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CHAPTER 15 Molecular/Targeted Therapy of Cancer 257

gene coding for ICP47 (ICP47 suppresses the immune response with greater potency are developed, or used in combination with
to the virus) has been removed. To date, increased survival or pro- other treatments, then safety should remain a concern. One of
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the major issues may be the development of resistance through
tection from metastasis has not been definitively demonstrated.
VetBooks.ir clinical studies. Recent pilot safety studies have been performed in immune clearance. Although immunosuppressive therapy has
In veterinary oncology, there have been a number of limited
been suggested as part of the treatment with OVs, this should be
dogs using systemically delivered recombinant oncolytic reovirus considered with caution relating to both safety and ensuring that
and vesicular stomatitis virus. 67,68 This demonstrated the feasibil- the optimal performance of the virus is not blocked.
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ity and safety of this approach and opens the door to future studies
to demonstrate efficacy in the clinical setting. A cautionary note, Conclusions
however, is that the majority of dogs in the United States and
Europe are vaccinated against some viruses such as canine adeno- Gene therapy promises a completely new approach to the treat-
virus and these types of vectors may not be able to overcome host ment of cancer and represents an emerging area of therapeutics.
immunity with long-term treatments. 1,69 It has suffered over the past 20 years as clinical trials in human
medicine have not delivered what they had originally promised.
Safety Considerations in Gene Therapy However, many of these studies were conducted in patients with
high-grade or end-stage disease and many studies were conducted
One of the major considerations in gene therapy revolves around prematurely without refining the delivery technologies. Clearly,
issues of safety, in particular the safety of the vectors used for gene there are a number of technical issues such as safety surrounding
delivery. In 1999, gene therapy suffered a major setback with the the delivery and efficiency of the vectors that need to be resolved
death of a patient as a direct result of adenovirus gene therapy. before gene therapy becomes established clinical practice. Despite
Problems associated with vector delivery include inappropriate gene therapy being very much in its infancy, the field is advancing
inflammatory responses caused by vector delivery (e.g., adenovi- at a rapid rate and resent successes have given the field a signifi-
ruses), the generation of replication-competent viruses (although cant optimistic boost. A number of clinical trials have begun in
this is unlikely with new generation vectors), and insertional companion animals, and products are in development for clinical
mutagenesis caused by integrating viruses (e.g., retroviruses). 1 application. However, although these treatments would appear to
Until recently, many gene therapy trials had utilized retroviral be powerful in preclinical models, it is likely that their greatest
vectors for gene delivery. There are many advantages to using ret- benefit will be in the management of patients with minimal disease
roviruses as outlined in Table 15.1; however, retroviruses are also states. Thus gene therapy will probably have its greatest advantage
associated with serious diseases of domestic animals and the use not as a stand-alone treatment but as an adjunct to more conven-
of these in gene therapy poses a risk of insertional mutagenesis tional therapies such as surgery, RT, or chemotherapy.
and/or the production of replication-competent viruses during
the manufacturing process. Realistically, insertional mutagenesis
leading to a malignant transformation is an unlikely event because SECTION B: SIGNAL TRANSDUCTION
cancer is a multistep process. In fact, there may be a greater risk AND CANCER
of malignant transformation from external beam RT than from
the use of retroviruses to treat cancer. The production of replica-
tion-competent retroviruses during the production process would CHERYL A. LONDON
also be unlikely because of the rigorous testing that is required
before clinical application. Many of these issues are resolving with In normal cells, signals are generated that begin at the outside of
1
the development of new generation vectors. As an example, in the cell and are transmitted through the cytoplasm to the nucleus,
the use of retroviruses and to prevent insertional mutagenesis in regulating cell growth, differentiation, survival, and death. Several
normal tissues, one group recently described the use of zinc fin- components of cellular signal transduction pathways are typically
ger nucleases (engineered DNA-editing enzymes) that allows the dysregulated in cancer cells, resulting in uncontrolled cell growth
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insertion of DNA to a site of choice within the genome. This and thereby contributing to tumorigenesis. Because many tumors
adds a further level of safety in a high-risk procedure. have similar alterations in signal transduction components, these
One might imagine that the delivery of naked DNA may offer have become promising targets for therapeutic intervention. This
a safer alternative. However, all of the potential safety issues using section focuses primarily on the role of a particular group of sig-
this technology are still not fully answered. These include poten- nal transducers called protein kinases, their role in normal cells,
tial risks of autoimmunity and also the actual fate of the DNA the mechanisms by which they contribute to tumorigenesis, and
when it has been delivered to the patient; in the case of the former, the use of agents designed to inhibit them when they become
however, there would appear to be no evidence of autoimmunity dysfunctional.
being a problem in preclinical models.
One of the most exciting developments in cancer gene therapy Protein Kinases and Normal Cells
is the use of conditionally replicating OVs. However, the safety of
these vector systems needs special consideration as many of them Protein kinases play critical roles in normal cell signal transduc-
in their native form could pose a risk to both human and animal tion, acting to tightly regulate cellular processes such as growth
health. Despite this, published trial data have not demonstrated and differentiation. These proteins work through phosphoryla-
any significant safety issues. Local delivery has been associated in tion; that is, they bind adenosine triphosphate (ATP) and use it
human medicine with mild flulike symptoms, which have resolved to add phosphate groups to key residues on themselves (a process
with symptomatic treatment with paracetamol/acetaminophen. called autophosphorylation) and on other molecules, thereby stim-
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In addition, OVs do not reach a maximum tolerated dose (MTD), ulating a downstream signal inside the cell. This process typically
mainly because of a high tolerance for the virus. However, as OVs occurs in response to external signals generated by growth factors