Transcript [Abstract 371] CHARACTERIZATION OF SOMATOSTATIN TYPE 2

Somatostatin Type-2
Receptor Expression in Bone
and Soft Tissue Sarcomas
William Ahrens M.D.
Department of Pathology
Yale School of Medicine
New Haven, Connecticut USA
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Somatostatin
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Initial description by Brazeau and Guillemin
“Somatotropin Release-Inhibiting Factor” (SRIF)
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Brazeau P et al. Science 1973;179:77-99.
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Somatostatin
14 amino acid cyclic peptide SST-14
 Produced in Central/Peripheral NS, endocrine
pancreas, gut, thyroid, retina, adrenal gland, salivary
gland, kidneys, prostate, placenta 1-3
 Inhibitory peptide- exo/endo/para/autocrine
 GH, GI hormones, gastric motility, intestinal
absorption, pancreatic enzyme secretion, etc… 4
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1Lucey
MR. Gut 1986;27:457-67.
2Reichlin S. N Eng J Med 1983;309:1495-501.
3Reichlin S. N Eng J Med 1983;309:1556-1563.
4Reichlin S. J Lab Clin Med 1987;109:320-36.
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Somatostatin Receptors
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Five types isolated and cloned (SSRT1-5)
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Differential expression in normal/neoplastic tissues 1
SSRT1-breast, prostate, pit. adenoma, gastroenteropancreatic, Sarcoma
SSRT2-neuroblastoma, medulloblastoma, breast,
lymphoma, small cell, hepatoma, prostate,
Sarcoma, pit. adenoma, gastroenteropancreatic
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SSRT3-pit. adenoma
SSRT4-Sarcoma
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SSRT5- pit. adenoma, gastroenteropancreatic
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1Reubi
JC et al. Eur J Nuc Med 2001;28:836-46.
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Somatostatin
Short T 1/2 in serum- 3 min- contin. IV
infusion
 Analogues-variable affinity for different
receptor subtypes, longer T 1/2, dec. side
fx.
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SSTR2-octreotide, lanreotide
Minor side effects-GI
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Somatostatin
Octreotide currently only approved for
treatment of Neuroendocrine tumors
 Clinical trials-Lymphoma, Breast,
Prostate, Small-cell Lung, Colorectal,
Gastric, Pancreatic, Hepatocellular1
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1Hejna
M et al. Ann Onc 2002; 13:653-68.
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Somatostatin-Sarcoma
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SSTR in Human mesenchymal tumors1
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SSTR in peritumoral veins2
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Autoradiography, ISH
Autoradiography
SST inhibition of angiogenesis in Kaposi’s3
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1Reubi
JC. Can Res 1996;56:1922-31.
2Denzler B. Cancer 1999;85(1):188-98.
3Albini A. FASEB 1999;13:647-655.
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Somatostatin-Sarcoma cont’d
Radiolabeled Octreotide detection of primary,
metastatic sarcoma1,2
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 SSTR expression in soft tissue sarcomas
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RT-PCR, Scintigraphy
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1Friedberg
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JW. Cancer 1999;86(8):1621-27.
2Ferrari S. Can Bioth Radiopharm 2003;18(5):847-51.
3Florio T. Antican Res 2003;23:2465-72.
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Somatostatin
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Goal of this study
Characterize SSTR2 expression in various
subtypes of sarcoma using several modalities
 Determine tissue site of expression
 Establish “threshold” of expression that
relates to clinical response
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Methods
Pre-operative scintigraphy 111IndiumPentetreotide (Octreoscan, 6mCi)
 Fresh tissue at time of definitive resection
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Frozen- RT-PCR
 Formalin Fixed- Immunohistochemistry
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Results
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38 Patients (34 malignant, 4 benign)
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M:F 17:21
Mean Age 53.5 yrs. (11-84 yrs)
30 Soft Tissue/8 Bone
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Thigh/Femur 17
Chest Wall/Peritoneum 4
Pelvis 4
Popliteal 4
Leg 4
Upper Extremity 3
Spine 1
Grade 1: 7
2: 8
3: 19
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Results cont’d
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Soft Tissue
Liposarcoma 12
 “MFH” 8
 Leiomyosarcoma 2
 MPNST 1
 Fibromatosis 2
 DFSP 1
 IM Myxoma 1
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Bone
Chondrosarcoma 4
 Osteosarcoma 3
 “MFH” 3
 GCT 1
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Results cont’d
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111In-Pentetreotide
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Scintigraphy
10/12 Positive
 Osteosarcoma 3/4
 “MFH” 4/4
 Liposarcoma 2/3
 Synovial Sarcoma 1/1
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Results cont’d
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RNA isolation possible from 30/38 cases
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5 cases treated with neo-adjuvant chemotherapy with >95%
response at resection Ewing (2), OS (1), “MFH” (2)
GCT, IM Myxoma, Chondrosarcoma
RT-PCR 29/30 cases with sstr2 expression
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1 osteosarcoma with >95% response
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Results cont’d
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Immunohistochemistry
36 cases with tissue available
 Rabbit polyclonal ab to 2nd extracellular loop
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(Abcam Cambridge, MA USA)
Grading 0-3+ by intensity/ % cells staining
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Immunohistochemistry
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Negative 6 cases
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“MFH” 3
Chondrosarcoma 2
Ewing sarcoma 1
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Positive 30 cases
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1+ 14 cases
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2+ 13 cases
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“MFH” 4
LS 2
Fibrom, OS, DFSP,
MPNST, Leio, Ewing,
Chondrosarc, GCT
LS 7
Fibrom, “MFH”, Leio,
OS, Chondrosarc,
Myxoma
3+ 3 cases
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Myxoid LS 2
Pleomorphic LS 1
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Cases
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Current Treatment Options
Hejna M. Ann Onc 2002;13:653-668.
Neuroendocrine tumors-symptom tx
 Lymphoproliferative disorders-mean time to
progression 10.9 months
 Breast Cancer-synergy with tamoxifen?
 Prostate Cancer-little/no activity
 Small-cell Lung Cancer-no activity
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Current Treatment Options
cont’d
Colorectal Cancer-? Helpful, dec. prolif
activity
 Pancreatic Cancer-? Inc. in duration of
survival
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“New” Modalities
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Radiolabeled Octreotrate in Patients with
Gastoenteropancreatic tumors Kwekkeboom DJ.
J Clin Onc 2005;23(12):2754-62.
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[177Lu-DOTA0,Tyr3]Octreotate
Median time to progression 36 months
Somatostatin analog coupled to cytotoxic
chemotherapeutics Letsch M. J Uro
2004;171:911-15.
 AN-238-2-pyrrolinodoxorubicin coupling
 Growth inhib of prostate tumors in mice of 62%
compared to control, survival advantage
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Conclusions
SSTR2 are present in soft tissue and
bone tumors
 SST analogs can be used to detect
disease
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Future
Additional cases needed
 SSTR1,4 investigation?
 Determination of true “threshold” within tumor
necessary for clinical response
 Combination with current chemo/radiotx.
 Coupling with radio/chemotherapeutic drugs
for more “directed” therapy
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Acknowledgements
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Orthopaedic Surgery
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Dr. Matt Dicaprio
Dr. Gary Friedlaender
Dr. Dave Magit
Dr. Dieter Lindskog
Surgery
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Dr. Irv Modlin
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Medical Oncology
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Dr. John Murren
Dr. Gina Chung
Pathology
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Dr. Miguel Reyes
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