Biology 207

Biology of Cancer Spring 2004

Lecture 26: Cancer Gene Therapy and New Biological Therapies

Source:

National Cancer Institute (NCI). Questions and Answers about Gene Therapy. http://cis.nci.nih.gov/fact/7_18.htm

Lecture outline:

1. Gene therapy

2. Replacement and knockout therapies

3. Suicide and immunotherapies

4. New biological therapies

Lecture:

“Gene therapy for cancer has moved from the realm of the imagination into laboratory practice and clinical trials.” InTouchLive.com

Gene therapy is the transfer of nucleic acids (DNA, RNA) into target cells to correct or disrupt a pathologic process. The idealized approach to gene therapy is the replacement or supplementation of a mutated gene with a corrected copy that restores normal function.

Key issues:

·  Identify genes with therapeutic potential for cancer, i.e. p53.

·  Develop and test better ways of delivering genes to tumor.

Strategies:

·  replacement gene therapy

·  knockout gene therapy

·  suicide gene therapy

·  immunomodulatory gene therapy

Replacement Gene Therapy=method for replacing a mutated or missing gene (usually a tumor suppressor gene) that serves to keep cell growth and division under control with a "healthy" (normal) copy of that gene.

The goals of tumor suppressor gene therapy include:

·  the induction of cell death (apoptosis), and

·  the production of changes in cell growth, behavior, invasiveness, or metastatic ability.

For example, because the gene coding for p53, is the most common gene mutated in cancer (more than half of all heritable cancers) and influences transcription, the cell cycle, cell death (apoptosis), and angiogenesis (the development of a tumor's blood supply), it has become a prime target for gene replacement—with some success experimentally.

The promise of replacement gene therapy with tumor suppressor genes is still limited by:

·  the large number of target genes clearly known to induce or maintain malignancy, and

·  the difficulty of transducing enough cancer cells to result in a cure.

Knockout gene therapy primarily targets the products of oncogenes in an effort to inactivate them and reduce cellular proliferation. Several approaches are being tried:

·  delivering a mutant oncogene that acts in a dominant manner to negate the effects of the cancer-causing oncogene

·  inhibiting translation of the oncogene by gene therapy

An unexpected bystander effect—the death of more cells than are actually transduced—has been observed in replacement and knockout therapies.

Suicide gene therapy—involves the transduction of a gene that transforms a nontoxic form of a drug (that is, a "pro-drug") into a toxic substance.

Immunomodulatory gene therapy--is a method to induce cellular immune responses to metastatic tumors. The strategy involves injecting into the skin of a patient a suspension of irradiated tumor cells that have been transduced with a cytokine gene to stimulate a systemic immune response against tumor-specific

antigens—in effect, vaccinating the patient against that specific cancer.

The basic idea of immunotherapy is to:

·  modify tumor cells outside the body with a cytokine gene

·  transplant the cytokine-gene modified cells back into the patient (after the cells have been irradiated to prevent further cell division)

·  let the host's system create an antitumor immune response

Many of the interleukin genes are being looked at for this strategy.

The future of cancer gene therapy requires:

·  increased competence with transduction

·  advances in techniques to induce expression of transduced genes

·  advances in inducing significant antitumor responses at the systemic level

Genetic Profiling

Individuals respond differently to chemotherapeutic regimens because of inherited variations in genes involved in drug metabolism.

Some individuals have been found to have variants of genes associated with poorer survival rates and weaker responses to chemotherapeutic drugs. Some examples:

·  CYP3A4, CYP3A5

·  GSTM1

·  MDR1 (multidrug resistance gene)

This approach, tailoring chemotherapeutic regimens to affected individuals, reflects the interplay between one's genes and the environment and may be one of the most important ways to think about the impact of genetics on cancer treatments.

Creative biological-based treatments for cancer in development

COBALT—combination bacteriolytic therapy

·  Developed by Bert Vogelstein’s lab at Johns Hopkins.

·  Large tumors are starved for oxygen and have many dead and dying cells.

·  Certain bacteria prefer oxygen—poor environments.

·  Spore-forming bacterial species called Clostridium novyi was genetically modified to remove toxin gene.

·  Inject bacteria along with chemotherapeutic drug into tumor.

·  Selectively targets large advanced colon tumors in mice.

·  Bacteria consume tumor from within, the chemotherapy treatment treats the tumor from the outside.

”More than half of the tumors treated, including very large tumors, were

completely destroyed within 24 hours. The tumors decomposed and turned into

blackened scars, while the surrounding healthy tissues remained intact. The

tumor scars then gradually disappeared over the next two weeks, leaving healthy

tissue behind”.

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