Emerging Treatments for Colorectal Cancer: Advancing Towards Precision Therapy

Introduction: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and second leading cause of cancer-related mortality worldwide. In 2020 alone, over 1.9 million new cases and nearly 935,000 deaths were reported globally and the global burden of CRC is projected to rise by 60% by 2030.1 Risk factors for CRC include both lifestyle and genetic factors. Modifiable risks include diets high in red or processed meats, low physical activity, obesity, smoking, and excessive alcohol use. Family history, genetic conditions like Lynch syndrome or familial

adenomatous polyposis (FAP), and inflammatory bowel diseases also increase susceptibility.

Current treatment strategies for CRC are multidisciplinary and depend on the stage and molecular characteristics of the disease. Surgical resection is the mainstay of treatment for localised CRC and patients are often subsequently given adjuvant chemotherapy to reduce recurrence risk. For rectal cancer, radiotherapy is particularly effective and neoadjuvant chemoradiotherapy is often used to shrink tumours and improve surgical outcomes. Advanced or metastatic CRC is usually treated with systemic therapies, including chemotherapy (e.g. FOLFOX, FOLFIRI), targeted agents such as EGFR inhibitors (e.g. cetuximab, panitumumab), and angiogenesis inhibitors such as bevacizumab. However, resistance to chemotherapy and targeted therapies ultimately occurs in most patients with advanced disease and subsequent treatment lines offer limited clinical benefit. Furthermore, current treatment modalities often compromise patient quality of life and do not address tumour heterogeneity, a hallmark of CRC, necessitating a more personalised approach to therapy.

In this article we will highlight emerging treatments that address these unmet needs, focusing on novel molecular targets, immunotherapies, and innovative drug delivery systems. These advancements hold promise for improving outcomes and advancing toward precision medicine in the management of CRC.

Molecular Targets in CRC

Large-scale genomic sequencing studies have provided insight into the molecular landscape of CRC. Key mutations frequently found in CRC include APC, TP53, KRAS, BRAF and PIK3CA. The APC gene encodes a tumour suppressor protein that regulates the WNT signalling pathway, which controls cell proliferation, differentiation, and apoptosis. Mutations in APC disrupt this regulatory function, thus driving tumorigenesis. KRAS and BRAF mutations further enhance tumour progression, while loss of TP53 loss results in genomic instability. Mutations in PIK3CA activate the PI3K/AKT pathway which promotes cell survival, proliferation, and resistance to apoptosis. In addition, PIK3CA mutations frequently co-occur with other mutations, including mutations in KRAS or APC, augmenting oncogenic effects. Epigenetic modifications, including DNA methylation and histone acetylation, contribute to gene silencing and tumour evolution, underscoring the complexity of CRC biology. In recent years, efforts to target these molecular aberrations have yielded significant advancements in CRC treatment.

Epidermal growth factor receptor (EGFR) inhibitors, such as cetuximab and panitumumab, are effective in treating left-sided CRC patients with wild-type KRAS and NRAS genes. These monoclonal antibodies block EGFR-mediated signalling pathways that promote cell proliferation and survival. In metastatic CRC, EGFR inhibitors have prolonged overall survival to over 24 months. However, resistance develops in most patients, and their effectiveness is significantly reduced in cases of KRAS wild-type right-sided tumours or tumours harbouring KRAS or NRAS mutations, emphasizing the need for molecular stratification prior to treatment.

The vascular endothelial growth factor (VEGF) pathway plays a central role in tumour angiogenesis. Bevacizumab, a monoclonal antibody that targets VEGF, has been shown extend overall survival up to 17.7 months when combined with chemotherapy in metastatic CRC. Other newer agents, such as aflibercept and regorafenib, also target VEGF-related pathways, and provide additional options for anti-angiogenic therapy.

Mutations in BRAF and KRAS occur in approximately 10% and 40% of CRCs, respectively and are linked to a poorer prognosis. The BRAF inhibitor encorafenib in combination with cetuximab has shown clinical efficacy in CRCs with BRAF V600E mutations. Recent advancements in targeting KRAS, previously considered undruggable, include the development of KRAS G12C inhibitors such as sotorasib and adagrasib. Although KRAS G12C mutations have shown potential for targeted therapy with sotorasib in lung cancer, resistance to this treatment emerges rapidly and to date, no clinically approved inhibitors are currently available for KRAS G12D, the most common KRAS mutation observed in CRCs.

Emerging Biomarkers

Biomarkers such as HER2 amplification and mutations in PIK3CA are expanding the landscape of targeted therapies in CRC. Dual anti-HER2 therapy has been shown to have clinically meaningful anti-tumour activity in patients with HER2-positive metastatic CRC, while there are ongoing trials of the PIK3CA inhibitor alpelisib. This further highlights the importance of molecular profiling in guiding treatment for patients with advanced CRC.

Immunotherapy Advances

Immunotherapy has transformed the treatment landscape for various cancers, including CRC. By leveraging the immune system to target and eliminate cancer cells, immunotherapeutic approaches are increasingly recognised for their potential in CRC, particularly in specific molecular and immunological subtypes. Microsatellite Instability (MSI) and Mismatch Repair Deficiency (dMMR) are predictive biomarkers for immunotherapy response. High microsatellite instability (MSI-H) tumours, which are characterised by defective DNA mismatch repair, have a high mutational burden and produce high levels of neoantigens, making them highly immunogenic and responsive to immune checkpoint inhibitors.

Programmed death-1 (PD-1) and its ligand, PD-L1, are immune checkpoint molecules that inhibit T-cell activation and allow tumours to evade immune surveillance. Antibodies targeting these proteins, such as pembrolizumab and nivolumab, block this interaction, restoring T-cell activity and promoting anti-tumour immunity. Pembrolizumab is FDA-approved for CRC patients with MSI-H or dMMR, which account for approximately 15% of all CRC cases. Clinical trials have shown durable responses and improved survival in these patients, making pembrolizumab a first-line treatment for advanced MSI-H/dMMR CRC.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is another immune checkpoint that inhibits T-cell activation. The combination of nivolumab and the CTLA-4 inhibitor ipilimumab has significantly improved outcomes in MSI-H metastatic CRC, demonstrating durable clinical benefits over more than four years of follow-up with high response rates, low disease progression rates, and improved long-term survival. In the non-metastatic setting, the recently published NICHE-2 study reported remarkable results with this combination in patients with locally advanced dMMR colon cancer. After just four weeks of treatment, pathological responses were observed in 98% of patients, with 95% achieving a major pathological response and 68% achieving a pathological complete response.

While chimeric antigen receptor (CAR)-T cell therapy has been highly effective in haematological malignancies, its application in CRC and other solid tumours has been limited by challenges such as the immunosuppressive tumour microenvironment and the lack of ideal targets. However, targets such as CEA and EGFR have shown promise in early-phase trials, and ongoing research aims to overcome the barriers posed by the immunosuppressive tumour microenvironment in CRC.

Precision Oncology and Personalised Medicine

Precision oncology and personalised medicine have the potential to revolutionise CRC treatment by tailoring interventions to the unique molecular and genetic profiles of each patient. Advances in diagnostic technologies and computational methods have enabled real-time monitoring, individualised treatment selection, and data-driven decision-making, offering the potential to improve outcomes while minimizing unnecessary toxicity.

Liquid biopsies, which analyse circulating tumour DNA (ctDNA) and other biomarkers in blood, provide a non-invasive method for monitoring CRC progression and treatment response and provide a dynamic picture of tumour evolution. ctDNA analysis could potentially facilitate the detection of minimal residual disease (MRD) after surgery, guiding the need for adjuvant therapy. Additionally, it could be used to identify emerging resistance mutations during treatment, enabling timely adjustments in therapy.

The incorporation of omics technologies into clinical care allows for comprehensive tumour profiling. Genomic sequencing can be used to identify actionable mutations to guide the use of targeted therapies and immunotherapies. The addition of proteomic profiling could provide insights into resistance mechanisms and uncover potential novel therapeutic targets, while metabolomic profiling could reveal metabolic vulnerabilities which could be exploited for treatment.

In research, artificial intelligence (AI) driven tools are increasingly employed to analyse complex omics datasets. These tools can predict treatment responses based on molecular profiles, optimise drug combinations, and identify novel biomarkers. Despite challenges related to data standardisation, interpretability, and integration into clinical workflows, AI-driven tools have the potential to enable truly personalised care. This approach could lead to improved patient outcomes and more efficient utilisation of healthcare resources.

Novel Drug Delivery Approaches

Traditional systemic delivery methods often fail to achieve optimal therapeutic concentrations in tumours and can be associated with significant toxicity. Novel drug delivery approaches have the potential to facilitate targeted drug delivery, provide controlled release, penetrate tumour microenvironments, preserve

drug stability, and reduce

systemic toxicity.

The use of nanoparticles (NPs) to encapsulate chemotherapeutic agents or molecularly targeted agents can enhance bioavailability and improve drug stability.

Clinical trials have shown that liposomal formulations of chemotherapeutic agents, such as irinotecan, have improved efficacy and reduced toxicity.

Antibody-drug conjugates (ADCs), which combine monoclonal antibodies with cytotoxic agents to deliver targeted therapy to the tumour, are another promising strategy. ADCs targeting HER2 (trastuzumab deruxtecan) and Trop-2 (sacituzumab govitecan) have shown promising early results in patients with advanced stage CRC.

Combination Therapies and Future Directions

Combination therapies in cancer treatment can enhance efficacy by targeting multiple pathways or mechanisms involved in tumour progression. This strategy not only improves treatment outcomes but also allows for the use of lower doses of individual agents, reducing toxicity and side effects for patients. Additionally, combination therapies can help overcome resistance, as cancer cells are less likely to evade multiple concurrent mechanisms of action. For example, dual inhibition of MEK and BRAF may potentially address resistance in BRAF-mutant CRC.

The combination of EGFR or VEGF inhibitors with immune checkpoint inhibitors is also being investigated as a strategy to modulate the tumour microenvironment and increase its susceptibility to immune-mediated destruction. The NRG-GI004/SWOG S1610 clinical trial is exploring the synergy between bevacizumab (an anti-VEGF agent) and atezolizumab (an anti-PD-L1 antibody) in metastatic CRC, aiming to harness the anti-angiogenic effects of bevacizumab to boost immune responses.

Recent pre-clinical studies from our lab have demonstrated that dual targeting of PI3K and the cell cycle using a CDK4/6 inhibitor exhibits potent anti-proliferative effects and significantly enhanced anti-tumour activity compared to single agent treatments.2,3 This combination may be a promising novel therapeutic strategy for colorectal cancer and warrants further clinical investigation.

Conclusion

Treatment for colorectal cancer has seen remarkable advancements, particularly in molecularly targeted therapies, immunotherapy, and precision medicine. The integration of immune checkpoint inhibitors, novel biomarkers, and real-time monitoring technologies has significantly improved outcomes for select patient populations, such as those with MSI-H/dMMR tumours or actionable mutations like BRAF or EGFR.

Despite these advancements, challenges remain. Resistance mechanisms, high costs, and the variability of patient responses pose barriers to widespread implementation. Additionally, many promising approaches, such as CAR-T therapy or multi-omics integration, require further validation in large-scale clinical trials before being incorporated into routine clinical practice.

Looking forward, the future of CRC treatment lies in combining therapies tailored to individual tumour profiles, leveraging real-time monitoring technologies, and incorporating artificial intelligence for data-driven decision-making. By addressing existing challenges and fostering multidisciplinary collaboration, these innovations will pave the way for more personalised and effective care, and ultimately improve outcomes for patients with CRC.

References available on request

Written by Dr Sinead Toomey1,2 and Professor Bryan Hennessy1,2

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