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New Mesothelioma Treatment Approaches

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					NEW MESOTHELIOMA TREATMENT APPROACHES
New approaches to treat malignant mesothelioma are currently being tested. They often combine
traditional treatments or include something entirely new. They include:
  Angiogenesis and Anti-angiogenesis Drugs
          Although progress has been made in the early detection of cancer, and in
          improved treatment options once cancer is diagnosed, there are still many
          cancers, including mesothelioma, which can not be cured and remain difficult
          to treat effectively. In recent years, researchers have learned a great deal
          about how cancer cells differ from normal cells and, in an effort to find drugs
          without the potentially severe side effects of chemotherapy, have now
          discovered drugs which target the tumor itself while sparing the body‟s
          normal cells. One such group are the anti-angiogenesis drugs.
          Learn more about anti-angiogenesis agents in the treatment of mesothelioma.

    Immunotherapy, sometimes called biological therapy, uses the body's own immune
     system to protect itself against disease. Researchers have found that the immune
     system may be able to recognize the difference between healthy cells and cancer
     cells, and eliminate those that become cancerous. Immunotherapy is designed to
     repair, stimulate, or enhance the immune system's natural anticancer function.
         Substances used in immunotherapy, called biological response modifiers
         (BRMs) alter the interaction between the body's immune defenses and cancer,
         thereby improving the body's ability to fight disease. Some BRMs, such as
         cytokines and antibodies, occur naturally in the body, however, it is now
         possible to make BRMs in the laboratory that can imitate or influence natural
         immune response agents. These BRMs may:
              Enhance the immune system to fight cancer cell growth.
              Eliminate, regulate, or suppress body responses that permit
             cancer growth.
              Make cancer cells more susceptible to destruction by the
             immune system.
              Alter cancer cell's growth patterns to behave like normal cells.
              Block or reverse the process that changes a normal cell into a
             cancer cell.
              Prevent a cancer cell from spreading to other sites.
         Many BRMs are currently being used in cancer treatment, including
         interferons, interleukins, tumor necrosis factor, colony-stimulating factors,
         monoclonal antibodies, and cancer vaccines.
         More on immunotherapy for mesothelioma.

    Photodynamic therapy (PDT) is a type of cancer treatment based on the premise
     that single-celled organisms, if first treated with certain photosensitive drugs, will die
     when exposed to light at a particular frequency. PDT destroys cancerous cells by
     using this fixed frequency light to activate photosensitizing drugs which have
     accumulated in body tissues.
         In PDT, a photosensitizing drug is administered intravenously. Within a
         specific time frame (usually a matter of days), the drug selectively
         concentrates in diseased cells, while rapidly being eliminated from normal
         cells. The treated cancer cells are then exposed to a laser light chosen for its
         ability to activate the photosensitizing agent. This laser light is delivered to
         the cancer site, (in the case of mesothelioma, the pleura), through a fiberoptic
         device that allows the laser light to be manipulated by the physician. As the
         agent in the treated cells absorbs the light, an active form of oxygen destroys
         the surrounding cancer cells. The light exposure must be carefully timed, so
         that it occurs when most of the photosensitizing drug has left the healthy cells,
         but is still present in cancerous ones.
       The major side effect of PDT is skin sensitivity. Patients undergoing this type
       of therapy are usually advised to avoid direct and even indirect sunlight for at
       least six weeks. Other side effects may include nausea, vomiting, a metallic
       taste in the mouth, and eye sensitivity to light. These symptoms may
       sometimes come as a result of the injection of the photosensitizing agent.
   Gene therapy is an approach to treating potentially fatal or disabling diseases by
    modifying the expression of an individual's genes toward a therapeutic goal. The
    premise of gene therapy is based on correcting disease at the DNA level and
    compensating for the abnormal genes.
       Replacement gene therapy replaces a mutated or missing gene, most often a
       tumor suppressor gene, with a normal copy of that gene which serves to keep
       cell growth and division under control. The p53 gene, the most common gene
       mutated in cancer has become a prime target for gene replacement, and has
       met with some success in inhibiting cell growth, inhibiting angiogenesis (the
       development of a tumor's blood supply), and inducing apoptosis (cell death).
       Knockout gene therapy targets the products of oncogenes (a gene that can
       induce tumor formation) in an effort to render them inactive and reduce cell
       growth.
       With constantly expanding knowledge of the genes associated with cancer,
       their functions, and the delivery systems used in administering these genes,
       gene therapy has a promising future.

   Complementary and alternative medicine covers a wide range of healing
    philosophies that conventional medicine does not commonly accept or make
    available to its patients. Some of these practices include the use of acupuncture,
    herbs, homeopathy, therapeutic massage, and Far Eastern medicine to treat health
    conditions.
        These therapies may be used alone as an alternative to conventional medicine,
        or in addition to conventional medicine, in which case they are referred to as
        complementary. Many are considered holistic, meaning their focus is to treat
        the whole patient - physically, mentally, emotionally, and spiritually. These
        treatments are not widely taught as a part of the medical curriculum, are not
        generally used in hospitals, and, for the most part, are not covered under
        insurance policies.
        Many cancer patients try various complementary and/or alternative medicine
        techniques during the course of their treatment, and although they may not
        work for everyone, some patients benefit by managing their symptoms or
        side effects. One important caveat, is to discuss any complementary or
        alternative treatments you may be considering with your doctor to be sure
        nothing interferes with your conventional care. For instance, dietary
        supplements such as herbs or vitamins may be "natural", but not necessarily
        "safe". They may lessen the effectiveness of certain anticancer drugs, or
        when taken with other drugs or in large doses, may actually cause harm.
        Since supplements of this nature are not governed by the FDA (Food and
        Drug Administration), and a prescription is not necessary to purchase, it is up
        to the consumer to make informed and conscientious decisions regarding
        their use.
        Your personal physician may be able to advise you about the use of
        complementary and alternative treatments and therapies, and how they relate
        to mesothelioma.
        The combinaton of complementary and conventional therapies is sometimes
        referred to as integrative medicine.

   Unconventional methods of cancer treatment make claims that can not be
    scientifically substantiated. They commonly claim to be effective against cancers
     that are considered incurable, and tout treatments with relatively few, if any, side
     effects.
         The use of these unconventional methods may result in the loss of valuable
         time and the opportunity to receive potentially effective therapy. It is always
         important to remain in the care of a qualified physician who uses accepted
         methods of treatment or who is participating in scientifically designed
         investigational therapies.

PROTON THERAPY TREATMENT OF MESOTHELIOMA
Proton beam radiotherapy employs a cyclotron to energize protons and uses magnetic fields to
direct the protons to the tumor. Proton therapy is most precise form of radiation treatment available
for cancer. Medical researchers are excited about this form of treatment because it is noninvasive
and painless and it promises to leave surrounding health tissue and organs intact and unharmed.

Radiation therapy (also called radiotherapy, X-ray therapy, or irradiation) is the use of ionizing
radiation to kill cancer cells and shrink tumors. It can be delivered internally (brachytherapy) or
externally (external beam radiotherapy). Radiation therapy injures or destroys cells in the area being
treated (the "target tissue") by damaging their genetic material, making it impossible for these cells
to continue to grow and divide. Although radiation damages both cancer cells and normal cells,
most normal cells can recover from the effects of radiation and function properly. The goal of
radiation therapy is to damage as many cancer cells as possible, while limiting harm to nearby
healthy tissue. Hence, it is given in many fractions, allowing healthy tissue to recover between
fractions.
Radiation therapy may be used to treat almost every type of solid tumor, including cancers of the
brain, breast, cervix, larynx, lung, pancreas, prostate, skin, stomach, uterus, or soft tissue sarcomas
as well has leukemia and lymphoma. The radiation dose given to each site depends on a number of
factors, including the radio sensitivity of each cancer type and whether there are tissues and organs
nearby that may be damaged by radiation. As with every form of treatment, radiation therapy is not
without side effects. Proton therapy is another form of external-beam radiation treatment.
MECHANISM OF PROTON THERAPY
Proton therapy, like all forms of radiotherapy, works by aiming energetic ionizing particles at the
target tumor. These particles damage the DNA of cells and ultimately cause their death. Because of
their high division rates and their reduced ability to repair damaged DNA, cancerous cells are
particularly vulnerable to this attack on their DNA. As protons do not scatter easily in the tissue
there is very little lateral dispersion; the beam stays focused on the tumor shape without much
lateral damage to surrounding tissue.
DIFFERENCES FROM CONVENTIONAL X-RAY THERAPY
Both standard x-ray therapy and proton beams work on the principle of selective cell destruction.
The major advantage of proton treatment over conventional radiation, however, is that the energy
distribution of protons can be directed and deposited in tissue volumes designated by the
physicians-in a three-dimensional pattern from each beam used. This capability provides greater
control and precision and, therefore, superior management of treatment. Radiation therapy requires
that conventional x-rays be delivered into the body in total doses sufficient to assure that enough
ionization events occur to damage all the cancer cells. The conventional x-rays lack of charge and
mass, however, results in most of their energy from a single conventional x-ray beam being
deposited in normal tissues near the body's surface, as well as undesirable energy deposition beyond
the cancer site. This undesirable pattern of energy placement can result in unnecessary damage to
healthy tissues, often preventing physicians from using sufficient radiation to control the cancer.
HOW IS PROTON THERAPY GIVEN?
The three-dimensional information is usually obtained by performing a computed tomography (CT)
scan through the region of interest (chest, pelvis, etc.) with images (sometimes called slices) being
taken at 2- to 3-millimeter intervals. Before performing the CT scan, some type of immobilization
device is made for the patient, so as to reproduce the patient's treatment position each day.
Typical immobilization devices include full-body moulds (form-fitting foam liners surrounded by
rigid plastic shells), for patients with tumors below the neck, and custom-manufactured masks, for
patients with eye, brain, and head tumor abnormalities.
TUMORS TREATED WITH PROTON THERAPY
The earliest treatment success by proton therapy was in the treatment of choriodal malignant
melanomas of the eye, where earlier enucleation (removal of the eye) was the only treatment
available. Other tumors successfully handled are that of the brain, head, neck, lung and prostrate
where therapy is often combined with other cancer treatment modalities. Specifically some of the
brain and cranial base tumors treated are acoustic neuromas, ependymomas, gliomas and
meningiomas, among spinal tumors those such as chordomas and chondrosarcomas and
gastrointestinal cancers like unresectable liver tumors have also been effectively managed through
proton therapy. Some of the pediatric tumors that respond well to proton therapy are astrocytomas,
ependymomas, germinomas, medulloblastomas and some sarcomas.
COMBINATION THERAPIES
Proton beam therapy can be used in conjunction with x-ray therapy. Such combinations are
typically done to areas with large tumors. The combination therapy often results in high remission
rates. Because the primary tumor may put out its colonies into nearby lymph nodes, doctors
sometimes feel combining proton therapy with that of conventional radiotherapy like x-ray is
advisable.
ADVANTAGES OF PROTON THERAPY
Proton therapy is of interest because of its ability to accurately target and kill tumors, both near the
surface and deep seated within the body, while minimizing damage to the surrounding tissues. For
this reason, it is favored for treating certain kinds of tumors where conventional X-ray radiotherapy
would damage surrounding radio-sensitive tissues to an unacceptable level (optical nerve, spinal
cord, central nervous system, head, neck and prostate). This is of significance in the case of
pediatric patients where long term side effects such as residual occurrence of secondary tumors
resulting from the overall radiation dose to the body are of great concern.

TOMOTHERAPY
The fields of radiation oncology changes rapidly as new and better methods of treatment are found.
Many of these changes are the result of enhanced computer applications and their integration into
diagnostic imaging and dose delivery equipment. The newest concept in this regard is called helical
tomotherapy, which allows the radiation oncologist to deliver radiation therapy to the patient with
surgical precision. This translates into more effective treatment of the mesothelioma tumor while
sparing healthy tissue and significantly reducing side effects.
Basically a combination of spiral CT scanning and Intensity Modulated Radiation Therapy (IMRT),
this state-of-the-art technology is now being used at a growing number of facilities nationwide.
Following is a brief description of steps in the helical tomotherapy process.
      3-D imaging is generally performed with standard CT imaging equipment.
      The radiation oncologist uses special software to establish the contours for each target
      volume and identifies organs or structures at risk. The doctor then decides what dose
      the target area(s) should receive as well as what dose(s) will be acceptable to the
      organs or structures at risk.
      The 3-D data and the contours of the target volume and organs or structures at risk are
      transferred to the tomotherapy treatment planning computer which performs delivery
      optimization calculations including leaf positions for the gantry angles and couch
      positions for the patient.
      Computer planning data is transferred to the tomotherapy unit for delivery
      implementation.
      A CT scan is taken just prior to treatment to verify the anatomical targets and patient
      position. This affords the opportunity to make any necessary adjustments and ensure
      correct dose delivery.
      After verification of the above, the dose is delivered to the patient. The radiation is
      produced by a linear accelerator (linac) which travels in circles around the gantry ring.
      The linac moves in unison with a multileaf collimator (MLC). The leaves of the
      collimator move in and out rapidly to modulate the radiation beam leaving the
      accelerator. Concurrently, the patient couch is being guided slowly through the center
     of the gantry ring. Each time the accelerator circles, the radiation beam is directed at a
     slightly different plane.
     While treatment is in progress, the amount of actual radiation to the patient is
     measured so that dose delivery can be verified and compared to the planned dose. If
     necessary, adjustments can be made for subsequent treatments.

SYSTEMIC TREATMENT REGIMENS FOR PATIENTS WITH UNRESECTABLE
MALIGNANT MESOTHELIOMA
A rare neoplasm, malignant mesothelioma mostly develops on the mesothelial surfaces of the pleural
cavity, on the peritoneal surface in a few cases, and seldom in the pericardium or tunica vaginalis.
The condition has an exceptionally poor prognosis irrespective of the therapeutic approach, with
median survival being 4 to 13 months in case of untreated patients and around 6-18 months in case
of patients who receive treatment.

PLEURAL MESOTHELIOMA
A variety of factors have made it difficult to develop systemic treatment approaches for pleural
mesothelioma. These factors include the relatively fewer number of patients; difficulty in assessing
the treatment benefits, if any, being derived by an individual patient; and the poor prognosis linked
with advanced disease.

 RESPONSE ASSESSMENT
The best way to assess the effectiveness of a new agent or combination drug therapy among
mesothelioma patients is the evaluation of survival benefit through a randomized trial.
Both the objective response rate (which is demonstrated on CT scan by a reduction of >30% in the
width of the pleural rind located perpendicular to the rib cage) as well as the progression-free
survival rate have been used as alternative ways to determine effectiveness in all phase III clinical
trials till date. In comparison to the objective response as evaluated using computed tomography
alone, the use of positron emission tomography in combination with CT scanning (PET/CT) to
ascertain a reduction in the tumor's metabolic activity may be a better indicator of time to
progression. In phase III trials however, the PET/CT factor has never been corroborated.

The interpretation of results has been limited by the diversity of study populations in various studies.
Analysis from the European Organization for Research and Treatment of Cancer (EORTC) and the
Cancer and Leukemia Group B (CALGB) have enabled the proper identification of the primary
prognostic factors and enhanced the ability to evaluate and generalize results among clinical trials.
Emerging techniques, for instance gene expression profiling, can eventually allow further
classification of patients into diverse prognostic subgroups.

BENEFITS ASSOCIATED WITH CHEMOTHERAPY
Analyses from three randomized clinical studies have helped establish that cisplatin-based doublet
chemotherapy considerably increases survival as compared to single agent chemotherapy or active
supportive care (ASC).
The sole randomized clinical trial, which directly evaluated chemotherapy in comparison to ASC,
failed to show any major improvement in survival irrespective of the treatment involving single
agent Vinorelbine or a conventional regimen of low-dose cisplatin, mitomycin, and vinblastine.
However, the study was discontinued prematurely due to poor accrual after the initial enrollment of
409 patients. The two chemotherapy groups that were still active were put together for a survival
analysis. The survival among those who were treated with both chemotherapy and ASC was slightly
prolonged. However, this difference was not significant in statistical terms (8.5 as opposed to 7.6
with ASC alone).
As opposed to the above finding, two trials that compared present-day doublets (high dose cisplatin -
75-80 mg/m2) in combination with an anti-folate (cisplatin plus raltitrexed and cisplatin plus
pemetrexed) demonstrated considerable increase in survival in comparison to cisplatin alone. With
cisplatin alone, the median survival was nine months in both these trials, something which was also
demonstrated in the other randomized trial with ASC alone.
 SINGLE AGENT CHEMOTHERAPY
For several different agents, phase II trials have demonstrated clinical activity, as made evident
through response rates. While single agent chemotherapy has not demonstrated to increase survival
in previously untreated patients, it is possible that these agents may be useful as second-line therapy
in certain patients.
Discussed below are some of the agents that have shown significant activity in phase II trials:
     Cisplatin - The meta-analysis of almost all phase II trials published during 2001
     showed that cisplatin was the most effective single agent. As far as combination
     chemotherapy regimens are concerned, cisplatin can be described as its backbone.
     Carboplatin can also demonstrate activity, although the available data is significantly
     less.
     Pemetrexed - As a single agent, pemetrexed demonstrated considerable activity in
     phase II trials and had an expanded access program. The results derived thereon have
     prompted the use of pemetrexed in combination with cisplatin, which has become the
     standard approach for preliminary systemic chemotherapy in mesothelioma patients.
     This agent may also be useful in the role of second-line therapy for patients who were
     not treated with this agent earlier.
Other antifolates that have demonstrated single agent activity include edatrexate, raltitrexed, and
methotrexate.
     Gemcitabine - This has demonstrated activity in phase II trials and may be useful,
     especially when used in combination with cisplatin.
     Anthracyclines - Several studies have demonstrated significant response rates with
     doxorubicin. Clinical activity may also be possible with the use of epirubicin and
     pegylated liposomal doxorubicin.
     Vinca alkaloids - Vinca alkaloids such as vinorelbine and vinflunine have
     demonstrated objective responses in phase II trials.


TREATMENT OF MALIGNANT PLEURAL MESOTHELIOMA WITH EXTRAPLEURAL
PNEUMONECTOMY FOLLOWED BY INTENSITY MODULATED RADITION
THERAPY (IMRT)
The majority of patients treated aggressively for mesothelioma fail locally, and this often leads to
their ultimate demise. As conventional chemotherapy has shown little activity in this disease, and
surgical resection alone has not been efficacious as well, efforts have been directed at better multi-
modality local control paradigms. Although it is known that mesothelioma can respond to radiation
therapy, the use of conventional external beam radiation has not been helpful due to both the
inability to provide an adequate dose over such a large area, and toxicity. Intensity Modulated
Radiation Therapy (IMRT) will be used in this protocol in order to deliver therapeutically significant
radiation doses (45 to 50 Gy for microscopic disease and 60 Gy for gross disease), while still sparing
the nearby critical normal organs. IMRT has the ability to very closely conform radiation dose
beamlet distributions to anatomic structures. The delivery of these beamlets, or IMRT fields, is
achieved by dividing the field into 1x1 cm voxels and optimizing the dose to each centimeter cube of
the patient.
The patients will first be carefully screened as candidates for surgical resection (extrapleural
pneumonectomy or EPP) with physiologic screening (cardiac and pulmonary function) and surgical
staging (mediastinoscopy, laparoscopy). All histologies will be included, and patients can have
ipsilateral, but not contralateral mediastinal lymph node disease. Careful marking of the true extent
of the native diaphragm and any other areas felt to be at particular risk is performed intraoperatively,
and the surgeon, radiation therapist and physicist perform radiation planning and review of planning
radiographs as a multidisciplinary team. Following 5-10 weeks of recovery from surgery, the IMRT
is administered to the patient over a 5 week period.
In a pilot evaluation of the protocol, 7 patients were treated with combination EPP/IMRT. Currently
with more than 12 months median follow-up in this group there has been no evidence of local tumor
recurrence in the radiation field, even though 6 of those patients were Dana-Farber Stage III.
Inclusion criteria for IMRT
     Patients must have undergone extrapleural pneumonectomy at M. D. Anderson Cancer
     Center.
     Patients must have a performance status >70 KPS.
     Patients must have adequate renal function in the contralateral kidney to tolerate
     obliteration of the ipsilateral kidney. This will be determined by renal scan, with more
     than 40% of the GFR contributed by the contralateral kidney.
     Patients must have normal liver function tests (no more than 50% elevation of SGOT,
     SGPT and Bilirubin) and no history of liver cirrhosis. If the primary tumor is left sided,
     cirrhosis is not a contraindication.
     Patients must be able to lie flat for the duration of the treatment planning sessions and
     treatment.
     Patients will have recovered from surgery, and have performance status >70 KPS.
     Typically this will be 3-5 weeks post-surgery.
Exclusion Criteria:
     All patients not meeting the inclusion criteria will be excluded.
     Patients having parietal pleural stripping or chemotherapy prior to protocol entry
     Patients having previous radiation therapy to the low neck, thorax or upper abdomen.
     Patients with metastatic disease.
     Patients must not be oxygen dependent at the time of radiotherapy treatment planning.
     Patients requiring renal dialysis.


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 term "targeted cancer therapies" refers to the development and use of drugs or other substances
to impede tumor development and growth. The therapy destroys specific molecules that are
identified as essential to a tumor, but not to healthy cells. By applying these therapies to these targets
or molecules, the tumor growth is interrupted.
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”.
Targeted cancer therapies reduce harmful effects to normal cells and may be more effective than
radiation therapy or chemotherapy since they focus on cancer cell changes. Targeted therapies have
different side effects and function differently than traditional cancer therapies. Target therapies have
been shown to play an important role in cancer cases where chemotherapy has not been too
successful, such as in kidney cancer cases.
 TYPES OF TARGETED THERAPIES
Studies are being conducted that use targeted cancer therapies as the only therapy as well as in
conjunction with other cancer treatment types. The U.S. Food and Drug Administration (FDA) has
approved several targeted cancer therapies for some cancer types. Other targeted therapies are in pre-
clinical testing or clinical trials. 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.

				
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