Targeted Therapy for Colorectal Cancer

The highly heterogeneous nature of colorectal cancer has meant that treatment of the disease calls for sophisticated methodology. While the main treatment methods — surgery and chemotherapy — have thus far proven effective in curing localized cancers (91% 5-year survival rate), the 12% survival rate for metastatic colorectal cancer, unfortunately tells a different story.

The effectiveness of chemotherapy diminishes with more advanced cancer in part due to lower specificity for cancer cells and emerging chemotherapy drug resistance. As such, more effective treatment methods are needed to improve the overall survival rates of metastatic cancer patients. One of these methods is targeted therapy, which is sometimes offered as second-line treatment or concurrently with chemotherapy.

As the name suggests, targeted therapy involves the administering of drugs that have specific molecular targets in biological pathways that are crucial to cancer growth, proliferation and migration.

At times, immunotherapy and targeted therapy are discussed in the same breath or used interchangeably. However, these treatments can be differentiated by considering their targets and objectives. Immunotherapy specifically uses the patient’s immune system to attack and destroy cancer cells by helping the T cells recognize them as foreign. On the other hand, targeted therapies interfere with specific cellular pathways that promote cell growth and proliferation at the molecular level. These pathways include those that directly regulate cell growth and division and pathways that support tumor growth.

The vascular endothelial growth factor (VEGF) pathway is one that is crucial to angiogenesis — the formation of blood vessels. Normal cells and tissue require oxygen and other nutrients carried by the blood to grow, and blood vessels are typically formed concurrently as the tissue develops.

In colorectal and other cancers, the tumor microenvironment has been associated with VEGF upregulation, but how does this happen?

Small tumors may remain dormant as the cancer cells undergo continuous proliferation and apoptosis, with the total cell count remaining constant. Over several rounds of cell division, more mutations are introduced into the cell until an angiogenic switch occurs. This happens when a mutation alters the balance between the growth-inhibiting and stimulating factors such that growth stimulation becomes favored, and the tumor begins to rapidly grow.

Large tumors, like other normal tissue, require a supply of oxygen and nutrients to grow larger than 1–2 mm. The rapid division and proliferation of cancer cells often mean that the formation of tumors outstrips the formation of blood vessels, creating a hypoxic condition lacking the oxygen required for the tumor to grow. Hypoxia triggers the upregulation of VEGF, which leads to the formation of blood vessels in the tumor.

However, poor vasculature, frequent branching and dead ends characteristic of tumor blood vessels result in insufficient oxygen reaching the cancer tissue, leading to hypoxia and further VEGF upregulation.

Drugs that target the VEGF pathway inhibit VEGF to reduce the formation of poorly formed blood vessels in tumors. This leads to more regularly formed blood vessels, which allows for better efficiency in delivering chemotherapy drugs to the tumor. At present, there are five FDA-approved targeted therapy drugs that are currently used to inhibit VEGF.

• Bevacizumab
• Ramucirumab
• Ziv-aflibercept
• Regorafenib
• Fruquitinib

The epidermal growth factor receptor (EGFR) pathway and the EGF family of peptide growth factors are important receptors and ligands involved in early embryonic development and the renewal of stem cells in normal tissue, including in the gut. However, this class of tyrosine kinase receptors is also implicated in promoting cancer cell growth and the formation of different carcinomas in many cancers, colorectal cancer included.

In normal cells, extracellular protein ligands bind to the inactive, monomeric transmembrane EGFR, which undergoes a transition to form an active homodimer and possibly pairing with another member of the EGF receptor family. This stimulates intracellular protein-tyrosine kinase activity, activating other pathways through signal transduction cascades, leading to DNA synthesis and cell proliferation.

The overexpression of EGFR in cancer cells results in uncontrolled proliferation, and drugs that target EGFR are inhibitors that prevent activation of the downstream pathways. However, given that the process is more complex and must also take into account the complex reactions within the EGF family of receptors and growth factors, they form an integrated system in which a signal to a single receptor type is frequently transmitted to other similar receptors in the same family. Understanding these reactions is important for the development of treatments that more efficiently inhibit EGFR signaling.

The two FDA-approved drugs that inhibit EGFR are

• Cetuximab
• Panitumumab

However, these drugs do not work on colorectal cancers with certain mutations, and so genetic testing of the tumor must be done first before incorporating these EGFR inhibitors into the treatment plan.

Though targeted therapy is shown to improve treatment when paired with existing chemotherapy and immunotherapy treatments, there are still some limitations.

It is challenging to successfully disrupt certain pathways related to colorectal cancer due to the complicated signaling processes involved. Currently, there is limited information about which targeted agents are effective in clinical studies. Many other targeted drugs for this condition are still being tested in early stage trials or have not yet been tested in humans.

Targeted therapy can lead to longer survival for people with cancer, but also it has some downsides. First, it can be more expensive than chemotherapy, especially if multiple targeted drugs are needed. Additionally, it can cause more side effects and may not work as well for everyone. In addition, many targeted approaches may require a companion chemotherapy to be administered. Lastly, drug resistance can occur, requiring further treatment that can be costly and toxic. These challenges need to be considered when developing targeted drugs in the future.

A patient’s well-being is of utmost importance, and the development of newer and more efficient treatment methods is promising. However, it is important to acknowledge that not all treatments are equally effective. For this reason, individuals, especially those with cancer, are encouraged to stay well-informed and maintain communication with their cancer care team. In doing so, they can gain an understanding of the available treatment options and make informed decisions based on their needs and circumstances.