World Cancer Day 2021: Gene and Cell Therapies for Colorectal Cancers

The fourth of February 2021 marks the 20th anniversary of World Cancer day (WCD). WCD, led by the Union for International Cancer Control, is a project aimed at uniting the globe to raise awareness and improving education around preventing cancer deaths. With annual deaths caused by cancer at almost 10 million, WCD is imperative in widening learning around this disease. This article will focus on colorectal cancer (CRC) and how cell and gene therapies are paving the way for new and exciting treatment options.

Back to Basics: What Exactly is Cancer?

On a fundamental level, cancer can be defined as the dysregulation of normal cell growth and division. Uncontrollable growth leads to tumour invasion and sometimes spread to surrounding and distant tissues, and can initiate in almost any tissue in the body. Each type of cancer will have specific signs and symptoms, however, in general, some warning signs of cancer are:

• Lumps
• Unexplained tiredness
• Mole changes
• Pain
• Significant weight change 

Colorectal Cancer and its Symptoms

Colorectal cancer (CRC) is a form of cancer that originates within a patient's colon or rectum. It's the second most common cause of cancer-related death in the U.S. The physiological function of the colon is to absorb water and salts from food material after it has been processed by the small intestine. These materials are then transported and stored in the rectum until excretion. As such, in addition to the general symptoms of cancer mentioned above, some specific signs of CRC include:

• A lasting alteration to your normal bowel habits, which can include diarrhoea, constipation or a change in stool consistency
• Narrow stool
• Rectal bleeding or bloody stool
• Long lasting abdominal discomfort including cramps, gas, or pain
• A sensation that your bowel is not emptying completely

Typically, most CRCs are adenocarcinomas, meaning that the cancer initiated in a gland that lines the inside of the organ. Other less common subtypes of CRCs include carcinoid tumours which evolve from hormone-secreting cells, gastrointestinal stromal tumours which originate from the "intestinal cells of Cajal" found in the colon wall, or more widely known tumour types such as lymphomas and sarcomas, although sarcomas of the colon or rectum are rare.

Traditional treatments for CRC normally include surgery as well as chemotherapy/radiotherapy. A patient’s treatment plan depends on many factors such as where in the bowel the cancer is and if it has spread. At the point of diagnoses it is common for patients to also have developed metastatic cancer in the liver, and currently, approximately 50% of patients ultimately develop liver metastases during the progression of the disease. Fortunately, there are many fantastic consortium-based research projects which aim to not only improve the pre-clinical evaluation of CRC but also to find new and to improve current treatment options. For example, the ACRCelerate Colorectal Cancer Stratified Medicine Network, is a CRUK funded European consortium made up of basic and clinical scientists. The principal aim of the ACRCelerate project is to bridge the gap between tumour molecular signatures and targeted clinical trials as a way of de-risking future experiments.

Gene and Cell Therapy Research for CRC

Cell and gene therapies signify an exciting and evolving option for the treatment and prevention of CRC. Gene therapies work to target genetic defects which have given rise to cancer, whereas cell therapies includes the delivery of immune cells that target and kill cancer cells. Thrillingly, there are currently 190 clinical trials involving gene therapies for CRC and a staggering 1046 trials involving cell therapies. This highlights the wealth of research and advances currently being explored and is fantastic to witness given the current impact the COVID-19 pandemic is having on cancer research.

I had the pleasure of speaking with Joaquim Miguel Oliveira, Ph.D., a principle investigator at the Research Institute of Biomaterials, Biodegradables and Biomimetics, University of Minho. Dr Oliveira is currently working on improving gene therapy options for CRC using dendrimer nanomedicines, with some of his resent exciting research linked here. He had the following to say on how this nanotechnology is influencing his field of research:

"Colorectal cancer (CRC) is the second most common type of cancer in the Western world. Regardless of improvements in treatment, CRC relapses in up to 50% of patients and ultimately proves to be fatal. CRC allows for a variety of treatments, from conventional chemotherapeutic methods to immunotherapy and various gene-therapy approaches (gene correction, virus-directed enzyme–prodrug therapy and virotherapy). In particular, gene therapy is most promising as it can allow a personalized approach and by this mean, overcome many cancer-related challenges and unmet clinical needs. The 3Bs-UMINHO, a tissue engineering established-research group, has been developing different mimetic in vitro tumour models for nanomedicines testing and validation. One example of nanomedicines that have been synthesized is based on the surface-engineered poly(amidoamine) (PAMAM) dendrimer nanoparticles. Our studies making use of a 'tumor-on-a-chip' model validated for investigating the efficacy of drug-loaded nanoparticles in a gradient fashion confirmed the dose-response effect of cells exposed to the drug-loaded CMCht/PAMAM nanoparticle gradients. These nanoparticle vehicles present an overall cationic nature and functionality and are most advantageous as they are also able to target specific cells types; thus opening up interesting possibilities and applications in targeted therapy approaches. It is our firm belief that by means of combining novel in vitro 3D models and nanotechnology (e.g. nanoparticles as vehicles for drugs/gene delivery), we will be able to better meet the requirements of precision cancer diagnosis and therapy with the benefit for the patient."

It is clear that gene and cell therapy offers a lot of potential in the treatment and prevention of CRC. Given the wealth of clinical trials and international efforts to improve these treatments, a new generation of therapeutics is within reach.

Dr. Mulholland is a postdoctoral research scientist in cancer genetics and Junior Research Fellow (Somerville College) at the University of Oxford. He is a member of the ASGCT Communications Committee.