Could Hyperactivating Cancer Growth Genes Help Treat Bowel Cancer?

Bowel cancer, also known as colorectal cancer, is the third most common cancer and the second leading cause of cancer death worldwide. Incidence is rising in people under 50, potentially leading to an increased global burden of the disease and prompting research into risk factors, disease pathophysiology, preventative strategies, and new therapeutics. 

Current treatment approaches for bowel cancer include surgery to remove the tumor, radiotherapy, chemotherapy, immunotherapy, or a combination of these. However, in nearly half of patients, the cancer recurs and becomes resistant to treatment. 

Aberrant signaling pathways, including Wnt/β-catenin, phosphoinositide 3-kinase (PI3K)/AKT, and MAPK/ERK, drive tumorigenesis, sustain cancer cell proliferation, enable metastasis, and can induce therapeutic resistance in bowel cancer. They become dysregulated by a series of mutations to cancer growth genes, including APC, KRAS, and PIK3CA. 

Organoid models derived from patients’ cancer cells enable researchers to study the genetic makeup of each person’s tumor and how the cancer develops over time, providing insight into how genes shape cancer progression and treatment resistance. 

Conventional drug discovery efforts have focused on inhibiting growth genes and pathways to stop or slow cancer progression. Still, there has yet to be a breakthrough in bowel cancer treatment. 

As part of a project funded by Cancer Grand Challenges, Dr. Vivian Li, a senior group leader and assistant research director at The Francis Crick Institute, is working to identify whether hyperactivating cancer growth genes—and pushing cancer cells over the edge—could form an alternative approach to treating bowel cancer. 

Technology Networks spoke to Li to find out more about this strategy and learn how patient-derived organoids (PDOs) are being used in drug candidate screening. 

Katie Brighton (KB): In your opinion, what are the biggest challenges that make bowel cancer difficult to treat effectively? 

Dr. Vivian Li (VL): One of the biggest challenges is treatment resistance. Many bowel cancer patients eventually develop resistance to standard therapies, including chemotherapy, immunotherapy, and targeted treatments. Cancer cells can adapt over time, meaning drugs that are initially effective may stop working. This can occur either through the acquisition of additional mutations or as they transition into a cell state that is less sensitive to treatment. 

KB: What first drew you to using organoids as a model system, and how has this technology changed the kinds of questions you can ask about bowel cancer biology? 

VL: I first encountered organoids during my postdoctoral training in the lab of Hans Clevers, where they were established as a powerful model system. Unlike conventional 2D cancer cell lines, organoids grow in three dimensions and better capture the structure and diversity of real tissues and tumors. This has transformed biomedical research, as organoids can be expanded long-term and used for applications such as drug screening and gene editing.  

In our lab, we routinely use organoids to study therapy resistance in bowel cancer, which has also helped reduce the need for animal experiments. PDOs retain tumor heterogeneity that is not captured in conventional 2D cancer cell lines, allowing us to investigate more complex aspects of cancer biology, such as cell-state transitions at single-cell resolution. 

KB: How could hyperactivating cancer growth genes help treat bowel cancer? 

VL: In cancer, genes that control cell growth and development are often mutated and become overactive, allowing tumors to grow uncontrollably. The traditional approach has been to block these genes to slow tumor growth. While this can work at first, cancer cells often adapt and find alternative ways to bypass the treatment, leading to drug resistance and relapse.   

Instead of simply blocking these genes, we want to explore what happens if we hyperactivate them even further.

Many growth-related signaling pathways operate within a “Goldilocks zone”: a moderate increase can drive tumor growth, but excessive activation may overwhelm the system and trigger cell death.

Together with our new Cancer Grand Challenge REWIRE-CAN team, we will test whether hyperactivating Wnt, MAPK, or PI3K pathways could offer a new way to eliminate cancer cells. 

KB: How do you plan to use PDOs to assess potential drug candidates and understand what happens when growth pathways are hyperactivated? 

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VL: In the Cancer Grand Challenge project, we will generate organoids from both primary and metastatic bowel cancer patients. These PDOs enable us to study how cancer cells respond to treatment in a controlled, physiologically relevant setting. 

By profiling molecular changes after exposing PDOs to candidate drugs, we aim to determine whether hyperactivating key pathways can drive cancer cell death or enhance sensitivity to existing therapies.

We will also perform a genome-wide CRISPR gene editing screen in PDOs to identify new therapeutic vulnerabilities. This approach will help us better understand treatment responses and identify new strategies to overcome drug resistance. 

KB: What are the steps to translating cancer growth gene hyperactivation into a therapeutic strategy? Are there any challenges associated with this approach? 

VL: To translate this hyperactivation strategy to the clinic, we will first evaluate its effects in preclinical models, including PDOs and mouse tumor models. These studies will provide essential go/no-go evidence to support progression to clinical trials.  

A key priority will be to assess potential toxicity in normal tissues and establish a safe therapeutic window. We are confident that this approach will enable the identification of dosing regimens that are both effective and tolerable.

KB: How do you imagine the hyperactivation approach might integrate with existing bowel cancer treatments? 

VL: We have evidence suggesting that pathway hyperactivation can shift cancer cells from a resistant to a more treatment-sensitive state, thereby exposing new therapeutic vulnerabilities. We will test whether activating key signaling pathways can sensitize bowel cancer cells to existing treatments, including chemotherapy or chemoradiotherapy.