Revitalising colorectal cancer treatment

Innovation is transforming how we understand and treat colorectal (bowel) cancer, the UK’s fourth most common cancer. Despite long-standing reliance on certain chemotherapy drugs, their full effects and side effects remain unclear. Dr John Knight uses cutting-edge techniques to explore how these treatments impact RNA and protein synthesis. His research aims to enhance drug effectiveness while minimising harm, ultimately bridging the gap between laboratory science and patient care. As he explains here, this work is paving the way for more targeted, personalised and tolerable cancer therapies.

Colorectal cancer is one of the world's most common cancers. Despite medical advances, the standard of care treatments - 5-fluorouracil, oxaliplatin, and irinotecan - have remained largely unchanged for decades.

These drugs, while effective for some, are non-targeted therapies that attack both healthy and cancerous cells, leading to severe side effects like peripheral neuropathy, which can leave patients with debilitating pain in their hands and feet for months after treatment.

Many of these chemotherapy drugs work by interfering with RNA - a vital molecule that helps translate genetic instructions into proteins necessary for cell growth and function. By disrupting this process, the drugs aim to stop cancer cells from multiplying, but their lack of precision means they also damage healthy cells, contributing to harmful side effects.

These treatments are also only effective for about half of colorectal cancer patients and, for those who don't find treatment successful, the reasons for their ineffectiveness are still poorly understood.

Research into these drugs has stagnated over the past two decades, partly due to a shift in funding priorities toward genomics and newer treatments. However, without fully understanding how these existing drugs work, or why they fail, it's difficult to improve upon them.

My research is focused on addressing this knowledge gap by using cutting-edge technology to revisit and refine our understanding of these therapies, paving the way for better, more effective and kinder treatments.

Making progress: rethinking colorectal cancer therapies

My team in Manchester are using advanced methods to uncover how standard colorectal cancer drugs work at the molecular level. We’re particularly looking at how these treatments affect RNA and protein synthesis - both processes that are essential for tumour growth.

This line of research is long overdue; much of the research we have on these drugs dates to the 1980s and 1990s, but advancements in technology now allow us to explore their mechanisms in unprecedented detail.

Our findings so far have been promising. By identifying the precise pathways these drugs target, we hope to isolate the beneficial effects while minimising harmful side effects. For example, our research could help us design new treatments that retain the effectiveness of current therapies, but are less toxic to healthy cells.

Collaboration is a cornerstone of our work. Manchester’s unique setup, with its proximity to hospitals and access to patient tissues through biobanks, allows us to conduct research that directly addresses clinical challenges. Having clinicians participate in our lab meetings provides invaluable insights into how treatments are administered and what patients experience during therapy. 

This close connection ensures that our research remains focused on real-world applications.

Future challenges and opportunities

Looking ahead, there are several pressing challenges for colorectal cancer research. One is the rise of early-onset colorectal cancer: this is cancer in people under 50 years old, which may be linked to lifestyle factors like diet. Understanding how early-onset tumours differ biologically from those diagnosed later in life is critical to developing tailored treatments.

Another priority is addressing health inequalities. Current research models often rely on cell lines derived from Caucasian patients, even though colorectal cancer affects diverse populations differently. 

By expanding our biobank to include samples from underrepresented ethnic groups, we hope to ensure that future treatments are effective for more people regardless of ethnicity or background.

Finally, we’re exploring the potential of RNA therapeutics. Inspired by the success of mRNA vaccines, we’re investigating whether similar technologies could be used to target the specific pathways driving colorectal cancer. The hope is that these approaches could offer a more targeted, less toxic alternative to traditional chemotherapy.

Looking ahead

Success for me means creating therapies that are not only more effective, but are also kinder to patients.

In the long term, I envision a future where non-targeted treatments are replaced with precision therapies that minimise side effects and improve quality of life. In the shorter term, our work aims to better understand why existing drugs work for some patients, but not others, allowing us to refine and improve their use.

Colorectal cancer remains a daunting challenge, but I’m optimistic about the progress we’re making. By combining cutting-edge research with a commitment to clinical relevance, I believe we can transform outcomes for patients and bring meaningful change to this field.