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SOMATOSTATIN RECEPTOR SUBTYPE 5 REGULATION OF ISLET NEOPLASIA

Award Number: R56DK046441
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2010
PERIOD OF PERFORMANCE END DATE: 08/31/2013

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SOMATOSTATIN RECEPTOR SUBTYPE 5 REGULATION OF ISLET NEOPLASIA - ABSTRACT: During the funding of the current R-01, our team made 4 discoveries related to human and mouse somatostatin receptor subtype five (hSSTR5, mSSTR5) and pancreatic duodenal homeobox-1 (PDX-1) that are highly translatable for patients suffering with islet neoplasia (INeo): 1. our SSTR5-/- mice develop INeo associated with hyperinsulinemia, hypoglycemia and PDX-1 overexpression, suggesting mSSTR5 regulates both insulin secretion and INeo via PDX-1; 2. PDX-1 regulates INeo cell proliferation and iv PDX-1 shRNA therapy prevents hypoglycemic death in a metastatic insulinoma mouse model, suggesting PDX-1 is a molecular target for INeo; 3. we found a germline hSSTR5 SNP with a proline to leucine substitution at C terminal position 335 (hSSTR5 P335L) in ~50% of human INeo tumors. Preliminary in vitro data reveal that hSSTR5 P335L is hypofunctional resulting in PDX-1 overexpression and lack of response to SSTR5 analogue PRL-1980 in INeo cells, suggesting genomic hSSTR5 variation predicts response to therapy; 4. our rat insulin promoter-thymidine kinase (RIP-TK) vector, which is activated by PDX-1, and F18-FHBG prodrug can be used to image PDX-1 expression in INeo tumors in mice and could be used to track response to therapy. Hypotheses: a) hSSTR5 regulates insulin and INeo via PDX-1, b) hSSTR5 P335L is a hypofunctional receptor with altered PDX-1 regulation of INeo, and c) genomic variation of hSSTR5 and variations in expression of hSSTR5, hSSTR5 P335L and PDX-1 predict response to targeted therapies. Specific Aim 1: to determine whether a) distribution of hSSTR5 genomic variation in INeo patients can be validated using TaqMan Allelic Discrimination assay and b) variations in expression of hSSTR5, hSSTR5 P335L and/or PDX-1 of INeo specimens can be validated using QPCR, Western blot and Quantum Dot (Q Dot) deconvolution imaging and image analysis. Specific aim 2: to determine whether a) hSSTR5 regulates insulin and INeo cell proliferation via PDX-1, b) hSSTR5 P335L is a hypofunctional receptor with altered PDX-1 regulation of INeo, and c) hSSTR5 genomic variation and variations in hSSTR5, hSSTR5 P335L and PDX-1 expression levels predict response to SSTR5-specific analogue PRL-1980 vs PDX-1 shRNA therapies in i) βTC-6hSSTR5 SCID mouse model, ii) βTC-6hSSTR5 P335L SCID mouse model, iii) βTC-6SSTR5KD (Knock Down) SCID mouse model, iv) hSSTR5 knock-in mice, v) hSSTR5 P335L knock-in mice and vi) SSTR5-/- mice. Specific Aim 3: to determine whether a) imaging agents to detect PDX-1 expression using rat insulin promoter-thymidine kinase (RIP-TK) in INeo mouse models from aim 2 can be validated using 18F-FHBG for microPET imaging and/or dual labeled analogues for optical imaging and tomography, b) the response to targeted therapies can be studied using RIP-TK/ 18F-FHBG microPET imaging and is dependent upon PDX-1 expression levels and c) microPET PRL- 1980-Cu64 imaging can differentiate between SSTR5 positive and SSTR5 negative INeo tumors and will confirm the role of PDX-1 in therapeutic response in vivo.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2010	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Trans-NIH Recovery Act Research Support	000	15	3/1/2013	COMPETING CONTINUATION	$0
2013	2010	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Trans-NIH Recovery Act Research Support	003	16	4/3/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2013	2010	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Trans-NIH Recovery Act Research Support	002	15	3/28/2013	COMPETING CONTINUATION	-$12,000
2013	2010	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Trans-NIH Recovery Act Research Support	001	16	3/28/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$12,000
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $220,647 )
2010	2010	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Trans-NIH Recovery Act Research Support	000	15	6/17/2010	COMPETING CONTINUATION	$220,647
														Subtotal = $220,647

Grand Total All Awards = $220,647

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SOMATOSTATIN RECEPTOR SUBTYPE 5 REGULATION OF ISLET NEOPLASIA

Award Number: R56DK046441

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2010

PERIOD OF PERFORMANCE END DATE: 08/31/2013

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