Tumor therapy

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Tumor therapy

• Liao, Kuang-Wen

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What is cancer ?
Cancer is a collection of diseases with the
common feature of uncontrolled growth.
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Cancer features

• Uncontrolled growth is their core property
• They are life-threatening
• The definition of cancer is invalid.

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History

• Cancer has been known in human societies from the
  ancient Egyptians.
• Cancer is not confined to human and the higher
  mammals but affects almost all multicellular
  organisms.
• About 140 years ago a German microscopist,
  Johannes Mueller, showed that cancers were made
  up of cells.

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Influence of age on cancer incidence (USA).
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Oncogenes

• Definition
• oncogenes are genes that gain oncogenic or
  transforming potential as a result of genetic
  changes in either their coding region or
  regulatory sequences.
• Proto-oncogene is oncogene present in normal
  cells to distinguish it from the altered gene in
  the cancer cell.
• c-src v.s. v-src (The first identification in
  Rous sarcoma virus)

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Repressor genes

• Certain repressor genes are inactivated by loss
  of both alleles of a gene, eg. Rb.
• Biological changes of some repressor genes result
  from inactivation of only one allele, eg. P53.

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Carcinogen Definition

• A carcinogen is a substance that causes cancer
  (or is believed to cause cancer).

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• Chemical carcinogens
• Polycyclic aromatic hydrocarbons (PAHs)
• Aromatic amines
• Nitrosamines
• Alkiating agents
• Oxidation
• Superoxide radical
• H2O2
• Hydroxyl radical
• Radiation carcinogens
• X-ray
• UV

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• Base excision repair
• Nucleotide excision repair
• Mismatch repair
• Homologous recombination
• DNA end-joining

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Rebuilding the road to cancer
Genetic events required to convert a normal human
cell into a tumor cell were elucidated. (1).
Immortalize cells by recovering telomerase
activity. (2). Inhibit both the p53 and
retinoblastoma (pRb) pathways. (3). Activate
oncogenes to allow cell growth in the absence
of growth factors.
(Weitzman and Yaniv, Nature 400 401-402, 1999
Hahn et al., Nature 400 464-468, 1999).
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Diagnostic Imaging

• X-ray
• CT Scans
• Ultrasound
• Magnetic Resonance Imaging (MRI)

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X-rays

• X-rays are the most common type of imaging. The
  images produced by X-rays are due to the
  different absorption rates of radiation from
  tissues. Calcium in bones absorbs X-rays the
  most, so bones look white on an X-ray film, also
  known as a radiograph.
• Muscle and other soft tissues absorb less
  radiation, and have more gray tones on the
  radiograph. Air absorbs the least, so lungs look
  black on a radiograph.

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CT Scans

• A computed tomography scan (also called a CT scan
  or a CAT scan) also uses X-rays to create images
  of the body. However a radiograph and a CT scan
  show different types of information.
• The data from a CT scan can then be
  computer-enhanced to be more sensitive. With both
  plain radiographs and CT scans the patient can be
  given a contrast agent in a drink and/or by
  injection to more clearly show the boundaries
  between organs or between organs and tumors.

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Ultrasound

• Ultrasound uses sound waves that are at a higher
  frequency than sound that is heard by the human
  ear.
• A transducer gives off the sound waves.  The
  sound waves are then reflected back to the
  transducer by organs and tissues in the body. 
  The reflected sound waves are then used to draw a
  picture on a computer screen showing what is
  inside the body.
• Ultrasound can be used to look for certain types
  of tumors, and can also be used to guide doctors
  during biopsies or treating tumors with radiation
  therapy.

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Magnetic Resonance Imaging (MRI)

• Magnetic Resonance Imaging (MRI) uses radio
  frequency waves in the presence of a strong
  magnetic field produced by an MRI machine to
  cause cells to emit a radio frequency.
• Different tissues (including tumors) emit
  different signal intensities based on their
  chemical structure.  Using these signals, a
  picture of what is inside the body can be created
  and shown on a computer screen. Much like CT
  scans, MRI can produce three-dimensional images
  of sections of the body, but MRI is sometimes
  more sensitive than CT scans.

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Surgery

• Surgery is the most effective form of treatment
  for cancer, and yet the most aggressive. Surgery
  offers the greatest chance for cure for many
  types of cancer, especially those that have not
  yet spread to other parts of the body. 
• Advances in surgical techniques today allow
  surgeons to successfully operate on a growing
  number of patients, and to do so with smaller and
  smaller incisions. 
• In many cases, additional therapies such as
  radiation or chemotherapy closely follow or
  occasionally come before cancer surgery. 

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Chemotherapy

• Chemotherapy is the treatment of disease with
  drugs that interfere with cancer cells growth
  and reproduction. These drugs may affect the
  cancer cells in different ways and can be given
  in a combination of several drugs together or as
  a single drug. Chemotherapy can also be used
  during radiation therapy. Depending on the type
  of cancer and how advanced it is, the goal of
  chemotherapy can be to cure the cancer, to
  control its spread or to relieve symptoms of the
  cancer.
• Chemotherapy can be given in a variety of
  different ways, depending upon the drug that is
  prescribed by your doctor. Most commonly,
  chemotherapy is given intravenously (through a
  vein), orally (by mouth), by injection (a shot)
  or topically (applied to the skin). Because some
  drugs work better together than alone, often two
  or more drugs are given at the same time. This is
  called combination therapy.

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Radiation Oncology

• Treating with Radiation
• The primary purpose of radiation therapy is to
  eliminate or shrink localized cancers. The aim is
  to kill as many cancer cells as possible, while
  damaging minimal healthy tissues. In some cases,
  the purpose is to kill all cancer cells curing a
  patient. In other cases, when cures are not
  possible, the purpose is to alleviate symptoms by
  reducing the size of tumors causing the symptoms.
• For certain types of cancer, radiation therapy
  alone is the preferred treatment. Other times
  radiation is used in conjunction with surgery,
  chemotherapy, or both, and survival rates for
  combination therapy in these cases are greater
  than for any single type of therapy. Radiation
  therapy is also useful for organ and function
  preservation, such as laryngeal, breast, bladder
  and limb cancers.
• Radiation therapy can then be used to treat the
  cancer and control the disease with low morbidity.

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• Tumor cell proliferation
• Angiogenesis
• Metastasis
• Immunosuppression
• Drug resistance (anti-apoptosis)

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Advanced Tumor therapy

• Targeting therapy
• Tumor vaccine
• Immunotherapy
• New oncogenic target

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• Epidermal growth factor receptor (EGFR) is widely
  expressed in a number of solid tumors including
  colorectal cancers. Overexpression of this
  receptor is one means by which a cell can achieve
  positive signals for survival and proliferation
  another effective means is by constitutive
  activation of EGFR.

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Tumor cell proliferation
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• Anti-EGFR antibody cetuximab
• EGFR tyrosine kinase inhibitor erlotinib
• CI-1033, a small molecule antagonist of EGFR

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• Vascular endothelial growth factor (VEGF) is a
  one of the most essential pro-angiogenic growth
  factors expressed by most cancer-cell types and
  certain tumor stromal cells.
• Blocking the action of VEGF appears to be a
  promising anti-angiogenic approach to treat
  multiple types of solid tumors including breast
  cancer, and clinical trials using agents which
  target VEGF were launched beginning in the late
  1990s.

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Tumor vaccine

• Tumor antigen as tumor vaccine
• HPV (cervical cancer vaccine E6, E7)
• Antigen-cytokine fusion protein
• Treansgenic tumor cells as vaccine (IL-2, GM-CSF)
  
• Dendritic cell fusion with tumor cell

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Immunosuppression by tumor

• Down-regulate the expression of MHC
• Polarization of immunity
• Inactivate NK cell activity
• Inactivate the activity of T cell by Tr
• Inactivate the immunity by TGF-beta secretion

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Host effect cells against tumor cell
T-Cell
B-Cell
NK-Cell
Tc
Ab
MHC/TAA
ADCC
No MHC
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Immunotherapy

• Immuno-regulatory drug
• Polyssacharide
• Cytokine gene therapy
• IL-12, IL-15, IL-2

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Other targets

• Anti-VEGF monoclonal antibody bevacizumab
  (Avastin)
• Anti-VEGFR-1 human neutralizing antibody,
  IMC-18F1
• ZD6474 is a VEGF flk-1/KDR receptor (VEGFR-2)
  tyrosine kinase inhibitor

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Thank You
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