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Targeted Therapy for Mesothelioma

What is targeted therapy in the treatment of cancer?

The traditional modalities of treatment used to treat cancer (chemotherapy, radiation) invariably destroy normal cells in addition to malignant cells. Cancer treatment usually addresses rapidly dividing cancer cells and it has the side effect of affecting rapidly dividing cells of the healthy tissues like bone marrow, gastrointestinal tract, liver, skin and other appendages. Conventional treatment used for cancer is indiscriminate and non-specific. Targeted therapy for cancer, one of the recent developments in the field of oncology, promises a solution for this problem.

The principle behind targeted therapy is interference with specific molecules involved in the development and growth of cancer. The normal cells are not affected. Since this novel therapy is targeted at only specific molecules involved, it is also called “molecularly targeted therapy”.

Types of targeted therapies

Targeted therapies are still in experimental stages, although some have been approved by the U.S. Food and Drug Administration. About 26 targeted molecular drugs have been approved by the FDA and about 50 more such drugs are in Phase III trials. The targeted therapies can be broadly divided in to three categories:

  1. Molecularly targeted drugs
  2. Monoclonal antibodies
  3. Gene therapies

Molecularly targeted drugs

The molecularly targeted drugs include monoclonal antibodies and small molecule drugs which are less than 600 Daltons in molecular weight. These drugs inhibit signaling pathways for growth and proliferation within cancer cells.

Cancer cells have the unique feature of proliferating indefinitely without undergoing the process of apoptosis (natural cell death). The molecularly targeted drugs try to prevent indefinite proliferation by the cancer cells which are induced by the signaling pathways. The disadvantage of molcularly targeted drugs is that indefinite proliferation there is not just a single defect but there are a myriad of defects which cause this indefinite proliferation and it is difficult to bring all those defective signaling pathways under control. So this modality of treatment is mainly meant for those cancers with a single defect.

The molecular targeted drugs are divided in to three categories depending on their site of action: (1) Drugs acting on the cell surface receptors, (2) Drugs acting on intracellular pathways, and (3) Drugs acting on multi-enzyme complex- Proteasome inhibitors

Drugs acting on the cell surface receptors

Many scientists are interested in the protein tyrosine kinase receptors which are G-protein linked receptors on the surface of the cells. There are at least 100 different protein tyrosine kinase receptors identified some of which are

  • Epidermal growth factor receptor (EGFR)
  • Vascular endothelial growth factor receptor (VEGR)
  • Cytosolic Abelson tyrosine kinase (Abl)

Some of the drugs approved by the FDA are

Gefitinib – This "small molecule drug" binds to the HER1 type of EGFR which is involved in many different types of cancers. It is used as a third line treatment for non-small cell lung cancer.

Imatinib –A small molecule drug that inhibits three different protein tyrosine kinases.

  • Bcr-Abl protein which is involved in chronic myelogenous leukemia
  • C-kit receptor which is involved in gastrointestinal stromal tumors
  • Platelet derived growth factor alpha which is involved in chronic myeloproliferative syndromes with eosinophilia

Trastuzumab – This humanized monoclonal antibody binds to the HER2 type of EGFR. This binding of the agent induces the natural killer cells and the monocytes to act against the cancer cells.

Drugs acting on intracellular pathways
Farnesyl transferase is an intra-cellular enzyme which activates the ‘Ras’ protein. This protein is a proto –oncogene which is over-expressed in many solid tumors and hematological malignancies. It is involved in the growth factor signaling. Drugs which inhibit this enzyme have been developed which is still in the experimental stage.

Proteasome inhibitors

Proteasome is a multi-enzyme complex found in all cells, involved in the regulation of cell cycle progression. Bortezomib is a small molecule drug that selectively inhibits proteasomes.

Monoclonal antibodies

These monoclonal antibodies attach to the cancer cells and mark them so that they are attacked and destroyed by one of the following means:

  • By the immune system
  • Direct interference of the transmembrane receptors
  • Recognition and targeted destruction by the chemotherapeutic agents and radioactive drugs

Monoclonal antibodies which are approved by the FDA include:

Rituximab - It the first monoclonal antibody available in the United States for treating malignant disease. It is a chimeric monoclonal antibody that binds exclusively to CD20 receptor which is found on the surface of mature B lymphocytes. It was used initially in the treatment of relapsed and refractory non-Hodgkin’s lymphoma. Now it is also used to treat chronic lymphocytic leukemia, multiple myeloma, Waldenstrom macroglobulinemia, hairy-cell leukemia and autoimmune cytopenias.

Gemtuzumab – This antibiotic–chemotherapy complex was the first of its kind. It is composed of recombinant humanized monoclonal antibody linked to a cytotoxic anti-tumor antibiotic called calicheamicin. It is used in patients with acute myeloid leukemia whish has relapsed after initial treatment and who are not ideal candidates for chemotherapy especially those above 60 years of age.

Alemtuzumab – This humanized monoclonal antibody binds to the CD52 receptor found on the surface of B and T lymphocytes. This is used in patients with B-cell chronic lymphocytic leukemia who have not responded to the conventional treatment with chlorambucil and fludarabine.

Ibritumomab tiuxetan – The first radio-conjugate drug approved by FDA for treatment of cancer. It consists of two parts.

  • Ibritumomab – A murine-derived antibody which binds to the CD20 surface receptors on mature B lymphocytes
  • Tiuxetan - A linker chelator complex with high affinity for the radio-isotope yttrium -90
    This agent is used to treat follicular B-cell non- Hodgkin’s lymphoma which has either relapsed or refractory to other treatment including rituximab.

Tositumomab – Another radio-conjugate complex consisting of two parts.

  • Tositumomab antibody – It binds to the CD20 surface receptors on the mature B lymphocytes.
  • Radio-active Iodine 131

It is used in the treatment of follicular non-Hodgkin’s lymphoma both with transformation and without transformation which has relapsed with the conventional chemotherapy and refractory to rituximab.

Bevacizumab – This recombinant humanized monoclonal antibody binds to the vascular endothelial growth factor which is responsible for the formation of blood vessels inside the tumor tissue. This agent is used to treat metastatic colorectal cancer.

Cetuximab – A chimeric monoclonal antibody, cetuximab binds to the epidermal growth factor receptor (EGFR). This agent is approved for the treatment of EGFR positive irinotecan refractory colorectal carcinoma.

Telomerase Inhibitors

Telomerase inhibitors may change the face of cancer therapy forever and give it a more positive, optimistic light. Telomerase is an enzyme found in most cancer and germline cells and cancerous tumours. Although telomerase is also found in other cells such as stem cells, it has recently been discovered that is one of the most reliable tumour markers for cancer detection because it does not exist in benign tumours. Creating an inhibitor for this telomerase enzyme may be a way to stop cancer growth and keep it from spreading throughout the body.

It’s important to remember that cancer in one organ, if caught in time, does not always spell death. Instead, it is when that cancer spreads to other organs and tissue that it is too late to stop the growth and save the life of the patient. Telomerase inhibitors give new hope that new cancer cells can be prevented from forming; thereby, preventing the spread of the disease.

Telomerase is essential to the life of a cell because it modifies structures called telomeres that form at the end of chromosomes. In healthy cells, such as stem cells, it keeps the telomeres long, which is essential to allow the cells to keep on dividing. This is essential for repairing damaged and worn tissue throughout the body. However, when it comes to cancer, telomerase actually promotes the growth of cells. When the telomerase and the growth of these cells are stopped, cancer growth can be stopped as well.

Stopping the growth of new cancer cells is truly an advance in cancer research and treatment. Currently, chemotherapy and radiation are the standard protocols to treat most forms of cancer. Both of these treatments kill off the bad cells or keep them from growing. That is a good thing. However, this is done using chemicals and toxins that also kill healthy cells. They do nothing to prevent the growth of new cancer cells once the course of treatment has ended.

A telomerase inhibitor, or a treatment that would prevent the telomerase from forming, would not only be safer, but possibly more effective. A telomerase inhibitor would prevent the growth of new cancerous cells. It would not kill healthy cells, and it would not require giving patients toxic chemicals or high doses of radiation just to treat the cancer.

Professors from Monash University have identified two proteins that can stop the production of telomerase in cancer cells: Smad3 and c-Myc. Both of these proteins can turn off the production of telomerase and inhibit cell growth. When the cancer cells are prevented from multiplying and spreading throughout the body, then the cancer can be stopped.

Since these proteins do turn off the production of telomerase and stop cell growth, it is believed by scientists that if anti-cancer agents can be developed that mimic these two proteins, it is very possible that the growth of cancer can be stopped in patients. Most recently, a telomerase inhibitor called GRN163L was developed that successfully mimicked the proteins Smad3 and c-Myc. In studies, GRN163L inhibited the telomerase and stopped the growth and spreading of lung cancer in laboratory mice. This is excellent news for scientists and the public alike.

Scientists and the medical community now have justified hope that with further research, studies, and the continued development of telomerase inhibitors, it’s very possible that a way will be found to stop cancer dead in its tracks. New inhibitors are being developed and studies are being put together to test these inhibitors on human cancer patients. In the near future, telomerase inhibitors may replace the use of chemotherapy and radiation on many cancer patients and become the closest we have ever come to finding a cure.


Gene therapies - a type of targeted therapy


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