Alexander Ramos Guimaraes MD, PhD, Presenter: Speakers Bureau, Siemens AG Expert Witness, Rice, Dolan, Kershaw

Vidhya Kumar, Abstract Co-Author: Nothing to Disclose

Rakesh K. Jain PhD, Abstract Co-Author: Board of Directors, XTuit Pharmaceuticals Stockholder, XTuit Pharmaceuticals

Ciprian Catana MD, PhD, Abstract Co-Author: Nothing to Disclose

Hong Ren PhD, Abstract Co-Author: Nothing to Disclose

Yves Boucher PhD, Abstract Co-Author: Nothing to Disclose

Jacob M. Hooker PhD, Abstract Co-Author: Nothing to Disclose

Andrew Hoover PhD, Abstract Co-Author: Nothing to Disclose

Diego Santos Ferreira PhD, Abstract Co-Author: Nothing to Disclose

Pancreatic ductal adenocarcinoma (PDAC) responds poorly to chemotherapy partly due to a collagen rich desmoplastic response that is a barrier to drug delivery. Recent studies, however, have demonstrated increased survival with FOLFIRINOX, a component of which is 5-fluorouracil. In addition, angiotensin receptor blockade (ARB) with Losartan ® has been shown to enhance the intratumoral penetration and efficacy of therapeutics in mice using in vitro techniques. The purpose of this study was to test the hypothesis that ARB leads to measurable increased drug delivery as evidenced by labeled 18F-5fluorouracil (5FU) using microPET in a mouse model of PDAC.

All experiments were approved by the local ethical review panel. Orthotopic tumors were generated by implanting 1mm3 chunks of AK4.4 spontaneously generated tumors (from a Ptfl-Cre/LSL-KrasG12D/p53Lox mouse model) into the pancreas of 6-8 week old FVB mice. Tumors were allowed to grow for 1 week prior to treatment. Animals were treated daily with an ip injection of 70mg/kg Losartan for 5 days. 18F-5FU was synthesized using novel, recently published approaches that produce increased yield. MicroPET studies were performed on a Triumph PET/CT Scanner. Orthotopic pancreatic tumor model mice were anesthetized using isoflurane and imaged in Treated-Control pairs. Dynamic PET images were acquired for 60 minutes, using a 18F-5FU tracer dose of 200 uCi per animal. CT scans for attenuation and anatomic coregistration were performed immediately following PET acquisition. ROI analysis was performed on dynamic co-registered images using Osirix ® with tumor time activity curves normalized to muscle. Statistical analyses compared both cohorts using a paired two tailed t-test.

N=6 animals (3 pairs) were studied. Losartan treated animals demonstrated a mean % increase of 148% in drug delivery as measured by 18F-5FU PET that was statistically significant (p<0.0001) as compared to control animals.

ARB in a PDAC orthotopic model demonstrates reproducible, increased drug delivery using PET and labeled 18F-5FU. This method is easily translatable to humans suffering from PDAC.

With the improved survival in patients with pancreatic cancer following FOLFIRINOX, this technique could be translated to study novel targeted modulation of the tumor microenvironment concomitant with 5FU based therapies.

Guimaraes, A, Kumar, V, Jain, R, Catana, C, Ren, H, Boucher, Y, Hooker, J, Hoover, A, Ferreira, D, Angiotensin Receptor Blockade Causes Measurable Increases in Drug Delivery in Pancreatic Cancer Model as Measured by 18F-5fluorouracil and PET.  Radiological Society of North America 2014 Scientific Assembly and Annual Meeting, - ,Chicago IL. http://archive.rsna.org/2014/14015668.html