Differentiated Thyroid Cancer Old and Newer Therapies

Usha A. Joseph, M.D.University of Texas Medical School at HoustonUsha.A.Joseph@uth.tmc.edu

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

DTC mortality ratesLow 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

DTC risk factorsLow dose 10 rads- 1500 rads, risk thyd ca -13 % >1500 rads, reduces ca risk from cell killing Thyd nodule + XRT head /neck ->40% risk; 60% in nodule; 40% else where in gland Females > males , ? hormonal/ reproductive factorsIncidence Increase in thyroid deficient areas FTC, anaplastic more commonHyper caloric diet increase risk; high fiber diet decrease risk. Inc TSH- stim growth of cancer

Prognostic factors in DTCPositive Family Hx assoc large tumor size, multi-focal, invasion of local structures, more LN mets at earlier stageAdvanced initial stage of tumor (III or IV)Extent of surg resection (lobectomy or near total)Age: 59 higher risk of recurrence/ cancer death

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

Negative I 131 WBSloss of Iodine uptake in 1/3 DTC from loss of differentiated behavior, P-53 genetic mutations, 1.6% anaplastic transformationMets- 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

Factors affecting RAI uptakeSerum TSH levelNormal residual thyroid tissue -normal thyroid conc 100 x more iodine than DTCDegree of tumor differentiation, DTC typeStunning >sub-lethal effects of beta rad on thyd cell from low dose I 131 used dxtic WBS ; high dose in Rx kills thyroid cells

I 123 diagnostic WBS in DTC pure gamma , stunning unlikely.159 kev, high count rate 20 fold more and 6 fold > detectability than equiv I 131-> 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

STUNNINGCourtesy Dr. Wan from MSKCC

LN mets on I123 WBSI131 post RX WBS same findings

FDG PET in DTC Progressive de-differentiation of DTC mets -> 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

FDG PET in DTCFDG positive: 25% stage 2;60% stage 3 ; 84% in stage 4always positive in Stg 4 with elev TG levels.stage 1 with low Tg no FDG positive

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

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%.

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

Discordant Tg and WBSMost common: pos Tg/ neg WBSLess freq discordant : pos WBS/ neg TgUndetectable Tg/ neg WBS = complete remissionConcordant: detectable or elev Tg /+ WBS = local/distant mets or resid thyd tissue

Neg I 131 WBSloss of Iodine uptake in 1/3 DTC loss of differentiated behavior, P-53 genetic mutations,1.6% anaplastic transformationMets: 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

Pre I131 and FDG neg, Elev Tg-> empiric I131 Rx -230 mci, + I 131 post Rx WBS in mediastinum

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% -> 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

Octreoscan uptake; Stokkel, MPM et al

MetastasisLung mets better prog: Xray neg, younger age, papillary tumor, positive I 131 uptake , absence of other distant metsLung 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

CT periph micro-nodules;I131 Rx bilat diffuse lung mets

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

I131 Rx in DTC indicationspost surg ablate residual thyd tiss (

WBS after 200mci I131RX-multiple metsDxtic WBS 4 mos later; some mets imp, hip same, may need XRT to bone mets in left hip

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 >200 rads; retained whole body activity of no > 120 mci; retained activity in diffuse lung mets of no > 80 mci at 48 hr

Complications of I131 RxEarly: radiation sickness, sialo-adenitis, transient BM suppression, pain in mets, CNS Symptoms from cerebral edema in Rx of brain metsLate: Infertility, chromosomal aberration a concern; 2 ary leukemiaAnaplastic transformation same +/- 131 Rx

New agent development in progressive thyroid cancer (TC) target intracellular molecules causing genetic alterations / dys-regulated growthnot tumor specific ( normal/ malig cells) but tumor selective- cancer more pathway activation, affected lower conc)Signific toxicity from effect on normal cells

New agent developmentBased : 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 pathwayinhibition of programmed cell death-apoptosis

Ras Pathway Ras main pathway in thyd ca; affects cell growth, apoptosis, angiogenesisMutations of genes encoding Ras, or activation of upstream regulatorsRas small GTP binding protein involved in cell proliferation, differentiation, survival.Regularly expressed in normal thyroid tiss

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

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)--> a cascade of events -> cell growth and reduced cell death.MEK1 and MEK 2

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 preventedInterferes with ribosomal assembly, blocks gene expression, inhibit protein synthesis

Anti sense compd

Drugs targeting intracellular signalingPhenyl 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.

Drugs targeting intracellular signalingFarnesyl 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

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.

Drugs targeting receptor tyrosine kinase- VEGFVEGF: stim vasc proliferation & permeability, induces metastasis, and apoptotic protector for new vesselsIncreased in differentiated thyroid ca and mets ;carries poorer prognosisAnti VEGF antibody neutralizes VEGF-> reduces angiogenesis

Drugs targeting receptor tyrosine kinase -EGFREGFR homo- or hetero-dimerized on binding to ligands-> phosphorylation of Tyrosine residues -> Ras and P13 k-> PKC & AKT-> cancer progression Her2/neu preferred hetero-dimerization partner of EGFR, over expressed in PTCHer2/neu/ EGFR implicated in Thyroid cancer progression

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

Drugs targeting receptor tyrosine kinaseEGFR expressed in DTC; over expression worse prognosis.EGFR blocking -> cell cycle arrest in G1 apoptosis, anti-angiogenesis, down regulation of metallo-proteins, decrease incidence of metastasisAnti EGFR antibody reduces availability of receptor by internalization

Drugs targeting receptor tyrosine kinaseover expressed Her2/neu can be activated without ligand. Her2/neu up regulated in papillary thyd caReceptor activation interrupted by monoclonal antibody, Trastuzumab, OR blocking receptors with small molecules or anti sense compounds

Drugs targeting angiogenesis by alternative pathwaysThalidomide, sedative drug; anti neoplastic in animal models; promising anti- angiogenenis properties Phase II trials- metastatic FTC,PTC, medullary cancerCombrestatin, tubulin binding protein - African willow, unique vascular targeting props, active against endothelial cells/ angiogenesis

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.

Targets of PI3 kinase signaling dys-regulation

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 propsPhase I study in advanced solid tumors including thyroid cancer

Drugs targeting apoptotic pathwaysThyroid cancer reduced sensitivity to cell death, can sustain genetic alterations & keep growingApoptosis: orderly process leading to cell death via specific signaling pathways Apoptosis initiated by intra/extracellular stimuliRecombinant TRAIL induces apoptosis in presence of protein inhibitor, cycloheximide

TRAILTumor 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

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

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

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 Hsp90Geldanamycin Blocks Hsp-90 -> enhanced degradation and decrease activation of signaling molecules, Akt, Raf involved in thyroid ca, thyroid cell growth

Demethylating agents DNA Hyper methylation in promoter regions of gene -> 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.

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).

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

Proteasome inhibitors26s proteasome involved in elimination of damaged proteins,apoptosis and cell cycle progression. PS-341 a selective inhibitor of 26 s proteasome -> growth arrest, inhibition of angiogenesis, enhanced radio and chemo sensitivity. Clin trials planned in thyd ca

Gene therapy induce expression of genes not normally expressed in particular cells induce re-expression of silenced genes inhibit expression of abnormal genesenhance therapeutic effect of other agents

Gene therapyIntra-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

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.

Gene therapy-p53 Heterozygous mutation-> 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 -> reduced or absent activityInhibition of normal P53 activity -> rapid cell cycle progression and growth without allowing for appropriate DNA repair or apoptosis

Gene therapy-p53Inactivating 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

Gene therapy application -NISRestore iodine uptake in thyroid ca by re-expression of NIS protein function . NIS important for iodine conc in thyroid cellDefective iodine uptake: hyper methylation of NIS gene promoter, altered sub cellular localization of NIS protein or reduced NIS gene expression by other mechanisms

Gene therapySuccessful 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

Suicide gene therapyInduce 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

New therapies in futuredevelop 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), angiogenesisGene therapy, suicide gene therapy, re-differentiation of tumors Rx ; Clinical trials

Newer Current TherapiesMeantime, new ways I 131 Rx: more effective dose to tumor using dosimetry-> enhanced cell kill and responseOut patient Rx vs inpatient Rx- pt convenienceRh TSH stim dxtic WBS avoids hypothydism pt friendly. Future- thyrogen stim pre I 131 RX I 123 Dxtic WBS avoid stunning-> more effective I131 Rx. FDG PET-non iodine conc thyd ca->surg or XRT. Empiric I 131 Rx in Tg +/ WBS as needed

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