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Biology of Multiple Endocrine Neoplasia

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Biology of Multiple Endocrine Neoplasia Powered By Docstoc
					Biology of Multiple Endocrine
          Neoplasia
             Douglas W. Ball, M.D.
 Associate Professor of Medicine and Oncology
  Johns Hopkins University School of Medicine
              September 21, 2009

            University of Maryland
MEN2
MEN1
        C-Cells MEN2
Follicular Cells MEN1
MEN2
MEN1   MEN1
MEN2
MEN1   MEN1


MEN1
MEN2
MEN2
MEN1   MEN1


MEN1
MEN2
        MEN1
 MEN2
 MEN1   MEN1


 MEN1
 MEN2
         MEN1

MEN2
MEN1
         MEN2
         MEN1   MEN1


        MEN1
        MEN2
                 MEN1

Medulla MEN2
 Cortex MEN1
 MEN2
 MEN1   MEN1


 MEN1
 MEN2
         MEN1

MEN2
           MEN1
MEN1
Multiple Endocrine Neoplasia Syndromes

Two distinct syndromes:
   MEN1 and MEN2

Both syndromes:
Autosomal dominant inheritance of
  multiple endocrine tumors
DNA-based diagnosis of pre-symptomatic patients

MEN1: Inactivation of tumor suppressor MENIN
MEN2: Activation of Ret proto-oncogene
                   MEN1
          Clinical Manifestations
3 P’s: Parathyroid, pancreas, pituitary
   Cardinal lesion: parathyroid adenomas
   >90% have hyperpara by age 50
GI tumors (50%)
       gastrinoma (40%), carcinoid (10%), insulinoma (10%),
       glucagon , VIP, somatostatin, “non-secretory”
Pituitary tumors (30%)
       prolactinoma (20%), non-secretory, GH (5%),
       ACTH (2%)
         MEN1:
    Additional tumors
Adrenocortical adenomas (25%)
Thyroid follicular adenomas (15%)
Lipomas (30%)
Angiofibromas

Thymic carcinoids (2%)
Bronchial carcinoid (2%)
              MEN1:
         Molecular Genetics
•Mutations in tumor suppressor gene MENIN at
     11q13 in >80% of families
•(>400 independent mutations identified)
•No genotype-phenotype correlations known
•Loss of MENIN in sporadic parathyroid
     adenomas, bronchial carcinoids
•Nuclear protein, function controversial
          MENIN Structure
• No homology to known proteins other than
  three NLS
• Multiple protein interacting domains
                  MENIN Structure
                                                                         Mutations I-IX,
                                                                         collectively 20%
Gene


Protein

Interactions




Other interactions: MLL, ERa, GFAP, vimentin, Smad1/5, others
                                               Lemos and Thakker., Hum Mutation. 29,22-32,2008
              MENIN Function
• Implicated in regulating transcription,
  proliferation, apoptosis, genome stability
• Functions in a histone methyltrasferase
  complex containing MLL A. Yokoyama et al., Mol.
  Cell. Biol. 24, 5639 (2004).
• MLL promotes trimethylation of H3K4,
  transcriptionally active mark
• Results in up-regulation of p27 and p18
   Physiologic Role of MENIN
• Menin down-regulation allows
  pancreatic islet hyperplasia during
  pregnancy SK Karnik et al., Science. 2007 Nov
  2;318(5851):806-9
• Menin gene is transcriptionally
  repressed downstream of prolactin
• Menin attenuation also seen in
  pancreatic islet response to obesity
MENIN regulation of parathyroid
           glands?
• Menin mRNA down-regulated in MEN1-
  associated parathyroid tumors, but up-
  regulated in primary and secondary
  hyperparathyroidism Bhuiyan et al., J Clin
  Endocrinol Metab 2000
MENIN as a tumor suppressor
Menin +/- mice:
• 9 months: pancreatic islet hyperplasia
  and insulinoma, parathyroid adenomas
• 16 months: larger, more numerous
  tumors involving pancreatic islets,
  parathyroids, thyroid, adrenal cortex,
  and pituitary
• LOH of other allele

               JS Crabtree et al.., Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1118-23.
Why does MENIN mutation result
     in endocrine tumors?
• Menin gene expression ubiquitous
• Possible tissue-specific combinatorial
  effects?
• Possible unique dependency of
  endocrine tissues for transcriptional
  actions of Menin?
                    MEN 2:
Clinical Overview


  MEN 2A
    Medullary Thyroid Cancer (>90% by age 40)
    Pheochromocytoma (50%)
    Hyperparathyroidism (15%)
  MEN 2B
    Medullary Thyroid Cancer
    Pheochromocytoma
    GI ganglioneuromatosis
    Marfanoid body habitus
  Familial MTC - FMTC
                MEN2:
           Molecular Genetics
•Activating mutations in Ret receptor tyrosine
kinase
•Functions as a dominant proto-oncogene
•>95% of families have mutations in 6 exons
•Strong genotype-phenotype correlations
•Acquired Ret mutations in 40-50% sporadic MTC
Activating Ret gene mutations cause MEN 2
•Limited number of mutations aid molecular diagnosis
•Germline Ret testing now standard of care for MTC patients
•Ret: a key target for MTC therapy




  Exon                   10   11     13 14     15 16
  Codon              611 620
                   609         634
                         618 634                   918
                                                 891
                                      768 804 883 918


                         Cys TM       Kinase

 Aggressive cases MEN 2A             Aggressive cases MEN 2B

                                     Somatic mutation in 30-50%
                                     of sporadic MTC tumors
Ret Protein




Castellone and Santoro Endocrinol Metab Clin North Am. 2008; 37:363-74
Ret Signaling

  GDNFR   a1-4




  Ichihara, Murakumo, Takahashi. Cancer Lett 2004
Ret Signaling

  GDNFR   a1-4




  Ichihara, Murakumo, Takahashi. Cancer Lett 2004
Ret Signaling

       Y1062F Knock-in




  Ichihara, Murakumo, Takahashi. Cancer Lett 2004
  Jijiwa, MCB 2004
Transgenic Ret mutations mimic MEN 2

  • Calcitonin promoter - Ret M918T: MTC @
    20-22 months Acton Oncogene 2000
  • Calcitonin promoter- Ret C634R: MTC and
    follicular thyroid tumors Reynolds Oncogene 2001
  • p18 knockout strongly promotes MTC in
    mice bearing Ret M918T VanVeelen Can Res 2008
Transgenic Ret mutations mimic MEN 2

  • Calcitonin promoter- Ret M918T: MTC @
    20-22 months Acton Oncogene 2000
  • Calcitonin promoter- Ret C6349R: MTC
    and follicular thyroid tumors Reynolds Oncogene 2001
  • p18 knockout strongly promotes MTC in
    mice bearing Ret M918T VanVeelen Can Res 2008
  • Ret M918T knock-in: C-cell hyperplasia
    and pheochromocytoma Smith-Hicks Embo J 2000
   Drosophila screen for pathways
        interacting with Ret
    WT       MEN 2B-enhanced   MEN 2B    MEN 2B-suppressed




• Ras, src, and jnk pathways modify Ret MEN
  2B eye phenotype Read Genetics 2005
• Vandetanib (tyrosine kinase inhibitor) inhibits
  eye phenotype Vidal Cancer Res 2005
 Ret inhibition: Proof of principle in
                 MTC
• Dominant negative form of Ret causes
  apoptosis and growth inhibition in MTC
  cells bearing activated mutant Ret C634W
 (Drosten, 2004)


• Neutralizing antibodies to Ret pY1062
  also inhibit growth (Salvatore, 2000)
       Risk Stratification using Ret
          status: Familial MTC
•Level 3 mutations: Codons 883, 918, or 922 highest risk



•Level 2 mutations: Codons 611, 618, 620, or 634 high risk


•Level 1 mutations: Codons 609, 768, 790, 791 804, and 891 least
high risk




                                       Brandi, JCEM 2001
       Risk Stratification using Ret
          status: Sporadic MTC
•Somatic mutation at 918 confers adverse prognosis for
metastasis-free and overall survival:




                                 Schilling Int J Cancer, 2001
Ret inhibitors usually cytostatic in cell culture




            Strock et al. Cancer Res 2003
Irinotecan + Ret inhibitor in MTC:
          Xenograft data




                     Strock, JCEM 2006
Clinical response to XL184-
 a ret-VEGF-met inhibitor
                                    Calcitonin levels decline in MTC patients
                                         treated with TKI’s targeting ret
a)                                  100
                                    100
                                                                                                                                                                                                                     Patient
                                     80
                                     80                                                                                                                                                                                   1001
     CTN change from baseline (%)




                                                                                                                                                                                                                          1002
     CTN change from baseline (%)




                                     60
                                     60                                                                                                                                                                                   1013
                                                                                                                                                                                                                          3001
                                     40
                                     40                                                                                                                                                                                   7002

                                     20
                                     20

                                      0
                                      0

                                     -20
                                     -20

                                     -40
                                     -40

                                     -60
                                     -60

                                     -80
                                     -80

                                    -100
                                    -100
                                                                         1 12
                                                                                1 40
                                                                                       1 68
                                                                                              1 96
                                                                                                     2 24
                                                                                                            2 52
                                                                                                                   2 80
                                                                                                                          3 08
                                                                                                                                 3 36
                                                                                                                                        3 64
                                                                                                                                               3 92
                                                                                                                                               4 20
                                                                                                                                                      4 48
                                                                                                                                                             4 76
                                                                                                                                                                    5 04
                                                                                                                                                                           5 32
                                                                                                                                                                                  5 60
                                                                                                                                                                                         5 88
                                                                                                                                                                                                6 16
                                                                                                                                                                                                       6 44
                                                                                                                                                                                                              6 72
                                                                                                                                                                                                                     7 00
                                                                                                                                                                                                                            7 28
                                                                                                                                                                                                                                   7 56
                                                                                                                                                                                                                                          7 84
                                                14
                                                     28
                                                          42
                                                               56
                                                                    84
                                           BL




                                                                                         Protoc ol scheduled visit (days)
                                                                                                                      )
                                                                                         Protocol scheduled visit (days
Responders to Vandetanib
                                                                                                                                        Wells, et al. ASCO 2007
         Take home messages

• MEN1 and MEN2 are non-overlapping
  syndromes with unique molecular etiologies
• MEN1-- tumor suppressor with LOF mutations
• MEN 2-- proto-oncogene with GOF mutations
• Ret is both a key diagnostic marker and
  therapeutic target for MEN 2 and MTC
• Menin less useful diagnostically and
  therapeutically in MEN 1, to date

				
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posted:2/14/2012
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