New Directions in the Treatment of Advanced Colorectal Cancer
New Directions in the Treatment of Advanced Colorectal Cancer
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 (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).
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. 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.
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
cells. Similarly, toxins such as ricin or Pseudomonas toxin have been attached
to an antibody for targeted delivery. Trials of several such agents have
begun to accrue patients.
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]). 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
Gene therapy is a broad area of current investigation with a
variety of potential applications. An excellent review of gene therapy was
published previously. Some of the classifications and potential targets of
gene therapy are listed in Table 1.
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
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
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.
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. For example, by transferring the gene for
thymidine kinase into the tumor cells, the antiviral agent 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.
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
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-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
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.
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. 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. In an early trial, C225 was combined with chemotherapy for
patients with refractory tumors. 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 (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.