New Directions in the Treatment of Advanced Colorectal Cancer

Introduction

During the past decade, the treatment of advanced colorectal cancer finally began to change. The development of new drugs with single-agent activity in colorectal cancer has changed the focus of clinical trials away from new methods of modulation of fluorouracil(Drug information on fluorouracil) (5-FU). Currently, new drug development in colorectal cancer is going beyond traditional cytotoxic therapy. This article is designed to broadly outline some of these new approaches, with a focus on two novel strategies, ie, targeting the epidermal growth factor receptor (EGFr) and targeting vascular endothelial growth factor (VEGF).

Immunotherapy Approaches

The term "immunotherapy" now encompasses several different approaches to treatment of malignancies. Reviews of immunotherapy approaches to colorectal cancer have been published.[1,2]

Using Monoclonal Antibodies

One immunotherapy approach is to use monoclonal antibodies against various cellular targets such as proteins located (and often overexpressed) on the surface of cancer cells. Examples of these include antibodies to glycoprotein 17-1a, carcinoembryonic antigen (CEA), HER2/neu, and C242.[1] While antibodies themselves may be able to produce an immune response to aid in tumor cell kill, it is also possible to use antibodies to deliver the chosen anticancer therapy. For example, anti-CEA antibodies have been radioactively tagged for the purpose of immunoscintigraphy. This is currently being evaluated for delivery of intratumoral radiation.[2]

Antibodies can also be used to enhance delivery of chemotherapy agents or their prodrugs to the tumor. The drug can be attached to an antibody targeted to the cancer. The agent would then be cleaved and activated by the cancer cells. Similarly, toxins such as ricin or Pseudomonas toxin have been attached to an antibody for targeted delivery.[1] Trials of several such agents have begun to accrue patients.

Using Vaccines

Another approach in early clinical testing is the use of vaccines against proteins that are either overexpressed or mutated in colorectal cancer cells. The immune response in this case may require specific human leukocyte antigen (HLA) types as is the case with the anti-ras vaccine developed by Carbone et al, which is currently undergoing evaluation in colorectal cancer. In addition, other approaches such as adding cytokines may increase the projected immune response to a vaccine. One such trial combined a monoclonal antibody to glycoprotein 17-1a with interleukin-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine]).[3] Of 20 patients enrolled, one had a partial response and two had stable disease.

While these approaches have not yet demonstrated efficacy in advanced disease, the trials are still early and results are limited. However, it is suspected that immune therapies will be most effective in the setting of minimal residual disease. For example, despite minimal activity in advanced disease, the monoclonal antibody to glycoprotein 17-1a, in one trial, appears to have reduced the risk of recurrence by 30% in patients with resected stage III colon carcinomas.[1]

Gene Therapy

Gene therapy is a broad area of current investigation with a variety of potential applications. An excellent review of gene therapy was published previously.[4] Some of the classifications and potential targets of gene therapy are listed in Table 1.

Viral Vectors

Recent advances in our understanding of the biology of cancer have focused on the genetic changes that lead to malignant transformation. Genes commonly mutated in colorectal cancer include, but are not limited to, p53, the ras family, DCC, APC, and genetic mutations that lead to microsatellite instability. If mutations in these genes can lead to cancer, then replacing the wild type genes theoretically may reverse the malignant process created by the mutant gene.[4]

Therefore, there has been much focus on development of viral vectors to "correct" the mutant gene. For example, by replacing wild type p53, it is hoped that tumor cells would more readily undergo apoptosis, the process of programmed cell death. The adenovirus Onyx-015 utilizes a different approach to gene therapy. Already in clinical testing, this virus replicates selectively in cells with mutated p53, which results in cell death. Evidence for clinical activity was seen in the first trials of intratumoral injection of the Onyx-015 adenovirus.

Immunomodulation

A method of gene therapy that crosses into the previously discussed category of immunotherapy is immunomodulation. One example is use of a viral vector to increase HLA B7 expression to enhance immune responses to malignancy. Another example is the transfer of cytokine genes into tumor cells in order to enhance immune response. These methods are being studied in the preclinical setting and in early clinical trials.

Transferring Genes

Finally, it may be possible to kill tumor cells by transferring genes that result in the production of certain enzymes that metabolize prodrugs to active cytotoxic agents.[4] For example, by transferring the gene for thymidine kinase into the tumor cells, the antiviral agent ganciclovir(Drug information on ganciclovir) (Cytovene) would then be selectively activated in the cancer cells resulting in regional toxicity without severe systemic effects. Other enzyme/prodrug pairs are listed in Table 1.

Molecular Targets

The new knowledge has also resulted in the development of chemicals and antibodies to molecular targets within tumor cells or the matrix within which they grow. Two molecular targets have entered clinical trials in colorectal cancer.

Epidermal Growth Factor Receptor

The epidermal growth factor receptor (EGFr), also known as HER1 and ErbB1, is a 170-kD transmembrane glycoprotein consisting of two major parts: an extracellular ligand-binding domain and an intracellular tyrosine kinase domain. Although EGF is a ligand for EGFr, other ligands have been identified, including transforming growth factor-alpha (TGF-alpha), heparin(Drug information on heparin)-binding EGF, amphiregulin, and betacellulin. When an activating ligand binds to EGFr, either homodimerization of EGFr or heterodimerization with another member of the HER family occurs. This results in receptor autophosphorylation and activation of the tyrosine kinase. The downstream effects of activating the tyrosine kinase appear to include cell survival and apoptosis, angiogenesis, cell motility, and tumor invasiveness.

The EGFr has been studied specifically in colorectal cancer. EGFr is frequently overexpressed in colorectal cancer. In addition, results of at least one trial suggest that EGFr overexpression may correlate with metastatic potential in colorectal cancer.[5]

Drugs that target one of the two major domains of the EGFr have been designed and are undergoing clinical testing. One approach to inhibiting EGFr through the extracellular domain is via the creation of antibodies to the extracellular domain of EGFr. Conjugating a toxin such as ricin to either an EGFr ligand or to an EGFr antibody can also target EGFr. Finally, antisense oligonucleotides to EGF receptor mRNA and to EGF receptor ligand mRNA have also been designed. Of these methods, antibodies to the EGFr have already entered clinical trials. The antibody ABX-EGF is a fully human IgG2 monoclonal antibody with a high affinity for EGFr.[6] ABX-EGF had significant activity against a variety of cell lines in the preclinical setting. Phase I trials are ongoing.

A second antibody, C225, is a chimeric antibody against EGFr. Although it is not fully human, C225 does not appear to induce antichimeric antibodies.[7] In an early trial, C225 was combined with chemotherapy for patients with refractory tumors.[8] Although the study reported on very few patients treated with a variety of agents, one patient with colorectal cancer has had a durable complete response. Therefore, a phase II study was initiated using irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) and C225 for patients with irinotecan-refractory colorectal cancer; preliminary results are to be presented at the American Society of Clinical Oncology Conference in May 2001.