing views on whether that’s always the most effective approach.
“Early evolutionary medicine considered cancer cells as units of selection and how some became resistant to drugs,” explains Professor Schiffman. “This concept has been taken further by scientists who recognised that treating cancer cells with a maximum tolerated dose of chemotherapy would initially wipe out most of the sensitive cells but then select for growth of resistant cells.”
Researchers are beginning to trial new kinds of treatment protocols that consider ways to reduce the growth of cancer cells that are resistant to treatment, which is a major challenge in cancer research and treatment. One approach is called adaptive therapy.
“By applying adaptive therapy techniques, researchers have begun to explore giving just enough treatment to knock down the sensitive cells but not destroy the entire chemo-sensitive population,” said Professor Schiffman. “The resistant cells thereby remain in check by the remaining sensitive cells for a period and do not grow out of control.”
This approach of stopping and readjusting chemotherapy has now been tried in early clinical trials. Patients with advanced prostate cancer lived longer receiving the ICR-discovered drug abiraterone as an adaptive therapy compared to patients being treated with the maximum tolerated dose for prolonged periods of time.
“In addition to living longer, patients on the adaptive therapy arms received nearly half as much exposure to the treatment, and its associated side effects, which further highlights the benefits of applying evolutionary medicine to cancer treatment.”
Professor Schiffman, as a paediatric oncologist, is focused on childhood cancers and how his evolutionary research could benefit young people with cancer. Having had cancer as a teenager – he had Hodgkin lymphoma – he is perhaps even more motivated than most researchers working in this area.
Why do children get cancer?
“Adults develop cancer through a lifetime of inflammation and carcinogenic exposures that increase with age, combined with at least 10 percent of cancer patients with an inherited genetic risk,” explained Professor Schiffman. “In fact, nearly 2 million adults in the USA and more than 365,000 adults in the UK may be carriers of genetic risk for developing cancer.”
Children, in contrast to adults, tend to have been exposed to only low levels of inflammation and carcinogens, so why do they develop cancer?
“Genetics may be playing a large role in the risk for paediatric cancers with at least one in three children potentially developing cancer from pathogenic gene variants,” said Professor Schiffman.
This translates to nearly 5,300 children in the USA and 850 children in the UK who will be diagnosed with cancer each year due to a known genetic cause and this number could be higher when considering cancer caused by genes not yet identified. Professor Schiffman believes that by studying genetic risk and the interplay with other risk factors, we can learn more about how children develop cancer and potentially use this information for prevention.
“I am particularly keen on studying TP53 gene variants in normal cells, which causes an inherited condition called Li-Fraumeni syndrome, which significantly increases a person’s risk of developing cancer,” said Professor Schiffman.
Li-Fraumeni syndrome usually leads to early onset of bone and soft tissue sarcomas, brain tumours, adrenocortical carcinomas, and other cancers. Children with Li-Fraumeni tend to get their first cancer at an early age and they have a high likelihood of developing multiple cancers because of the germline TP53 mutation.
Why do mutations in the TP53 gene increase cancer risk by so much?
“Simply put, the TP53 gene is the superhero gene of our bodies,” said Professor Schiffman. “As the 'Guardian of the Genome', TP53 is responsible for keeping us safe from cancer and has two main roles in terms of cancer prevention – it stops mutated or precancerous cells from dividing so they can be fixed or eliminates those cells through cell suicide if the mutations cannot be repaired.”
The important role that normal TP53 plays in cancer prevention means that if someone has a faulty or missing TP53 gene, this can have devastating consequences for widespread tumour development – this makes early detection of cancers even more important in this high-risk population.
Working with families with a predisposition to cancer due to faulty or missing TP53 genes, Professor Schiffman and his colleagues were able to detect cancers on MRIs before the cancer presented itself and had spread beyond treatment. Understanding the genetic risk and evolution of cancer in patients with Li-Fraumeni syndrome has allowed for life-saving intervention with early cancer detection.
Professor Schiffman not only studies cancer within families but also recognises the importance of better understanding cancer in animals to learn how we might help people with cancer.
What can we learn about cancer from animals?
Anyone who has had a dog, particularly a pedigree one, will know that cancers occur commonly in our canine pets. Professor Schiffman explained that cancer is in fact the leading disease-related cause of death in dogs. And because we understand the genetics of how humans have bred dogs, they can be a useful way to study cancer. This study of cancer in different animal species is called comparative oncology.
Dogs and humans share both the same genes and types of tumours leading to tremendous potential for research and discovery. Some investigators have even discovered Li-Fraumeni syndrome in a pedigree of dogs from an inherited and mutated canine TP53 gene.
“Through breeding, we create specific types of dogs, but this also carries the same redundant flow of genetic information and unique predispositions for cancers. Purebred pet dogs have been created through multiple generations of inbreeding, and each breed of dog has a very specific type of cancer risk. We therefore have a wealth of opportunity to study cancer and inherited genetic predispositions in our furry pets to find novel interventions for cancer.”
Not all animals are like dogs, however. Elephants, for example have a natural resistance to cancer and this may be related to the same TP53 gene that is faulty in patients with Li-Fraumeni Syndrome. Professor Schiffman explained that elephants have 40 copies of the TP53 gene instead of the two copies humans carry – and these TP53 genes are the only genes in elephants with significant extra copies. This discovery was originally made by cancer researcher Professor Carlo Maley, with whom Professor Schiffman teamed up given his interest in human patients with Li-Fraumeni missing working copies of theTP53 gene.
“We worked with zoos and a circus company to successfully obtain blood samples from elephants and that helped us unlock the secrets of their TP53 genes,” he recalled. “These elephant TP53 genes have evolved to work even more effectively than the comparative human gene and we found that elephant cells exposed to radiation were incredibly sensitive to DNA damage – these damaged elephant cells self-destructed rather than try to fix their mutations, thereby removing their risk to develop further into uncontrollable cancer.”
How might we harness the elephant’s defences against cancer?
By growing human osteosarcoma genes in the lab and adding the elephant TP53 gene, Professor Schiffman showed the cancer cells began to rapidly self-destruct. By combining the different types of extra elephant TP53 genes together in the osteosarcoma cells, he showed the strongest decrease in this deadly paediatric bone tumour.
Professor Schiffman’s laboratory group undertook similar experiments adding elephant TP53 to several different human cancer cells which were all rapidly destroyed, bursting into smithereens rather than continuing to divide in the dish. This powerful response of cell death supports Professor Schiffman’s conclusion that elephant TP53 may have evolved in elephants to help protect them from cancer.
“How can this be applied to patients?” Professor Schiffman asked. “Working with a chemical engineer specializing in drug delivery, we co-founded a biotech company called Peel Therapeutics that engineers molecules from nature into new medicines. Our efforts to translate evolutionary biology into drugs began with our discovery of the unique properties of elephant TP53 and trying to figure out how to learn from evolution to help patients.”
Peel is the Hebrew word for elephant, but Peel Therapeutics did not stop with elephants – they are now looking to evolutionary biology to unlock other medicines for patients with cancer and inflammation.
The impact of evolutionary biology on research at the ICR
Like Professor Schiffman, many of the ICR’s researchers focus on evolutionary biology to better treat cancer. The ICR’s Centre for Evolution and Cancer brings together leading researchers to thwart the evolutionary resilience of cancer to reduce the burden of cancer on society. They apply Charles Darwin’s principle of natural selection within ecosystems to our understanding of why we develop cancer and why it is so difficult to treat.
Founded by Professor Sir Mel Greaves and now led by Professor Trevor Graham, the Centre for Evolution and Cancer is based within the ICR’s new Centre for Cancer Drug Discovery, which means researchers share space with leading drug discovery scientists – encouraging collaboration and new ideas for how to apply evolutionary principles when treating cancer.
“Through scientific research the field of medicine has developed an amazing range of treatments for our patients,” said Professor Schiffman. “However, we can go even further by listening to the lessons of Charles Darwin.”
“We can look to comparative oncology to help researchers develop a greater understanding of evolutionary risk and resistance to cancer. With an open mind and rigorous scientific approach, we can learn to read nature’s roadmap to better, safer, and more targeted medicines. Too often, discoveries stay in the lab and do not reach the patients who can benefit the most – it was a pleasure to come to the ICR and discuss how we can change that with the study of evolution.”
Professor Joshua Schiffman is a Professor of Paediatric Hematology-Oncology and Investigator at Huntsman Cancer Institute at the University of Utah, Salt Lake City, USA, where he holds the Helen Clise Presidential Endowed Chair in Li-Fraumeni Syndrome Research. After graduating from the Brown University School of Medicine in 2000, followed by clinical training in paediatrics and paediatric haematology-oncology at Stanford University from 2000-2008, Dr Schiffman specialised in hereditary cancers including leukaemia and sarcomas. In addition, he previously ran a family clinic to treat paediatric patients with a predisposition to cancer and provide care before the cancer was diagnosed.
Professor Schiffman is now the CEO and Co-Founder of Peel Therapeutics, a USA-Israeli biotech unlocking evolutionary biology to treat cancer and inflammation (“PEEL” – Hebrew word for elephant). Professor Schiffman’s academic research and biotech efforts focus on cancer risk in children and studying animals that evolved protection from cancer, such as the elephants discussed in his Darwin Lecture.