Manipulation of tumor suppressor genes and oncogenes

Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)

Expression of tumor suppressor genes

The most straightforward application of gene therapy involves introduction of genetic material that inhibits the progression of malignancies (tumor suppressor genes).

Tumor suppressor genes are genes lost during carcinogenesis and have the following qualities:

  • They link the cell cycle to DNA damage and repair mechanisms.
  • They stop cell division in the setting of irreparable DNA damage.
  • They may affect tumor adhesion factors (metastasis-suppressive factors).

Tumor suppressor genes control the progression through cellular mitotic checkpoints and thus cell division and tumor growth. Approximately 50% of human cancers are noted to be deficient in the tumor suppressor gene p53, which encodes a transcription factor involved in cell progression; conversely, 100% of persons with Li-Fraumeni syndrome caused by p53 mutations develop malignancies.

The p53 tumor suppressor gene exerts exquisite control of the G1/S transition in the setting of DNA damage through bax and fas signaling. Introduction of p53 into human malignancies has been studied as a way of inducing tumor regression.

The recently approved agent gendicin consists of a recombinant adenovirus-expressing p53 targeted to patients with head and neck cancers. Phase I and II trials have been carried out using retroviral vectors targeting lung malignancies.

Other examples of tumor suppressor genes include the following:

  • E-cadherin
  • Retinoblastoma (RB) gene
  • PTEN

Tumor suppressor gene therapy may also be used to increase responsiveness to radiotherapy or chemotherapeutic agents, regardless of tumor p53 status. Trials of p53 gene therapy involving radiation therapy (XRT) and cisplatin responsiveness are ongoing.

Correction of mutant oncogenes

Gene therapy may also prove useful by correcting mutations in human oncogenes. Mutations in the proto-oncogene k-RAS are common in a wide variety of human malignancies and may confer resistance to emerging therapies such as EGFR inhibitors such as cetuximab.

Knockdown of expression of oncogenes may be accomplished by antisense nucleotides as well as emerging therapies such as RNAi or ribozyme correction of mRNA templates. Antisense technology uses stable DNA molecules to bind complementary sequences of RNA or DNA and suppress transcription or translation of further gene products.

The anti-bcl-2 antisense agent G3139 (oblimersen) has been studied in prostate cancer patients.


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