Differentiated Thyroid Cancer Old and Newer Therapies

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Differentiated Thyroid Cancer Old and Newer
Therapies

• Usha A. Joseph, M.D.
• University of Texas Medical School at Houston
• Usha.A.Joseph_at_uth.tmc.edu

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Differentiated thyroid cancer (DTC) types

• Papillary thyroid Cancer (PTC) 80 Follicular
  thyroid cancer (FTC) 10-15 Combined 85-98
• recurrence rate of 20.
• appropriate Rx long term survival gt 90
• Massin- lower rate of lung metastasis in pts
  receiving post op I-131 ablative Rx

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DTC mortality rates

• Low risk 2-5 rec rate 10. 33-50 death rate
  in lobectomy only pts developing recurrence.
  Near total thyroidectomy preferable.
• High risk 40-50 rec rate 45. Rx near total
  thyroidectomy, I 131 ablation, TSH suppression

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DTC risk factors

• Low dose 10 rads- 1500 rads, risk thyd ca -13
  gt1500 rads, reduces ca risk from cell killing
• Thyd nodule XRT head /neck -gt40 risk 60 in
  nodule 40 else where in gland
• Females gt males , ? hormonal/ reproductive
  factors
• Incidence Increase in thyroid deficient areas
  FTC, anaplastic more common
• Hyper caloric diet increase risk high fiber diet
  decrease risk. Inc TSH- stim growth of cancer

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Prognostic factors in DTC

• Positive Family Hx assoc large tumor size,
  multi-focal, invasion of local structures, more
  LN mets at earlier stage
• Advanced initial stage of tumor (III or IV)
• Extent of surg resection (lobectomy or near
  total)
• Age lt20 or gt59 higher risk of recurrence/ cancer
  death

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Bad Molecular-genetic prognostic factors in
aggressive DTC

• aneuploid PTC, Hurthle Cell Cancer (HCC),
  decreased cAMP response to TSH, inc epidermal
  growth factor binding, poor Iodine uptake, N-ras
  and gsp or p53 mutations, inc expression of c-myc
  m RNA all assoc poorly differentiated,
  aggressive cancer

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Negative I 131 WBS

• loss of Iodine uptake in 1/3 DTC from loss of
  differentiated behavior, P-53 genetic mutations,
  1.6 anaplastic transformation
• Mets- defect in iodine trapping mech, but retain
  ability Tg synthesis
• Less responsive to traditional therapeutic
  modalities.
• TSH directly stimulates Iodine trapping iodine
  deficiency less direct stim

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Factors affecting RAI uptake

• Serum TSH level
• Normal residual thyroid tissue -normal thyroid
  conc 100 x more iodine than DTC
• Degree of tumor differentiation, DTC type
• Stunning gtsub-lethal effects of beta rad on thyd
  cell from low dose I 131 used dxtic WBS high
  dose in Rx kills thyroid cells

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I 123 diagnostic WBS in DTC

• pure gamma , stunning unlikely.
• 159 kev, high count rate 20 fold more and 6
  fold gt detectability than equiv I 131-gt better
  images. Dose 5-15 mci
• 24 hr I 123 WBS highly comparable (98) to I
  131 post Rx scan
• Radiation to thyroid is 1/5 or less than 2
  mci of I 131. Disadv higher cost

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STUNNING
Courtesy Dr. Wan from MSKCC
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LN mets on I123 WBS
I131 post RX WBS same findings
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FDG PET in DTC

• Progressive de-differentiation of DTC mets -gt
  loss of Iodine conc ability but increase
  metabolism from higher growth rate- Flip-Flop or
  inverse relationship
• False Neg WBS 20 metastatic DTC, Hurthle Cell
  Cancer (HCC), aggressive and anaplastic ca

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FDG PET in DTC

• FDG positive 25 stage 2 60 stage 3 84 in
  stage 4
• always positive in Stg 4 with elev TG levels.
• stage 1 with low Tg no FDG positive

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Neg WBS,CXR and FDG scan, path anaplastic
component
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FDG PET

• FDG,a glucose analogue, accumulates in cell
  with increased glucose metabolism.
• DTC 6-17 mortality in 5 yrs
• more recurrence with cerv LN involvement (32)
  than without (14)- Harwood
• PET changed management in 51.
• Low TG levels, FDG NPV of 93
• Elev Tg, FDG occult disease in 71,PPV 92.

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Thyrogen (rhTSH)

• Thyrogen exogenously stim TSH secretion,
  increases uptake of I 131 and Tg secretion by
  neoplastic follicular cells.
• Abnormal Tg level is gt 2ng/ml.
• Tg value decreased by Tg Antibody (Tg Ab )
• Tg Ab in 15-25 pts, may indicate active tumor
• Thyrogen stim Tg neck US high accuracy in
  persistent disease ( 96 vs 85 for Tg alone)

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Discordant Tg and WBS

• Most common pos Tg/ neg WBS
• Less freq discordant pos WBS/ neg Tg
• Undetectable Tg/ neg WBS complete remission
• Concordant detectable or elev Tg / WBS
  local/distant mets or resid thyd tissue

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Neg I 131 WBS

• loss of Iodine uptake in 1/3 DTC loss of
  differentiated behavior, P-53 genetic
  mutations,1.6 anaplastic transformation
• Mets defect in iodine trapping mech, but retain
  Tg synthesizing capability,so less responsive to
  traditional I131 Rx
• Iodine trapping directly stimulated by TSH
  less directly by iodine deficiency

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Pre I131 and FDG neg, Elev Tg-gt empiric I131 Rx
-230 mci, I 131 post Rx WBS in mediastinum
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Octreoscan- Somatostatin receptor scan (SRS)

• Neuro endocrine tumors or mets express
  somatostain receptors (SSTR)
• PTC high expression of SSTR5 - SRS possible.
• Thyroxine withdrawal increases yield of SRS
  67 -gt 85. SRS guides therapy surgery local
  Rx chemo extensive mets
• Sens for mets 74. Higher uptake in mets without
  iodine conc ability. Potential for Octreotride Rx

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Octreoscan uptake Stokkel, MPM et al
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Metastasis

• Lung mets better prog Xray neg, younger age,
  papillary tumor, positive I 131 uptake , absence
  of other distant mets
• Lung mets survival CT neg (100), micro-nodular
  mets (86), nodular mets (25)
• 10 yr surv 87.
• Lung most common distant met in thyd ca- 4
• Advanced Lung mets survive many yrs-I131 Rx
• Bone mets 10 yr surv 44, Brain mets incid rare

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CT periph micro-nodulesI131 Rx bilat diffuse
lung mets
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I 131 therapy in DTC

• Most empiric fixed dose Rx location of mets
  (Bierwaltes ). Max 300 mci/ time yearly
  intervals, cumulative life time dose of 800mci to
  decrease 2ary Leukemia.
• 100 mCi for residual thyd tissue in neck METS
  150-175 mCi for cervical LN
• 175-200 mCi lung 200 mCi skeletal / brain

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I131 Rx in DTC indications

• post surg ablate residual thyd tiss (lt1 cm),
  I131 Rx- recurrence or mets
• Lengthen disease free survival
• 10 yr survival 85 FTC 93 PTC
• 1997 upto 200 mci I131 as OP Rx in USA.
• Advanced cancers become resistant, lose ability
  to concentrate iodine

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WBS after 200mci I131RX-multiple mets
Dxtic WBS 4 mos later some mets imp, hip same,
may need XRT to bone mets in left hip
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I-131 dosimetry in DTC

• maximize dose delivery to tumor, limit whole
  body exposure, minimize risks/ complications
  (severe B M depression, gram neg sepsis, 2ary
  leukemia .
• Benua criteria blood dose of no gt200 rads
  retained whole body activity of no gt 120 mci
  retained activity in diffuse lung mets of no gt 80
  mci at 48 hr

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Complications of I131 Rx

• Early radiation sickness, sialo-adenitis,
  transient BM suppression, pain in mets, CNS
  Symptoms from cerebral edema in Rx of brain mets
• Late Infertility, chromosomal aberration a
  concern 2 ary leukemia
• Anaplastic transformation same /- 131 Rx

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New agent development in progressive thyroid
cancer (TC)

• target intracellular molecules causing genetic
  alterations / dys-regulated growth
• not tumor specific ( normal/ malig cells) but
  tumor selective- cancer more pathway activation,
  affected lower conc)
• Signific toxicity from effect on normal cells

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New agent development

• Based mech of action, freq of pathway abnormal
  in thyroid ca
• Over expression/ uncontrolled activation of
  receptor tyrosine kinase (RTK) or down stream
  signaling molecules in Ras pathway
• inhibition of programmed cell death-apoptosis

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Ras Pathway

• Ras main pathway in thyd ca affects cell growth,
  apoptosis, angiogenesis
• Mutations of genes encoding Ras, or activation of
  upstream regulators
• Ras small GTP binding protein involved in cell
  proliferation, differentiation, survival.
• Regularly expressed in normal thyroid tiss

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Ras pathway activation

• activated receptor K interacts with GRB2 (adaptor
  protein), then binds ptn, Son of sevenless
• RAS is activated by exchanging GDP for GTP
• GTP Ras phosphorylates targets with cascade of
  events ? cellular proliferation.
• Ras inactivated by hydrolysing GTP-gt new GDP
  available for another cycle

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Drugs targeting intracellular signaling-RAF
inhibition

• Many RAS activation effects via down stream
  effector -Raf
• Activated (GTP bound) Ras localizes Raf to
  membrane.
• Raf phosphorylates MAPK kinase (MEK)--gt a
  cascade of events -gt cell growth and reduced cell
  death.
• MEK1 and MEK 2

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Drugs targeting intracellular signaling

• antisense compd small synth DNA seq to
  particular targeted mRNA. On binding to mRNA
  prevent translation
• Ribonuclease H cleaves mRNA strand but not
  anti-sense compound, thus transcription /
  translation prevented
• Interferes with ribosomal assembly, blocks gene
  expression, inhibit protein synthesis

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Anti sense compd
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Drugs targeting intracellular signaling

• Phenyl acetate inhibit cell growth via effect on
  post translational processing of Ras.
• Decrease TSH /non TSH induced cell growth, inc
  iodine uptake, inc Tg secretion.

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Drugs targeting intracellular signaling

• Farnesyl transferase inhibitors (FTI) post
  transational modification is required for
  trans-location of activated Ras to cytoplasmic
  membrane
• inhibition of enzyme farnesyl transferase,
  inhibits membrane accumulation of Ras
• Four FTI s

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Receptor tyrokinase (RTK) over activation

• Over activation of RTK- EGFR, VEGR with enhanced
  signaling by many ligands EGF( epidermal growth
  factor) or VEGF( Vascular endothelial growth
  factor)
• Freq mutations result in constitutive
  activation.
• Most common over-expressed receptor in thyroid
  ca.

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Drugs targeting receptor tyrosine kinase- VEGF

• VEGF stim vasc proliferation permeability,
  induces metastasis, and apoptotic protector for
  new vessels
• Increased in differentiated thyroid ca and
  mets carries poorer prognosis
• Anti VEGF antibody neutralizes VEGF-gt reduces
  angiogenesis

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Drugs targeting receptor tyrosine kinase -EGFR

• EGFR homo- or hetero-dimerized on binding to
  ligands-gt phosphorylation of Tyrosine residues -gt
  Ras and P13 k-gt PKC AKT-gt cancer progression
• Her2/neu preferred hetero-dimerization partner of
  EGFR, over expressed in PTC
• Her2/neu/ EGFR implicated in Thyroid cancer
  progression

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Drugs targeting receptor tyrosine kinase

• Gene amplification of Her2/neu assoc with poor
  prognosis.
• Over expression of Her2/neu acts as potent
  oncogene
• Herceptin, humanized monoclonal antibody binds
  to HER2/neu receptor

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Drugs targeting receptor tyrosine kinase

• EGFR expressed in DTC over expression worse
  prognosis.
• EGFR blocking -gt cell cycle arrest in G1
  apoptosis, anti-angiogenesis, down regulation of
  metallo-proteins, decrease incidence of
  metastasis
• Anti EGFR antibody reduces availability of
  receptor by internalization

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Drugs targeting receptor tyrosine kinase

• over expressed Her2/neu can be activated without
  ligand. Her2/neu up regulated in papillary thyd
  ca
• Receptor activation interrupted by monoclonal
  antibody, Trastuzumab, OR
• blocking receptors with small molecules or anti
  sense compounds

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Drugs targeting angiogenesis by alternative
pathways

• Thalidomide, sedative drug anti neoplastic in
  animal models promising anti- angiogenenis
  properties
• Phase II trials- metastatic FTC,PTC, medullary
  cancer
• Combrestatin, tubulin binding protein - African
  willow, unique vascular targeting props,
• active against endothelial cells/ angiogenesis

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Drugs target Akt/ mammalian target of rapamycin
(MTOR)

• mTOR activation increases cell cycle progression
  /cell growth by dys regulation of targets .
  mTOR directly controlled by kinase, Akt -
  elevated in thyd ca
• targets of mTOR dys-regulation, over expressed
  in thyroid cancer like cell cycle stimulators
  C-Myc, cyclin D1.
• Level directly correlate with aggressive ca.

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Targets of PI3 kinase signaling dys-regulation
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Drugs targeting mammalian target of rapamycin
(MTOR)

• Rapamycin a macrolide antibiotic with immuno-
  suppressive properties (used to prevent allograft
  rejection in organ transplant) anti tumor props
• Phase I study in advanced solid tumors including
  thyroid cancer

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Drugs targeting apoptotic pathways

• Thyroid cancer reduced sensitivity to cell death,
  can sustain genetic alterations keep growing
• Apoptosis orderly process leading to cell death
  via specific signaling pathways
• Apoptosis initiated by intra/extracellular
  stimuli
• Recombinant TRAIL induces apoptosis in presence
  of protein inhibitor, cycloheximide

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TRAIL

• Tumor Necrosis Factor related apoptysis inducing
  ligand (TRAIL) - benign and malignant tissue.
• Cancer cells more sensitive to TRAIL
• Reduces cell growth by inducing apoptosis via
  caspase pathway

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TRAIL

• TRM-1 human monoclonal antibody, high affinity
  binding to TRAIL-R1 receptor to induce
  apoptysis.
• Inhibition of Bcl-2 by phosphorylation-gt
  resistance to apoptosis.
• Over expression Bcl-2 -gtcell proliferation in
  thyd ca.
• Bcl-2 antisense compd used for Rx

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Cox-2 inhibitors

• Cox 2 key enzyme in synth of prosta-glandin
  occurs freq in thyroid / other ca.
• Over expression/ over activation of Cox 2
  inhibits apoptosis, enhances angiogenesis
• Cox-2 inhibitor (celecoxib) potent therapeutic
  agent alone or with chemo in malignancies
  including thyroid ca

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90-kDa Heat shock proteininhibitor (Hsp 90)

• Hsp 90 chaperone molecule for activation/
  stabilization of proteins in signal transduction
  pathways. Serine /threonine kinase ,Raf1 and Akt,
  need Hsp90
• Geldanamycin Blocks Hsp-90 -gt enhanced
  degradation and decrease activation of signaling
  molecules,
• Akt, Raf involved in thyroid ca, thyroid cell
  growth

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Demethylating agents

• DNA Hyper methylation in promoter regions of
  gene -gt altered binding of co- factors?
  altered/reduced gene expression reduced binding
  of transcription factors
• Blocking induces re-expression of tumor
  suppressor genes, reduces cell growth or inc
  expression of genes facilitating therapy
• 5-Azacytidine and 5-Aza-2deoxycitidine.

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Histone deacetylase inhibitors

• Histones small positively charged major protein
  of chromosome. Binds tightly to negatively
  charged DNA to form condensed Protein-DNA
  complex.
• Bond relaxation by enzyme modification enables
  transcription of DNA into mRNA. Bond disruption
  induces cell cycle arrest, differentiation, and
  aptosis in cancer cell lines.
• In vitro work - anaplastic/ FTC is promising
  (increase TG and Iodine conc).

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Lithium

• Lithium occasional adjunct to improve uptake in
  de- differentiated tumors that concentrate
  Iodine poorly or none at all
• Reduces release of iodine and increase I131
  effective half life in thyroid tissue

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Proteasome inhibitors

• 26s proteasome involved in elimination of damaged
  proteins,apoptosis and cell cycle progression.
• PS-341 a selective inhibitor of 26 s proteasome
  -gt growth arrest, inhibition of angiogenesis,
  enhanced radio and chemo sensitivity. Clin trials
  planned in thyd ca

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Gene therapy

• induce expression of genes not normally
  expressed in particular cells
• induce re-expression of silenced genes
• inhibit expression of abnormal genes
• enhance therapeutic effect of other agents

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Gene therapy

• Intra-tumoral gene delivery via direct injection
  of c DNA encoding gene of interest or of viral
  vectors
• Systemic Rx of mets more difficult due to host of
  immune response to vector and first pass through
  liver

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Gene Therapy -p53

• critical regulator of cell cycle progression
• p53 protein activation allows for repair of DNA
  mismatches from external events like radiation or
  aging.
• With enough damage, p53 activates a cascade of
  events resulting in apoptosis.

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Gene therapy-p53

• Heterozygous mutation-gt reduced function of
  normal p53 or direct inhibition of p53 activity
  (dominant negative effect)
• Homozygous missense mutation in coding region of
  both alleles of p53 -gt reduced or absent activity
• Inhibition of normal P53 activity -gt rapid cell
  cycle progression and growth without allowing
  for appropriate DNA repair or apoptosis

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Gene therapy-p53

• Inactivating mutations of p53 most common in
  poorly differentiated solid malignancy including
  anaplastic thyroid ca
• Malignant cells bearing wild- type p53 more
  susceptible to chemotherapy agents compared to
  mutant p 53

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Gene therapy application -NIS

• Restore iodine uptake in thyroid ca by
  re-expression of NIS protein function . NIS
  important for iodine conc in thyroid cell
• Defective iodine uptake hyper methylation of NIS
  gene promoter, altered sub cellular localization
  of NIS protein or reduced NIS gene expression by
  other mechanisms

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Gene therapy

• Successful induction of NIS re-expression by
  gene Rx in malignant cell lines including FTC
• Suicide gene therapy goal -induce expression of
  proteins in cancer cells which are directly toxic
  to cancer cell OR
• induce sensitivity of cancer cells selectively
  to particular medication

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Suicide gene therapy

• Induce expression of viral enzyme TK in target
  cells so gene encoding TK is controlled by a type
  specific TG promoter with expression of TK in
  cancer cell only. Promise- future
• Expression of TK increases sensitivity to
  antiviral drug, ganciclovir with DNA strand
  break and subseq cancer specific cell death
  only. Enhances efficacy of y-radiation.
• TK not normally expressed in mammalian cells

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New therapies in future

• develop compounds targeting intracellular
  molecules involved in dys-regulated growth, or
  in pathways of cell growth, apoptosis, or
  angiogenesis
• Ras directed Rx, drugs targeting receptor
  tyrosine kinase (RTK), angiogenesis
• Gene therapy, suicide gene therapy,
  re-differentiation of tumors Rx Clinical trials

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Newer Current Therapies

• Meantime, new ways I 131 Rx more effective dose
  to tumor using dosimetry-gt enhanced cell kill and
  response
• Out patient Rx vs inpatient Rx- pt convenience
• Rh TSH stim dxtic WBS avoids hypothydism pt
  friendly. Future- thyrogen stim pre I 131 RX
• I 123 Dxtic WBS avoid stunning-gt more effective
  I131 Rx.
• FDG PET-non iodine conc thyd ca-gtsurg or XRT.
  Empiric I 131 Rx in Tg / WBS as needed

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DTC References

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• Bushnell,DL.1992 J Nuc Med 3312, 2214-2221
• Kebebew, K .2000. World J of Surg24,942-951
• Pacini, F. 2002. Eur J Nuc Med,29,Suppl 2, Aug
  2002
• Mazzaferri, EL. 2003.J Clin Endocrinology and
  Metab. 8841433-1441

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DTC References

• Toubeau,M.2004 J Nuc Med 45 6 988-994
• Ma, C. 2005. J Nuc Med 46 9,1473-1480
• Jarzab, B. 2003. Eur J Nucl Med Mol Imaging. 30
  1077-1086
• Lippi,F.2001.Eur J of Endocrinol 144 5-11
• Lupoli,GA.2005.Med Sci Monit 11(12)RA 368-73
• Alzaharani, AS. 2001. J Clin Endocrinology and
  Metabolism 86115294-5300
• Stokkel, MPM. 2004 July 31(7) 950-957

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DTC References

• Wang,W.1999.J Clin Endocrinology and Metabolism.
  84 7 2291-2302
• Cushing SL.2004. Laryngoscope.114 2110- 2115
• Pacini, F. 2003. J Clin Endocrinol Metab 88 8
  3668-3673
• Verburg, F.2005.Eur J Endocrinol15233-7
• Datz, FL.1986. J Nuc Med. 27637-640