Bowel cancer is the second leading cause of cancer death worldwide. Finding better treatments poses both a challenge and an opportunity for Vivian Li, as she joins a Cancer Grand Challenges team targeting bowel cancer cells with an unusual approach.
Patient-derived organoids from a person with bowel cancer. Credit: Stem Cell and Cancer Biology Laboratory, the Crick.
As bowel cancer rates in young adults increase, research into this complicated type of cancer is picking up the pace.
“We can track bowel, or colorectal, cancer progression within the same patient – from the initial tumour to secondary tumours that develop elsewhere in the body,” explains Vivian Li, who leads the Crick's Stem Cell and Cancer Biology Laboratory, also known as the Bowelbabe Laboratory. “We also have the technology to grow lab-based models from patients’ cancer cells, called organoids, which allow us to study the unique genetic makeup of each individual tumour.”
Looking to unlock new insights from organoids, Vivian has joined a team of 10 researchers, funded amongst this year’s Cancer Grand Challenges, to find new treatments for bowel cancer. As part of this, they will build a bank of patient-derived organoids, some from healthy donors and others from the same patient’s primary and secondary tumour. These organoids will prove invaluable to assessing how a tumour progresses and evolves over time, with the end goal of finding new treatments that work in quite an unorthodox way.
“Across many cancer types, including a majority of bowel cancer cases, genes for cell growth and development are often mutated and become overactive,” Vivian says. “This allows tumours to grow uncontrollably, replicate and spread around the body.”
In the quest to get one step ahead, researchers have generally focused on blocking these mutated genes, applying the brakes on cancer’s acceleration. Some drugs that work as inhibitors are already on the market or in clinical trials, but there’s a big problem: cancer cells can start to use alternative growth pathways. This can result in drug resistance and relapse, even if the treatment worked well to begin with.
“There’s not been a major breakthrough yet when we’ve tried inhibiting cancer genes,” says Vivian. “So, what if we hyperactivated these mutated genes instead, pushing cancer cells over the edge?”
This idea might sound counterintuitive at first. But, as Vivian explains, it’s based on evidence that key cell growth genes operate within a very narrow window. “Boosting the activity of these genes by a small amount is beneficial for the cancer cell; it grows and replicates more quickly,” she says. “But switching them on too much is toxic; it pushes cells to a stressed state, causing them to die. We think we could exploit this vulnerability.”
Bart Vanhaesebroeck at UCL, who is leading the ‘REWIRE-CAN’ Cancer Grand Challenge team, first developed this idea a few years ago: that key signalling pathways, often mutated in cancer, might work within a ‘Goldilocks range’. In this vein, the newly-formed team will focus on developing activators rather than inhibitors, believing that off-target effects are less likely: the gene pathways will stay within a ‘normal’ range in healthy cells, only crossing the threshold into toxic levels in the tumour.
Vivian’s lab at the Crick will test new compounds that act as activators against bowel cancer tumours, in both patient-derived organoids in a dish and transplantations of these organoids into mice. They will use a genetic screening approach, where the potential drug is administered, and then cancer genes are switched off one by one to see which is likely targeted by the potential activator.
“We’ll also look for second hits, other genes that are impacted by the cell being pushed into this hyperactive state,” Vivian adds.
The second hits Vivian and her team are seeking through genetic screening represent the other half of the ambitious challenge. This stems from the knowledge that, within a single tumour, cancer cells can exist in a variety of different states, with some resembling stem cells and others fully matured. Some cancer cells can even adopt a foetal-like state, a condition not seen in healthy adult tissues.
“This foetal-like state allows cancer cells to hide from drugs that are designed to kill dividing cells, helping them develop resistance to treatments,” says Vivian. “We want to see if we can push them out of this ‘hidden’ state using signalling activators or other newly identified targets, so that the treatments we already have – such as chemotherapy – can work more effectively.”
So, it’s a two-pronged attack: directly killing cancer cells by inducing toxicity, and pushing these foetal-like cancer cells out of hiding.
The team also aims to optimise treatment plans for these new activators by testing ‘treatment holidays’—treating mice with tumours for a period of time, pausing, and then re-treating them—to maximise effectiveness while minimising potential side effects.
“We also have a patient advocate in the team, because we understand that the idea of hyperactivation can sound concerning,” says Vivian. “That’s why we’re being thorough, making sure these activators don’t cause secondary cancers or harm healthy cells. We don’t expect them to, but we want to make sure nothing is left unchecked.”
It’s clear that new cancer treatments need an out-of-the-box approach, given the uphill battle against resistance. For the 44,000 people diagnosed with bowel cancer each year, the new project offers fresh hope for a new era of therapies developed by a bold approach.
