Project 5

Enhancement of Antitumor Activity in Pancreatic Cancer with SHIDO-ST

Advanced pancreatic ductal adenocarcinoma (PDAC) is often inoperable and is only transiently responsive to existing therapies. Indoleamine 2,3-dioxygenase (IDO) is commonly over expressed in PDAC and plays a major role in accelerating disease progression by suppressing antitumor immunity. ShIDO-ST is a novel Salmonella typhimurium (ST)-based therapy we have developed that expresses a small hairpin (sh)RNA to specifically silence tumor-derived IDO. ST as a shRNA delivery vehicle offers superior colonization of tumor tissue due to its motility and affinity for poorly vascularized, hypoxic tumor tissue. To improve penetration of tumors by shIDO-ST, we are investigating PEGylated human recombinant hyaluronidase (PEGPH20, Halozyme Inc. by MTA), which increases vascular permeability by depleting hyaluronan, an abundant component of the tumor matrix in PDAC tissue. The combination of IDO silencing and abundant ST tumor colonization inhibits PDAC progression mainly through the recruitment and activation of polymorphonuclear neutrophils (PMN), which induces apoptosis of tumor cells and tumor-associated stromal cells via oxidative stress.
 
To best assess the capabilities of this therapeutic class to inhibit PDAC progression, we are currently applying the shIDO-ST to orthotopic murine models of PDAC. The orthotopic model utilizes patient-derived tumor lines and a murine tumor line derived from KrasG12D;Trp53R127H;Pdx1-Cre (KPC) mice which develop spontaneous PDAC that closely resembles its human counterpart. The long-term objective is to develop shIDO-ST into a suitable, effective therapy for the treatment of patients with advanced inoperable PDAC that can also be explored with other solid tumors.
 

Publications

 
1. Manuel ER, Chen J, D’Apuzzo M, Lampa MG, Kaltcheva TI, Thompson CB, Ludwig T, Chung V, Diamond DJ. Salmonella-Based Therapy Targeting Indoleamine 2,3-Dioxygenase Coupled with Enzymatic Depletion of Tumor Hyaluronan Induces Complete Regression of Aggressive Pancreatic Tumors. Cancer Immunol Res. 3(9):1096-1107, 2015. PMC4561205
 
2. Xu X, Hegazy WAH, Guo L, Gao X, Courtney AN, Kurbanov S, Liu D, Tian G, Manuel ER, Diamond DJ, Hensel M, and Metelitsa LS. Effective cancer vaccine platform based on attenuated salmonella and a type III secretion system. Cancer Research, 74(21):6260-70, 2014. PMC:4216746
 
3. Gao C, Kozlowska A, Nechaev S, Li H, Hossain DMS, Zhang Q, Kowolik CM, Chu P, Swiderski P, Diamond DJ, Pal SK, Raubitschek A, Kortylewski M. TLR9 signaling in the tumor microenvironment initiates cancer recurrence after radiation therapy. Cancer Research, 73(24):7211-21, 2013. PM24154870
 
4. Manuel ER and Diamond DJ. Tumor growth control with IDO-silencing salmonella–     Reply. Cancer Research, 73(14):4592-4593, 2013. PM:23832663.
 
5. Manuel ER and Diamond DJ. A road less traveled paved by IDO silencing: Harnessing neutrophils for anti-tumor activity. OncoImmunology, 2:3, e23322, 2013.  PMC3661160
 
6. Blache CA, Manuel ER, Kaltcheva TI, Wong AN, Ellenhorn JDI, Blazar BR, and Diamond DJ. Systemic Delivery of Salmonella Typhimurium Transformed with IDO shRNA Enhances Intratumoral Vector Colonization and Suppresses Tumor Growth.  Cancer Research, 72:6447-6456, 2012. PMC3525777
 
7. Fan H, Zhang IY, Chen X, Zhang L, Wang H, Carvalho da Fonseca AC, Manuel ER, Diamond DJ, Raubitschek AA, and Badie B. Intracerebral CpG Immunotherapy with Carbon Nanotubes Abrogates Growth of Subcutaneous Melanomas in Mice. Clin.Cancer Res., 18(20):5628-5638, 2012. PMC3483143
 
8. Manuel ER, Blache CA, Ellenhorn JDI, Diamond DJ. Survivin the Battle Against Immunosuppression: Author’s View. OncoImmunology, 1(2): 240-241, 2012. PMC3377007
 
9. Manuel ER, Blache CA, Paquette R, Kaltcheva TI, Ellenhorn JDI, Hensel M, Metelitsa L, and  Diamond DJ. Enhancement of Cancer Vaccine Therapy by Systemic Delivery of a Tumor Targeting Salmonella-based STAT3 shRNA Suppresses the Growth of Established Melanoma Tumors. Cancer Research, 71:4183-4191, 2011. PMC3117077
 
10. Zhao D, Alizadeh D, Zhang L, Liu W, Farrukh O, Manuel E, Diamond DJ, Badie B. Carbon nanotubes enhance CpG uptake and potentiate antiglioma immunity. Clinical Cancer Research. 17 (4):771-782, 2011.  PMC3041854

Project Members: Edwin R. Manuel, Ph.D., Marcela Salazar, Ph.D., Laleh G. Melstrom, M.D., Jeremy Chen, Melanie G. Lampa, Joseph Kim, M.D., Vincent Chung, M.D., Massimo D’Apuzzo, M.D., Ph.D., and Don J. Diamond, Ph.D.
 
Company Involvement: Halozyme Therapeutics Inc.
 
 

Project Members

Edwin R. Manuel, Ph.D., Marcela Salazar, Ph.D., Laleh G. Melstrom, M.D., Jeremy Chen, Melanie G. Lampa, Joseph Kim, M.D., Vincent Chung, M.D., Massimo D’Apuzzo, M.D., Ph.D., and Don J. Diamond, Ph.D.
 
Company Involvement: Halozyme Therapeutics Inc.
 

Grant Funding

 
NIH (R21 CA0174306-01A1), Thinkcure, The Nesvig Foundation
 

Opportunities

 
For inquiries about this project or employment opportunities, please contact Melanie Lampa.
 
Experimental Therapeutics Project 7