Targeting the Somatostatin Receptors in Neuro-endocrine Tumors

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Targeting the Somatostatin Receptorsin
Neuro-endocrine Tumors
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Carcinoid tumors are generally quite rare.
Although the majority of patients do not have
symptoms associated with the tumor, when flushing
and diarrhea occurs, the patient is said to have
Carcinoid Syndrome. It is estimated that
approximately 10 of patients with carcinoid
tumors will develop the syndrome. The overall
incidence of carcinoid tumors is approximately
2.0 to 2.5 per 100,000 population. The most
common site for men is the small intestine
whereas in women it is the appendix. A positive
family history is an important risk factor of
carcinoid tumors and there is an association with
the development of Multiple Endocrine Neoplasia
Type 1 (MEN-1). The majority of patients with
NET's present in the fifth decade of life.
Carcinoid tumors (Neuroendocrine tumors)

• Carcinoid tumors belong to a larger group of
  tumors called neuroendocrine tumors (NET's). This
  broad group of tumors also includes the
  pancreatic islet cell tumors. Although both
  carcinoid and pancreatic islet cell tumors share
  similar morphological features, they secrete
  different classes of either bioactive amines or
  peptides, respectively. Carcinoid tumors are the
  most common form of NET's. The majority of
  carcinoids arise in the appendix and to a lesser
  extent in the small bowel, stomach, and duodenum
  whereas pancreatic islet cell tumors arise
  predominantly in the pancreas.

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Somatostatin Receptors

• Five subtypes cloned SSTR 1-5
• SOM.14 and 28 bind to all receptor subtypes
• All receptor subtypes are 7 TM receptors and
• G-Protein coupled
• Effector mediators are C-AMP, CA2 /K FLUX,
• TYROSINPHOSPHATASES
• Octreotide binds to SSTR2 and SSTR5
• SSTR2 mediates biochemical and tumour responses
• SSTR3 mediates apoptosis
• SSTR5 mediates anti-tumour response different
• from SSTR2 (NOT VIA PTPI-C BUT CA 2 /K FLUX?)

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Neuroendocrine Gut and Pancreatic Tumours
Tumour Biology, Diagnosis and Treatment
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The Gut and Pancreatic Neuroendocrine Cell System

• Gut

• ECL-cells (Histamine, CgA, gastrocalcin?)
• G-cells (Gastrin)
• S-cells (Somatostatin)
• P-cells (unknown secretory product)
• EC-cells (Serotonin, Tachykinins, CgA)
• Other neuroendocrine cells and peptidergic
  neurons
• Common stem-cell in the pancreatic ducts
• ß-cell (Insulin)
• a-cell (Glucagon)
• D-cell (Somatostatin)
• PP-cell (Pancreatic polypeptide)
• D1 (unknown secretory product)

Pancreas
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Modes of Regulation

• Endocrine

Autocrine

• Neurocrine

Paracrine
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Genes Involved in Neuroendocrine Tumour
Development

• Menin(MEN I)
• PLC- ß3
• Ret-Proto Oncogen (MEN II, MTC)
• Prad
• BRCA I?

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Tumour Biology

• Growth Factors/Receptors

• ICF-1
• TGF-a1, EGF-R
• TGF- ß, family
• PDGF family

Adhesion Molecules
cd44 (exon v6, v10)
b-FGF VEGF
Angiogenetic Factors
Seven Transmembrane Receptor (G-PROTEIN COUPLED)
Cell-Growth Signals
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Clinical Sydrome
Secretory Products Causing the Syndrome
Tumour Location

• Carcinoid syndrome
• Zollinger Ellison syndrome
• Hypoglycemic (Insulinoma)
• Verner-Morrison (WDHA)
• syndrome
• Glucagonoma syndrome
• Somatostatinoma syndrome

Serotonin, Histamine, Tachykinins,
Bradykinin Serotonin, Tachykinins Bradykinin Gas
trin Insulin, proinsulin IGF-I/II VIP,
PHM Glucagon, (Glicentin) Somatostatin CgA,
HCG-a/ß, PP, PYY (no endocrine related symptoms)
Lung, Stomach and Pancreas Foregut Ileum and
Jejunum Midgut Pancreas Duodenum Pancreas
(Sareomas) Pancreas, Ganglioneuro-mas,
Paraganglioma, Lung Pancreas Pacreas,
Duodenum Pancreas, Colon
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Carcinoid Tumours
Frequency Secretory Products
Foregut (10-15) Thymus ACTH, CRF, GHRH,
ADH Lung
Serotonin, Histamine, Gastrin,
Calcitonin, Tachykinis, CgA, HCGa/ß
Stomach CgA, Histamine, Gastrin,
Serotonin, Gastrocalcin?
Duodenum Gastrin, Somatostatin, CgA Midgut
(30-60) Appendix No known secretory
product Ileum Caecum
Serotonin, Tachykinins, CgA Colon
ascendence Hindgut (25-30) Colon
CgA, PP, HCGa Rectum PYY,
Somatostatin

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Carcinoid Syndrome
Causal Agent

• Flushing
• Diarrhea
• Right Heart Failure
• Broncho Constriction

• Tachykinins, Bradykinins
• Serotonin , Prostaglandins?
• Unknown (TGFß ?)
• Tachykinins, Bradykinins?

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Carcinoid Tumour Diagnosis

• Histopathology
• Tumour Markers
• Other Markers
• Stimulatory Tests
• Radiology
• Other Investigations

• Argyrophil/argentaffin staining CgA, Serotonin
• CgA, u-5-HIAA, p-NPK, p-Subst-P
• P-ACTH, pCRF, PGHRH, s-calcito-
• nin, p-ADH, s-PP, s-HCGa/ß, u-
• Histamine
• Flush provocation Pentagastrin 0,6
• ug/kg bw i.v., measuring p-NKP every 5 min for
  30 min
• Octreoscan (111Ind-DTPA-octreotide)
• CT, US, MRI, (CT-angiography)
• Endoscopy (endoscopic ultrasound)

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Zollinger Ellison Syndrome

• Tumour Location
• Symptoms

• Pancreas 50-60
• Duodenum 40-50
• (sometimes both, MEN-I)
• 20-25 Related to MEN-1
• 50-70 Malignant (lymphnode metastases)
• Gastrinoma Triangle 80
• Gastritis
• Recurrent ulcers

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Zollinger-EllisonSyndrome/Diagnosis

• Histopathology
• Tumour Markers
• Stimulatory Test
• Radiology
• Other Investigations

• Argyrophil staining/CgA/Gastrin
• S-Gastrin, p-CgA
• Secretin infusion 2-3 CU/kg b.w. Secretin
• i.v. measuring gastrin every 5 min for
• 30 min (Protein stimulatory test)
• Meal stimulatory test (MEN-I)
• Endoscopic US
• Octreoscan
• CT, MRI
• Gastroscopy

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Hypoglycemic (Insulinoma)Syndrome
Tumour Location Symptoms
Pancreas 85 Benign tumours Neuroglycopenic
symptoms Catecholamine related symptoms
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Hypoglycemic (Insulinoma) Syndrome/Diagnosis

• Histo-pathology
• TumourMarkers
• StimulatoryTest
• Other Diag.Tests
• Radiology

• Argyrophil staining/Synaptophysin/Insulin/proinsul
  in, CgB
• s-insulin, s-proinsulin, p-CgB
• (Malignant tumours may also produce gastrin and
  glucagon)
• 48-72 hrs fasting measuring s-insulin/proinsulin,
  b-glucose
• Fasting b-glucose
• Fasting b-glucose lt2.8 mmol/l suggest an
  insulinoma
• CT-angiography
• US (liver metastases)
• Endoscopic ultrasonography

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Glucagonoma Syndrome

• Tumour Location
• Symptoms

• Pancreas
• gt90 malignant
• Necrolytic migratory erythema
• Weight loss
• Anemia
• Trombosis
• Impaired glucose tolerance
• Diarrhoea

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Necrolytic migratory erythema
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Glucagonoma Syndrome/Diagnosis

• Histopathology
• Tumour Markers
• Radiology

• Agyrophil staining, CgA, glucagon,
• glicentin
• p-CgA, p-glucagon
• Octreoscan, Endoscopic ultrasound,
• CT-angiography, MRI

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Verner-Morrison Syndrome (WDHAs)

• Tumour Location
• Symptoms

• Pancreas
• Lung
• Ganglioneuromas
• gt80 Malignant
• (Pancreatic nesidioblastosis)
• Watery diarrhea (secretory) 3-20 litres/day
• Hypokalemia, Hypomagnesemia,
• Hypercalcemia
• Acidosis
• Flushing
• Flaccid distended gallbladder
• Ileus/subileus

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Verner-Morrison Syndrome/Diagnosis

• Histopathology
• Tumour Markers
• Radiology

• Argyrophil staining, CgA, VIP
• p-VIP, p-PHM, s-Calcitonin
• Octreoscan
• CT-angiography, MRI
• Endoscopic ultrasonography

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Somatostatinoma Syndrome

• Tumour Location
• Symptoms

• Duodenum
• Pancreas
• Colon/Rectum
• gt80 mixed tumours
• Gallstones
• Steatorrhea
• Impaired glucose tolerance
• Often non-functioning tumours!

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Somatostatinoma Syndrome/Diagnosis

• Histopathology
• Tumour Markers
• Radiology

• Argyrophil staining, CgA
• Somatostatin
• p-CgA, p-Somatostatin
• (s-Gastrin, p-Glucagonom, mixed tumour)
• Endoscopic ultrasonography
• CT-angiography, MRI
• Colonoscopy
• US (liver metastases)

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Somatostatinoma Syndrome/Diagnosis

• Tumour Location
• Symptoms

• Pancreas
• Colon/Rectum
• gt80 malignant
• Sometimes part of MEN-I
• Large abdominal mass
• Intestinal obstruction
• Gastrointestinal bleeding
• Fever
• Abdominal pain

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Non-Functioning Tumours/Diagnosis

• Histopathology
• Tumour Markers
• Stimulatory Test
• Radiology

• Argyrophil staining, CgA
• PP, Somatostatin
• p-CgA, s-PP, s-HCGa/ß
• p-somatostatin
• Meal stimulatory test (MEN-I)
• Octreoscan
• CT-angiography, MRI
• US (liver met. biopsy)
• Colonoscopy

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Multiple Endocrine Neo-Plasia Type I (MEN-I)

• Genetics
• Tumours

• Autosomal dominantly inherited
• Mutations of the MENIN-gene on Chr 11q13
• Parathyroid adenoma 95-100
• Endocrine pancreatic tumours 80
• Pituitary tumours (Prolactin, GH)
  30-50
• Carcinoids (lungs, thymus, gastric, duodenal)
  20-50
• Lipomas 10-20
• Thyroid Nodules 10-15
• Lymphomas lt5

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Pedigree MEN-I
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Neuroendocrine PancreaticTumours (MEN-I)

• Multiple tumours/mixed hormone production
• Gastrinomas (gt45 Duodenal tumours)
• Non-functioning tumours
• Insulinomas
• Glucagonomas
• VIP-omas

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MEN-I Diagnosis

• Genetic Diagnosis
• Biochemical Diagnosis
• Stimulatory Test
• Radiology

• Mutation in MENIN-gene
• s-prolactin
• s-IGF-1
• s-Ca (albumin modified)
• s-PTH
• p-CgA
• s-PP, Gastrin, Insulin
• p-VIP, Glucagon
• Meal stimulatory test
• Endoscopic ultrasonography
• Octreoscan
• CT-angiography, MRI
• Intraoperative US

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Diagnosis General Considerations

• Histopathology

• Argyrophil staining
• Argentaffin staining (carcinoids)
• CgA
• Synaptophysin
• NSE
• Specific peptides (e.g. gastrin, glucagon)

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Argyrophil staining
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Tumours Markers
Elevated In Circulation

• Chromogranin A 90-100
• Pancreatic Polypeptide 40-60
• HCG a/ß 15-30

General Markers
General Stim. Test for Neuroendocrine Pancreatic
Tumours Meal stimulation test with Measurement
of PP every 10 for 1.5 hrs.
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Chromogranins (Cg)

• The Cg Family
• Function

• Chromogranin A (CgA)
• Chromogranin B (CgB)
• Chromogranin C (CgC)
• (Seretogranin II)
• (Largely unknown)
• Storage protein in secretory granules
• Precursor molecule for other active peptides
• (Vasostatins, Pancreastatin, Parastatin)
• Antibacterial effects
• Growth regulatory effect
• Tumour marker for Neuroendocrine Tumours

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Radiology of Neuroendocrine Tumours

• Total BodyScreening and Staging
• Disclosure of Endocrine Pancreatic Tumours
• Newer Techniques
• Traditional Techniqeus (always a compliment)

• Octreoscan (111Ind-DTPA-octreotide) (SRI)
• Sensitivity lt10 mm 40
• gt10 mm 90
• Liver metastases 90
• Endoscopic ultrasonography
• (EUS) sensitivity lt10 mm 50
• SRI EUS sensitivity lt10 mm 90
• Positron emission tomography with
• C11-5 HTP or C11-L-dopa (PET)
• CT ( angiography), MRI
• US sensitivity small tumours 10-30
• Liver metastases 90

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Octreoscan (111Ind-DTPA-octreotide) (SRI)
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The Ultimate Goals for the Treatment of
Neuorendocrine Tumours

• Total erradication by surgery (not possible in
  most cases)
• Abrogation of tumour growth and/or
• amelioration of clinical symptoms
• Improving and maintaining a good quality of life

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Therapy of Neuroendocrine Gut and Pancreatic
Tumours

• Surgery
• (even palliative and tumour reduction)
• Embolisation Chemotherapy
• Irradiation
• ? conventional for bone metastases
• ? experimental 111Ind-DTPA-octreotide 45-60 Gy
• (local) 90
  Y-DOTA-octreotide
• Medical Treatment
• _ ? Somatostatin analogues
• ? a-interferons
• ? chemotherapy

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Embolisation of Liver Metastases
Biochemcial Tumour Resp
Resp

• Embolisation
• (Spongostan,
• Gel-Foam)
• CHEMOEMBOLISATION
• (DOXORUBICIN)

30-50
20-30 median duration 7-10 months
50 80 40-50 median
duration 10-20 months
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Chemotherapy of Neuro-Endocrine Gut and
Pancreatic Tumours
Response Rate

• Endocrine Pancreatic Tumours
• Midgut CarcinoidTumours

Streptozocin 5 FU 40-60 Streptozocin
doxorubicin 60 Cisplatinum Etoposide
50 (low differentiated tumours) Taxol
doxorubicin 40-50 Streptozocin 5
FU 10-30 Cisplatinum Etoposide
10-15
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Treatment with a-Interferons (a-IFNs)

• Types of a-IFNS
• Recommended doses for classical midgut
  carcinoids

Human leukocyte IFN Lymphoblastoid IFN
(Welferon) Recombinant IFNa 2a (Roferon) Recombina
nt IFNa 2b (Intron-A) IFNa 2b
3-5 MU x III-V/week s.c.
NB! Individual dosing according to tolerance and
leukocyte count (lt3.0 x 109/l) is recommended
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a-IFN Treatment

• Subjective Responses
• Biochemical Responses
• Tumour Responses

50-70 30-70 10-15
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Somatostatin Receptors

• Five subtypes cloned SSTR 1-5
• SOM.14 and 28 bind to all receptor subtypes
• All receptor subtypes are 7 TM receptors and
• G-Protein coupled
• Effector mediators are C-AMP, CA2 /K FLUX,
• TYROSINPHOSPHATASES
• Octreotide binds to SSTR2 and SSTR5
• SSTR2 mediates biochemical and tumour responses
• SSTR3 mediates apoptosis
• SSTR5 mediates anti-tumour response different
• from SSTR2 (NOT VIA PTPI-C BUT CA 2 /K FLUX?)

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Treatment with Somatostatin Analogues
(Octreotide)

• Octreotide
• CarcinoidSyndrome
• Carcinoid Crises
• Octreotide LAR

Recommended dosing 100-600 µg/day s.c. given as
2-3 doses Experimental 1,500-3,000 µg/day s.c.
Preoperatively 100 µg
s-c- 30 prior to operation and thereafter 50
µg/hr i.v. infusion during op., continue postop.
either with s.c. or i.v. therapy Octreotide
i.v. 50-100 µg/hr (Foregut carcinoid with
histamine production, continue with H1 and H2
receptor blockers) Long-acting formulation,
dosing 20-30 mg i.m./4 w.
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Octreotide Treatment

• Subjective Response
• Biochemical Response
• Tumour Response

30-75 (Dose dependent) 30-60 (Dose
dependent) 0-15 (Not dose dependent)
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Future Programme Tumour biology based therapy
programme including

• Proliferation markers (KI-67, PCNA)
• growth factors/receptors
• adhesion molecules
• angiogenetic factors
• somatostatin receptor subtypes
• induction of IFN sensible genes
• (2-5 A-synthetase, PKR)