Abstract 5182: A rapid in vivo screen for pancreatic ductal adenocarcinoma therapeutics using the tumor marker Rgs16::GFP
Authors: Ocal Ozhan , Pashkov Victor , Kollipara Rahul K. , Lorens James B. , Swift Galvin H. , Brekken Rolf A. , Wilkie Thomas M. 
Published: July 2016

Pancreatic Ductal Adenocarcinoma (PDA) is the most lethal major cancer in the USA due to lack of early diagnostics and effective treatments. Activating Kras mutations (such as KrasG12D) occur early in tumor progression and are present in about 90% of PDA. Pancreatic Intraepithelial Neoplasms (PanIN) are the most common initial neoplastic lesions and those with activating Kras alleles typically progress to carcinoma in situ and metastasize.

Receptor Tyrosine Kinases (RTK) and G-protein Coupled Receptors (GPCR) can indirectly activate Kras and are therefore potential drug targets. We previously showed that a feedback inhibitor of GPCRs, Regulator of G-protein Signaling 16 (Rgs16), is expressed in pancreatic progenitors during embryonic development. Rgs16 expression continues postnatally in ducts and beta cells during isletogenesis but is absent in normal glycemic adults. On the other hand, Rgs16 expression returns to ducts and islet beta cells after chronic hyperglycemia in mouse models of Type 1 and Type 2 Diabetes mellitus. Our hypothesis is that Rgs16::GFP is induced in these pancreatic cells in response to GPCR agonists released during chronic stress. In an effort to conduct drug screens in primary duct cell culture, we investigated Rgs16::GFP expression in pancreatic neoplasia by crossing it into a mouse model of aggressive PDA, called KIC (KrasG12D; Cdkn2aL/L; Ptf1a::Cre).

In Rgs16::GFP-KIC mice, Rgs16 was expressed at the initiation of PDA in early PanINs, as early as two weeks after birth (P15), and throughout tumor progression. Rgs16::GFP expression increased with tumor mass through one month of age (P29). We used this tumor specific characteristic of Rgs16 expression to set-up a two-week in vivo quantitative assay to test chemotherapeutic drug effectiveness. In a proof-of-principle study, the standard PDA therapeutics gemcitabine and nab-Paclitaxel reduced Rgs16::GFP expression and tumor burden compared to untreated mice at P29. Targeting Axl, an RTK highly expressed in PDA, with two different inhibitors of Axl signaling, BGB324 or warfarin, in combination with gemcitabine and nab-Paclitaxel further reduced PDA initiation and progression compared to standard chemotherapy alone. Survival studies with Rgs16::GFP-KIC mice showed that treatment with gemcitabine and warfarin extended median life span about two weeks while nearly doubling the maximum life span compared to untreated group.

In summary, Rgs16::GFP-KIC mice provide an in vivo model to rapidly identify more effective PDA chemotherapeutics and treatment protocols.

Citation Format: Ozhan Ocal, Victor Pashkov, Rahul K. Kollipara, James B. Lorens, Galvin H. Swift, Rolf A. Brekken, Thomas M. Wilkie. A rapid in vivo screen for pancreatic ductal adenocarcinoma therapeutics using the tumor marker Rgs16::GFP. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5182.