Hormone therapy, cytokines, targeted therapy, and other investigational therapies

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• Hormone therapy, cytokines, targeted therapy,
  and other investigational therapies
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  2006.
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• n_haim_at_rambam.health.gov.il

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Hormone therapy in breast cancer

• Antiestrogens.
• Progestins.

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Antiestrogens

• Block estrogen action by inhibiting estradiol
  binding to the ER.
• Examples
• -Tamoxifen the tamoxifen-bound receptor
• exhibits both estrogen agonist and
• antagonist properties.
• -Selective ER modulators (SERMs), e.g.
• Raloxifene (Evista)
• -Faslodex..
• Contd

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Fulvestrant (Faslodex)

• Estrogen receptor antagonist and binds to
  estrogen receptor in a competetive manner.
  Classified as a pure antiestrogen unlike
  tamoxifen, does not have an agonist effect).

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Progestins

• Indirect action on the hypothalamus-pituitary
  axis consisting of inhibition of
  gonadotropin-releasing hormone release.
• Direct action resulting in the inhibition of
  cellular proliferation.
• Examples
• -Medroxyprogesterone acetate (Provera)
• -Megestrol acetate (Megace)

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Hormone therapy in breast cancer

• Aromatase Inhibitors
• Selective aromatase inhibitors.
• Aminogluthetimide.

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Selective Aromatase Inhibitors-mechanism of action

• In postmenopausal women the majority of estrogen
  is produced by aromatization of adrenal androgens
  in the peripheral tissues, such as fat and
  muscle.
• The conversion of androstenedione to estrone in
  the peripheral tissues is catalyzed by aromatase,
  a complex enzyme consisting of cytochrome P-450
  (CYP450) and a flavoprotein.
• Conversion of androgens to estrogens is the
  rate-limiting step in the biosynthesis of
  estrogens.
• Selective aromatase inhibitors compete with
  androgens for binding to the enzyme (competitive)
  or bind to the enzyme irreversibly (non
  competitive).
• Contd

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Selective Aromatase Inhibitors-mechanism of
action (Contd)

• Non steroidalType IIreversible
• Anastrazole (Arimidex)
• Letrozole (Femara)
• SteroidalType Iirreversible
• Exemestane (Aromasin)
• Smith IE and Dowsett M. N Engl J Med 348
  2431-42, 2003 (Review)

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Aminogluthetimide

• Aminogluthetimide is a non selective aromatase
  inhibitor. Although it inhibits aromatization of
  androgens to estrogens, its main action is
  inhibition of adrenal steroidogenesis at early
  steps (inhibition of the synthesis of
  aldosterone, cortisol ,and androgenes).

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Hormone therapy in prostatic cancer

• Androgens.
• Anti-androgens.
• Ketoconazole.
• LHRH analogues.

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Androgens

• Possible anti-tumor effect in breast cancer
  inhibition of gonadotropin-relrasing hormone
  (negative biofeedback), and , therefore,
  inhibition of estrogen production.

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Anti-androgens

• Steroidal anti-androgens
• Inhibition of nuclear androgen binding
• Suppression of gonadotropin production by a
  negative biofeedback mechanism and , therefore,
  suppression of gonadal androgen production.
• Example cyprosterone acetae (predominant
  activitycompetitive inhibition of androgen at
  the receptor level).
• (megestrole acetate-a progestational compound-
  also inhibit androgen production via a negative
  feedback production, and , therefore, act as
  anti-androgen).
• Contd

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Anti-androgens (Contd)

• Non-steroidal anti-androgenes
• Do not suppress gonaotropins and testosterone
  production, but are specific inhibitors of
  nuclear androgen binding (bind to cytosol
  androgen receptors and competitively inhibit
  binding of androgenes).
• Examples
• -Flutamide (Eulexin)
• -Bicalutamide (Casodex)

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Ketoconazole

• High doses inhibit gonadal and adrenal
  steroidogenesis by inhibiting the P-450-dependent
  enzyme system.

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Luteinizing hormone-releasing hormone (LHRH)
analogues

• Gonadotropin hormone-releasing hormone (GHRH) is
  responsible for the synthesis and release of the
  pituitary hormones, LH and FSH.
• Initial stimulatory phase, which is associated
  with depletion of pituitary LH stores. Initial
  rise in LH and testosterone, which lasts for
  approximately 7 days, followed by progressive
  decrease in the hormone levels, reaching nadirs
  after approximately 4 weeks.
• Examples
• -Goserelin (Zoladex)
• -Leuprolide acetate

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Cytokines

• Cytokines
• Interferon alpha.
• Interleukin 2.

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Cytokines

• Soluble proteins or glycoproteins produced by
  mononuclear cells of the immune system that have
  regulatory actions on other cells of the immune
  system or target cells involved in immune
  reactions
• True hormones, acting on other cells at a
  distance from the secretory cells

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Interferon alpha

• Direct effects antiprolifetrative and
  differentiating
• Composite results in alterations in tumor cell
  surface antigen expression.
• Indirect effects on immune system and
  antiangiogenic effect

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Interleukin 2

• Induction of activated T-cell proliferation
• Stimulation of cytotoxicity in NK and T cells
• Acting as cofactor in activating macrophages and
  B cells

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Targeted therapy-Monoclonal antibodies

• Trstuzumab (Herceptin).
• Rituximab (Mabthera).
• CAMPATH-1H (Alemtuzumab).
• Bevacizumab(Avastin) .
• Cetuximab (Erbitux).

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Trastuzumab (Herceptin)

• HER human epidermal growth factor receptor
• HER2 proto-oncogene encodes the HER2 receptor
• The HER2 protein is a transmembrane thyrosine
  kinase that is a member of the epidermal growth
  factor.
• HER2 is overexpressed in 20-30 (15-25) of human
  breast cancers (in the majority, HER2
  overexpression is usually caused by amplification
  of the HER2 gene). HER2 is involved in cell
  differentiation and growth. HER2 positive tumors
  have poorer prognosis.
• Contd

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Trastuzumab (Herceptin) (Contd)

• Herceptin is humanized anti-HER2 MAB (95
  human and 5 murine). It binds with the
  extracellular domain of the HER2 cell-surface
  receptor, thereby inhibiting the growth of breast
  tumor cells that over express HER2.
• Tumors strongly overexpressing HER2 (IHC 3)
  and/or with proven HER2 gene amplification (FISH
  positive) are most responsive to herceptin.

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Rituximab (Mabthera)

• CD20 antigen
• It is present in high levels on over 95 of
  B-cell non-Hodgkins lymphoma cells.
• The antigen is also expressed on normal
  differentiated B-lymphocytes, but is absent from
  critical host cells such as stem cell or early
  B-cell precursors.
• The antigen does not internalize, is not shed
  from the cell surface, and does not circulate as
  free protein.
• Evidence suggests that it has a biological
  function.
• Contd

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Rituximab (Mabthera) (Contd)

• Rituximab is a genetically engineered chimeric
  murine/human monoclonal antibody (containing
  human IgG1 immunoglobulin constant regions and
  murine variable regions specific for CD20)
  directed against the CD20 antigen.
• Proposed mechanism of action Antibody-dependent
  cell-mediated cytotoxicity (ADCC),
  Complement-dependent cytotoxicity (CDC),
  Antibody-dependent phagocytosis, Direct antibody
  effects on CD20 ligation, and induction of
  apoptosis, and sensitization to chemotherapy.
• It acts synergistically with chemotherapy.

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Y(90)-ibritumomab tiuxetan (Zevalin)

• Zevalin is the first radioimmunotherapy for
  advanced refractory lymphoma.
• It comprises ibritumomab (a murine IgG1 ANTI-cd20
  mAb), covalently linked to the radioisotope
  yttrium-90 (pure beta-emitter, with half-life of
  64hr and a median path length of 5 mm in soft
  tissue).
• The binding of ibritumomab to the radioisotope
  is via the linker, tiuxetan.
• Hagenbeek A, and Levington V. Ann Oncol 16
  786-92, 2005

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I-131-Tositumomab

• Tositumomab is a murine IgG2a monoclonal
  antibody that selectively bind to CD20 on the
  surface of normal and malignant B cells. It can
  be labeled with iodine 131 to yield I-131-labeled
  tositumomab. The actions of I-131 tositumomab
  depend on ionizing irradiation from the decaying
  I-131 and on the antibody-mediated effects.
• Kaminski MS et al. N Engl J Med 352 441-9,
  2005

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CAMPATH-1H (anti-CD52 monoclonal antibody)
(Alemtuzumab)

• CD52 is cell surface antigen on lymphocytes
  monocytes.
• Campath is a humanized immunoglobulin G1 (IgG1)
  anti-CD52 monoclonal antibody that binds to the
  cell membrane of greater than 95 of all normal
  human blood lymphocytes , as well as to most
  B-and T cell lymphomas.
• Active in pts with advanced and chemotherapy
  resistant CLL.
• Osterborg A et al. J Clin Oncol 15 1567-74,
  1997
• Frampton JE et al. Drugs 63 1229-43, 2003

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Avastin (Bevacizumab)

• VEGF (vascular endothelial growth factor) , a
  diffusible glycoprotein produced by normal and
  neoplastic cells ,has been shown to have central
  role in the control of angiogenesis and to be
  essential for the development of tumor
  vasculature.
• VEGF binding to its receptor leads to receptor
  dimerisation, autophosphorylation of VEGF
  receptor and cascade of downstream signaling.
• Avastin is a humanized anti- (VEGF) monoclonal
  antibody. It binds to VEGF (ligand) and prevents
  the interaction of VEGF to its receptors.
• (regression of existing vasculature,
  normalisation of mature vasculature, inhibition
  of production of new vasculature).
• (In addition to its direct antiangiogenic
  effects, avastin may also improve the delivery of
  chemotherapy by altering tumor vasculature and
  decreasing the elevated interstitial pressure in
  tumors) (Midgley R, and Kerr D. Ann Oncol 16
  999-1004, 2005)(review)

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Cetuximab (Erbitux)

• Epidermal growth factor receptor is a
  transmembrane glycoprotein that plays an
  essential role in the cell growth,
  differentiation and survival of healthy tissues.
• In malignant tissue its activation can reduce
  apoptosis and facilitate cell proliferation,
  angiogenesis, and tumor cell migration.
• The EGFR comprises an extracellular
  ligand-binding domain and intracellular tyrosine
  kinase domains. Binding of specific ligands to
  the EGFR such as EGF and transforming growth
  factor alpha (TGF-alpha), results in the
  dimerization of the receptor either with another
  EFGR (homodimerization) or another member of the
  EGFR family (heterodimerisation) and a subsequent
  cascade of intracellular signaling pathways.
  Phosphorylation of the tyrosine kinase domains is
  an integral part of signal transduction.
• contd.

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Cetuximab (Erbitux)-contd.

• A recombinant, human/mouse, chimeric
  monoclonal antibody (IgG1) that binds to the
  extracellular domain of the human epidermal
  growth factor receptor (EGFR) and competitively
  inhibits endogenous ligand binding.

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Targeted therapy-low molecular weight TKIs

• ZD1839 (Iressa).
• Erlotinib (Tarceva).
• Lapitinib.
• SU11248 (sunitinib malate).

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Low-molecular weight inhibitors of the EEGFRs
tyrosine kinase

• The epidermal growth factor receptor (EGFR) is a
  tyrosine kinase receptor of the ErbB family (
  type I receptor tyrosine kinasesErbB receptors)
  that is abnormally activated in many epithelial
  tumors. ErbB2 is the only member of the ErbB
  family without an exogenous ligand.
• This receptor family is comprised of the
  following 4 related receptors, that trigger
  downstream signaling pathways
• HER1, HER2/neu, HER3, HER4.
• EGFR is a 170-kd transmembrane glycoprotein with
  an extracellular ligand-binding domain, a
  transmembrane segment and intracellular
  component. Activation takes place following
  ligand binding the receptors dimerize with
  either another EGFR (homodimerization) or another
  member of the EGFR family (heterodimerization).
  Dimerization results in cross-phosphorylation of
  the C-terminal tyrosine kinase domains, leading
  to activation of various EGFR signaling
  pathwayscontd

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Low-molecular weight inhibitors of the EGFRs
tyrosine kinase-contd

• Low-molecular weight tyrosine kinase inhibitors
  interfere with with receptor signaling by
  competing with ATP for binding to the tyrosine
  kinase portion of the receptor.
• Mendelsohn J and Baselga J. J Clin Oncol 21
  2787-99, 2003 (Review)

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ZD1839Gefitinib (Iressa), Erlotinib (Tarceva)

• HER human epidermal growth factor receptor
• HER1 (EGFR) activation starts a
  signal-transduction cascade that promotes tumor
  cell proliferation and has an important role in
  the survival and growth of many types of cancer.
• Iressa Tarceva are small molecules that
  selectively inhibits HER1 tyrosine-kinase
  (HER1-TKI).

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Lapitinib

• Is an orally active small molecule that
  reversibly inhibits ErbB1 and ErbB2 tyrosine
  kinases.

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SU11248 (sunitinib malate)

• A selective inhibitor of certain protein tyrosine
  kinases, including vascular endothelial growth
  factor (VEGF)-R types 1 to 3 and platelet-derived
  growth factor (PDGF).
• Motzer RI et al. J Clin Oncol 24 16-24, 2006(in
  metastatic renal cell carcinoma)
• Vogelzang NJ. J Clin Oncol 24 1-3,
  2006(Editorial)
• Faivre S et al. J Clin Oncol 24 25-35, 2006
  (phase I safety and P/K).

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Targeted therapy-Imatinib (STI571) (Glivec)

• .

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Imatinib (STI571) (Glivec)

• GIST
• Kit is a 145-KD transmembrane glycoprotein-a
  product of the c-kit gene. The proto oncogene is
  type III receptor tyrosine kinase (structurally
  related to PDGFs and M-CSF).
• C-Kit is a mutated KIT receptor overexpressed in
  certain malignancies such as Gastrointestinal
  Stromal Tumors (GIST). It has tyrosine kinase
  activity.
• 
  Contd

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Imatinib (STI571) (Glivec) (Contd)

• Kit mutation results in ligand independent
  activation of KIT tyrosine kinase activity and
  stimulation of downstream signaling pathways
  including MAP kinase, P13kinase and STAT
  pathways.
• Imatinib (STI571) is 2-phenylaminopyrimidine
  derivative.
• Imatinib inhibits tyrosine kinase activity of
• c-kit ,which is activated in GIST as a result
  of gene mutation (Imatinib is a small molecule
  TKI (tyrosine kinase inhibitor)).
• Heinrich MC et al. J Clin Oncol 20 1692-703,
  2002 (review)
• Contd

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Imatinib (STI571) (Glivec) (Contd)

• CML
• The mechanism of action is due to inhibition
  of the Bcr-Abl tyrosine kinase created by the
  Philadelphia chromosome abnormality in CML.

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Thalidomide

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Thalidomide

• Antiangiogenic effect
• Immunomodulatory effects stimulation of
  cytotoxic T-lymphocyte proliferation, induction
  of secretion of interferon-gamma and
  interleukin-2, modulation of natural-killer cell
  activity. other.

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Other investigational therapies

• Farnesyltransferase inhibitors.
• Telomerase inhibitors.
• Antisense oligonucleotides.
• Cyclin-dependent kinase inhibitors....
• Gene therapy.

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Farnesyltransferase inhibitors

• Farnesyltransferase transferase is an enzyme that
  transfers farnesyl isoprenoid,an intermediate in
  cholesterol biosynthesis, to certain proteins
  that associate with cell membranes such as ras
  proteins (and regulate many physiologic
  processes).
• To be active, the protooncogene ras must be
  associated with cell membrane. This depends on
  its farnesylation.
• Farnesyltransferase inhibitors may have a
  cytotxic effect.

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Telomerase inhibitors

• Telomers are specialized nucleoprotein structures
  at the chromosome ends..gradually shorten with
  every cell division unless they are actively
  maintained. Telomerase is an unusual reverse
  transcriptase that contains an RNA molecule as
  well as various protein subunits.
• Activation of telomrerase is necessary for cells
  to become immortal. It is expressed in most human
  cancers but not in normal somatic tissues.
• Telomerase inhibitors may have an antitumoral
  effect.

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Antisense oligonucleotides

• Antisense oligonucleotides are complementary
  nucleic acids fragments that hybridize to target
  sequences within RNA to form DNA-RNA complex,
  resulting in a block of translation of messenger
  RNA into the protein, thus blocking the
  expression of spesific genes.

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Cyclin-dependent kinase inhibitors

• The cell cycle is regulated by the
  cyclin/cyclin-dependent kinase (CDK) complexes.
  These CDKs regulate the transition from one cell
  cycle to the next.
• CDKs have been targeted for drug discovery.

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Gene therapy

• Introduction of a therapeutic gene into a target
  of cell to correct a genetic error or provide a
  new biologic function to the cell. The vectors
  used to transfer the gene can be retroviral,
  adenoviral, and non viral.
• Examples genes that code for cytokines, tumor
  antigens, MDR, and suicide genes.

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Proteasome inhibitors

• The 26S proteasome is a large intracellular
  adenosine 5-triphosphate-dependent protease that
  identifies and degrades proteins tagged for
  destruction by the ubiquitin system.
• The orderly degradation of cellular proteins is
  critical for normal cell cycling and function,
  and inhibition of the proteasome pathway results
  in cell-cycle arrest and apoptosis.
• Bortezomib is the first inhibitor to enter
  clinical studies.
• Rajkumar VC et al. J Clin Oncol 23 630-9,
  2005 (review)
• see also Mani A and Gelmann E. J Clin Oncol
  23 4776-89, 2005 (review on the role of the
  ubiquitin-proteasome pathway and its role in
  cancer) Yang CG et al. Ann Oncol 17 813-7, 2006
  (limited activity without OR in metastatic breast
  cancer).

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Bisphosphonates

• .

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Bisphosphonates

• Bisphosphonates are analogs of pyrophosphates in
  which a carbon atom replaces the central oxygen
  atom (and , therefore, the two phosphate groups
  are linked to the central carbon atom).
• The P-C-P moiety of bisphosphonates is
  responsible for their strong affinity for
  divalent atoms, such as calcium ions, and for the
  skeleton.
  Contd

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Bisphosphonates (Contd)

• Antiresorptive properties
• Inhibit osteoclastic bone resorption (lead to
  osteoclast inactivation, diminish osteoclast
  maturation, inhibit movement of osteoclasts to
  the bone surface where they resorb bone, induce
  apoptosis of osteoclasts) and therefore, reduce
  the occurrence of pathological fractures, bone
  pain, hypercalcemic episodes, and the need for
  radiation therapy and surgery in patients with
  osteolytic bone metastases.
• Contd

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Bisphosphonates (Contd)

• Direct antitumor effects
• There is experimental evidence of direct
  antitumor activity (see Santini D et al. Ann
  Oncol 14 1468-76, 2003, Review).
• Contd

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Bisphosphonates (Contd)

• Pmidronate (Aredia).(IV)
• Zoledronic acid (Zometa Zomera (in Israel).IV
• Clodronate (Bonefos).IV PO
• Ibandronate (Bondronate)....IV PO
• not registered in Israel