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.
STATEMENT: Effective molecular adjuvant therapies for islet neoplastic (INeo) disorders are urgently needed. Our exciting preliminary data suggest that SSTR5 and PDX-1 can serve as highly translatable therapeutic targets for INeo and that the genomic profiles of SSTR5 and PDX-1 can predict response to targeted therapies, which could represent a meaningful advance in the treatment of INeo patients. Furthermore, preliminary data suggest that PDX-1 expression in INeo cells can be detected by using our RIP-TK vector and optical and microPET imaging, therefore optical and PET imaging could represent a noninvasive means to image response to our therapies.
| Zhou, G; Yu, J; Wang, A et al. (2016) Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma. Curr Mol Med 16:83-90 |
| Liu, Shi-He; Smyth-Templeton, Nancy; Davis, Alan R et al. (2011) Multiple treatment cycles of liposome-encapsulated adenoviral RIP-TK gene therapy effectively ablate human pancreatic cancer cells in SCID mice. Surgery 149:484-95 |
| Li, Donghui; Tanaka, Motofumi; Brunicardi, F Charles et al. (2011) Association between somatostatin receptor 5 gene polymorphisms and pancreatic cancer risk and survival. Cancer 117:2863-72 |
| Liu, Shi-He; Patel, Sanjeet; Gingras, Marie-Claude et al. (2011) PDX-1: demonstration of oncogenic properties in pancreatic cancer. Cancer 117:723-33 |
| Zhou, Guisheng; Gingras, Marie-Claude; Liu, Shi-He et al. (2011) SSTR5 P335L monoclonal antibody differentiates pancreatic neuroendocrine neuroplasms with different SSTR5 genotypes. Surgery 150:1136-42 |
