GENETICS

Genetic Therapy: The Next Step Forward

Cancer remains the second leading killer after cardiovascular disease but statistics indicate that it will supersede cardiovascular disease within the next ten years. A new cancer is diagnosed every 25.8 seconds and a person dies of cancer every 60 seconds. In the United States alone, over 552,200 cancer deaths are expected in 2000.

Number of New Cancer Cases 2000 Estimates

* This paper was first presented to a lay audience in 1994.

The major modalities of therapy remain surgery, radiation therapy and chemotherapy. Biologic response modifiers such as BCG have been used successfully in the treatment of superficial bladder cancers. Interferons have been used in certain types of leukemia and renal cell carcinoma. We now are entering the age of genetic therapy to treat cancer. The rationale for this is that cancers are DNA disorders. Defects in our DNA either turn cell division "on" or do not turn "off" cell division. Genes responsible for turning on cell division in a cancer cell are termed Oncogenes. Genes that function to turn off aberrant cell growth are called Tumor Suppressor Genes. Defects in these genes create and perpetuate cancers. New approaches to cancer utilizing genetic therapy involve manipulating these genes to halt cancer. Studies todate indicate that a cell must sustain damage to one oncogene & three tumor-suppressor genes to create malignancy.

Mechanisms of DNA Injury

Defective genes may be inherited from parents as occurs in early-onset colorectal cancer, and cancers of the prostate, breast, lung, and brain. Acquired genetic defects may be induced as a result of viral infection as seen with HIV, hepatitis C, B, and E-B viruses to name a few. Various electro- magnetic energies may induce genetic damage. Radiation from sun exposure, nuclear fallout, and excessive x-ray exposure are known factors that increase risk of cancer. Environmental toxins such as insecticides, cigarette smoke, asbestos, benzene, aflatoxin, radon, and vinyl chloride have well known associations with various types of cancers. Combinations of exposures to cigarette smoke, and asbestos, for example, further increase the risk of cancer. These toxic exposures therefore are synergistic in their carcinogenesis.

Tumor-Suppressor Genes: p53

There exists a gene that keeps watch over DNA during cell division; this is the tumor suppressor gene p53 which in its natural state is known as wild- type p53. Wild-type p53 may block tumor growth by inducing apoptosis (programmed cell death) and by causing reversible arrest in the G1 phase of the cell cycle. p53-dependent apoptosis seems to be the mechanism for the anti-tumor effect of radiation, and certain chemotherapy drugs.

Mutations in p53 are detected in more than 50% of all human cancers e.g. lung, breast, brain, bladder. Cancer cells with mutated p53 are more resistant to chemotherapy & radiation therapy and provide a genetic basis for drug resistance. We also know that cancers with frequent mutations in p53 respond poorly to therapy whereas cancers that rarely have p53 mutations respond well to therapy e.g. testicular ca, Wilms' tumor, acute lymphocytic leukemia. We can use this information to guide treatment decisions

Telomeres and Telomerase

Telomeres are short strips of DNA found at the tips of chromosomes. A young cell has more than a 1000 telomeres. During cell division the cell loses 10-20 telomeres. With continued cell division the telomere number drops to a certain level and cell division stops. The cell has aged and cell death occurs. This is, in essence, a built-in biological clock that affects all normal cells in our body.

There is an enzyme called Telomerase which protects the telomere chain thus prolonging the life of cell. Telomerase is found only in two cell types: sperm cells and cancer cells. Telomerase in essence immortalizes these cell types. Geron Corp. is working on drugs that inhibit Telomerase production or block its action..to mortalize the cancer cell.

Angiogenesis

Angiogenesis relates to the formation of new blood vessels. Cancer growth is restricted to less than 1 million cells in the absence of new blood vessels. Tumor growth is therefore angiogenesis-dependent. This has been histologically confirmed in studies on breast and prostate cancer correlating the number of vessels seen with the microscope with the rate of metastasis.

The cancer cell has the ability to trigger blood vessel formation which feeds the tumor and allows for its spread. However, a protein called Thrombospondin(TS) has been discovered that inhibits blood vessel growth. TS appears to be regulated by the p53 oncogene. Mutations in p53 may turn off TS resulting in angiogenesis and further tumor growth.

Anti-metastasis genes: nm23 and MTS1

nm23, a non-metastasis gene, helps mature cells stop dividing and allows the cells to arrange themselves in an orderly fashion. nm23 given to mice with tumors resulted in reduction in formation of metastasis by 90%. MTS1 is a multiple tumor suppressor gene. Defects in MTS1 may cause various cancers such as lung, breast, melanoma and brain tumors. Treatment with MTS1 may inhibit tumor growth.

GOALS Worth Pursuing

We can "teach" cancer to be patient friendly. Research is needed in designing drugs that convert mutant p53 to normal (wild-type) p53. We need to learn how to genetically splice wild-type p53 into p53 negative tumors. We can learn to mortalize the cancer cell with drugs that block Telomerase action or inhibit its production. Other areas of pursuit involve inhibition of angiogenesis with synthetic Thrombospondin or stopping tumor growth with MTS1.

 

Prostate Cancer Research Institute (PCRI)
 

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