Targeted Therapy: What Is the Function of A Tumor Suppressor Gene?

Targeted cancer therapy is a treatment with medications that target specific cell processes that cause cancer. Unlike traditional treatments like chemotherapy, targeted therapy does not directly kill cancer cells, but instead alters the cancer-causing mechanism to halt cancer growth.

Targeted therapies are of two types of medications:

• Small molecule drugs: Tiny particles that can attach to proteins on the surface of the cell or get right inside the cancer cell and modify the cell’s activity.
• Monoclonal antibodies: Larger molecules that cannot get inside the cell, but attach to the cell surface and activate immune activity.

Cancer is a group of diseases caused by uncontrolled proliferation of defective cells in the body. Cancers arise primarily due to mutations in certain genes, which may be inherited, caused by environmental factors, certain viral infections, and sometimes for no identifiable reason.

A normal human cell undergoes a strictly regulated cycle of growth, division (replication), differentiation (maturation with a specialized function) and programmed death (apoptosis). Cancer cells flout these regulatory mechanisms to continue growing nonstop. Cancers can develop anywhere in the body and may eventually spread throughout the body (metastasis).

Cancers usually occur due to the accumulation of multiple genetic mutations. Genetic mutations arise when the DNA is copied incorrectly during cell division. All mutations, however, do not necessarily result in cancer, and some mutations may even be beneficial.

Mutations in the following two types of genes can lead to cancer:

• Proto-oncogenes: Proto-oncogenes instruct (encode) proteins that are involved in growth and development. Mutations in proto-oncogenes can give rise to oncogenes, which have a high potential to cause cancer by remaining permanently activated.
• Tumor suppressor genes: Tumor suppressor genes encode proteins to modulate the process of cell growth and replication. Mutations which inactivate the tumor suppressor genes enable cancer cells to grow, unrestrained.

The function of tumor suppressor genes includes the following:

• Detect and repair damage or copying errors in the DNA during replication.
• If DNA damage cannot be repaired, stop further cell growth and division, and initiate apoptosis.
• Stop the cells from proliferating by a process known as contact inhibition. Contact inhibition makes cells stop dividing once they fill up their natural space and come into contact with other cells.
• Inhibit cell migration and metastasis.

Targeted therapies for enhancing tumor suppression activity involve identification of the specific tumor suppressor genes that are inactivated, and activating them with targeted medication. Therapies targeting activation of tumor suppression are all small molecule drugs. Cancer cells can, however, develop resistance to targeted medications.

Following are the targeted therapies for enhancing tumor suppression:

DNMT inhibitors

DNA methyl transferase (DNMT) is an enzyme that catalyzes a process known as DNA methylation. DNA methylation is the addition of a methyl molecule to specific portions in the DNA, which silences the gene activity in those portions. DNMT inhibitors block the DNMT enzyme and activate the silenced tumor suppressor genes in the cancer cells.

Methylation of tumor suppressor genes is a necessary, normal and reversible process during the cell growth and division phase. The tumor suppressor genes in a normal cell are activated if there is damage to the DNA, or after the cellular division process is completed. In cancer cells the tumor suppressor gene remains inactivated.

The FDA has approved two DNMT inhibitors for treatment of a group of cancers known as myelodysplastic syndrome (MDS) which can develop into acute myeloid leukemia (AML)

• Azacytidine
• Decitabine

HDAC inhibitors

Histone deacetylase (HDAC) is an enzyme that plays a regulatory role in gene transcription (copying of a gene’s DNA), cell growth, survival and proliferation. HDAC inhibitors block HDAC enzyme and activate the tumor suppressor genes.

Histones are proteins that form a supportive structure to the DNA strands, which are coiled around them. HDACs and histone acetyltransferases (HATs) are two enzymes which work together to modulate the cell mechanisms that replicate DNA and repair damaged DNA.

HATs add an acetyl molecule to the histone, which activates the tumor suppressor gene, while HDACs reverse the process making the histone inaccessible for repair by the tumor suppressors.

Many targeted therapies are in different stages of trials and the FDA has approved one HDAC inhibitor as a third-line therapy:

• Vorinostat for the treatment of advanced cutaneous T-cell lymphoma (CTCL)

Vorinostat is currently in clinical trial for the treatment of two other cancers:

• Mesothelioma
• Non-small-cell lung carcinoma

Many combination therapies with both DNMT and HDAC inhibitors are in development because the two processes work together to inactivate the tumor suppressor genes.

P53-HDM2 inhibitors

P53 is a tumor suppressor gene that plays a crucial role in controlling cell division and death. HDM2 is a protein that suppresses P53 gene’s activity. Therapies inhibiting HDM2 are in early phases of trials.