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  • Review Article
  • Published:

Cancer gene therapy: fringe or cutting edge?

Nature Reviews Cancer volume 1, pages 130–141 (2001)Cite this article

Key Points

  • Gene therapy is a rational approach to the direct attack of cancer cells based on their molecular defects, but despite encouraging preclinical results and signs of efficacy in early stages of clinical testing, its clinical utility has not been proved.

  • There are three broad approaches to direct cancer gene therapy: expressing tumour-suppressor genes in tumours that lack them (or blocking the expression of activated oncogenes), suicide gene therapy, and selectively replicating viruses.

  • Expression of tumour-suppressor genes in tumour cells causes cell-cycle arrest and/or apoptosis, even though such cells harbour many other genetic changes. Surprisingly, there is also some evidence, at least for expression of TP53, that these effects are not cell autonomous. Clinical trials have revealed that this approach is safe, and there are some signs of efficacy.

  • Blocking the expression of oncogenes, using ribozymes or antisense oligonucleotides, can cause growth arrest or apoptosis in vitro, but its effects are cell autonomous. Pharmacological inhibition of oncoproteins, using small molecules or antibodies, might ultimately prove to be a more viable approach.

  • Suicide gene therapy relies on the expression of an enzyme that converts a harmless prodrug into a potent toxin. Its main advantage is that the toxin can then kill surrounding cells that aren't expressing the vector. Again, suicide gene therapy has proved safe in the clinic but has shown little, if any, therapeutic benefit. Second-generation vectors might address this lack of efficacy.

  • Selectively replicating viruses rely on a property of the tumour cell (such as loss of tumour-suppressor function) that make tumour cells uniquely susceptible to productive infection with the virus. Clinical trials have revealed that the approach is safe, and there are some signs of efficacy.

  • In all these approaches, lack of bioavailability and attack of the viral vectors by the B-cell arm of the immune system are significant problems. Several approaches are being developed to solve these problems, but none have yet been tested in the clinic.

Abstract

Direct targeting of cancer cells with gene therapy has the potential to treat cancer on the basis of its molecular characteristics. But although laboratory results have been extremely encouraging, many practical obstacles need to be overcome before gene therapy can fulfil its goals in the clinic. These issues are not trivial, but seem less formidable than the challenge of killing cancers selectively and rationally — a challenge that has been successfully addressed.

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Figure 1: Cancer gene therapy and immunotherapy trials currently listed as open by the US Recombinant Advisory Committee.
Figure 2: Cancer gene therapy by delivery of tumour-suppressor genes or inhibition of oncogene expression.
Figure 3: Suicide gene delivery.
Figure 4: Conditionally replicating viruses.
Figure 5: Alterations in the p53 pathway in adenovirus-infected cells and tumours.

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Authors and Affiliations

  1. University of California San Francisco, Cancer Research Institute, 2340 Sutter Street, San Francisco, 94115, California, USA

    Frank McCormick

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  1. Frank McCormick
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DATABASES

CancerNet:

brain tumour

breast cancer

cervical cancer

chronic myelogenous leukaemias

colorectal cancers

metastatic melanoma

non-small-cell lung tumours

ovarian cancer

squamous cell carcinoma of the head and neck

 Genbank:

adenovirus

HSV-tk

ICP34.5

ribonucleotide reductase

SV40 large T-antigen

 LocusLink:

ABL

APC

BCR

BRCA1

BRCA2

CAR

β-catenin

cyclin D1

cytochrome P450

E2F

EGFR

endostatin

ERBB2

fibroblast growth-factor receptor

HRAS

IGF-1

IGF1BP

INK4A

matrilysin

MDM2

MUC1

c-MYC

p300

probasin

PSA

PTEN

RB

TCF-4

thrombospondin

TIMP-2

TP53

tumour necrosis factor

VEGF

 Medscape DrugInfo:

cisplatin

cyclophosphamide

5-fluorouracil

ganciclovir

Gleevec

Herceptin

lovastatin

Rituxan

 Patent database:

Novartis US Patent 5,998,205

 Protein Data Bank:

structure of CAR

Glossary

THERAPEUTIC WINDOW

The concentration range over which a drug has a therapeutic effect without having unacceptable toxicity.

RETROVIRAL VECTOR

Gene-therapy vector derived from a retrovirus. The gag, pol and env genes, necessary for replication of the virus, are replaced with a therapeutic gene, preventing viral replication.

ADENOVIRAL VECTOR

Gene-therapy vector derived from an adenovirus. Genes necessary for replication of the virus can be deleted to make replication-defective vectors.

ANTISENSE OLIGONUCLEOTIDE

An oligonucleotide that is complementary to a portion of an mRNA. It binds to the mRNA and arrests translation by physical blockade of ribosomal machinery and/or by activation of endogenous RNases.

RIBOZYMES

RNA molecules with catalytic activity. They can be engineered to cleave specific mRNAs, thereby blocking gene expression at the mRNA level.

PRODUCER CELLS

Cells used to produce replication-defective viral vectors; they are transfected with the genes that are missing from the vector itself, and so provide the products of these genes in trans.

GAP JUNCTION

A junction between two cells that allows the passage of molecules (up to 9 kDa).

EARLY REGION PROTEIN

Viral proteins expressed before the onset of viral DNA synthesis, usually involved in driving the infected cell into the S-phase of the cell cycle.

E3 UBIQUITIN LIGASE

The third enzyme in a series — the first two are designated E1 and E2 — that are responsible for ubiquitylation of target proteins. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating ubiquitylation of the selected substrates.

MUC1

A large, transmembrane glycoprotein of the mucin family. It is often expressed on cancer cells, especially breast cancer cells.

HUMANIZED MONOCLONAL ANTIBODY

An antibody, usually from a rodent, engineered to contain mainly human sequences. This process reduces the immune response to the antibody in humans.

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McCormick, F. Cancer gene therapy: fringe or cutting edge?. Nat Rev Cancer 1, 130–141 (2001). https://doi.org/10.1038/35101008

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