Abstract PR14: PTEN-Long and gemcitabine combination treatment as a therapeutic for pancreatic cancer

Abstract

PTEN is the second most frequently altered tumor suppressor found in human cancer, and is downregulated in a majority of pancreatic tumors. PTEN-Long is an endogenously expressed translational variant of this tumor suppressor that is identical to PTEN with the exception of an additional N-terminal region that gives this variant the ability to cross the cell membrane. Purified PTEN-Long can be used therapeutically to restore lost PTEN function, and has provoked profound regressions in PTEN null xenograft models. Here we explore the effect of PTEN-Long therapy in pancreatic cancer, both in the presence and absence of endogenous PTEN. In preliminary data, we found that combining PTEN-Long with chemotherapy extended overall survival in a clinically predictive genetically engineered mouse model of PDA (K-rasLSL.G12D/+; p53LSL.R172H/+;PdxCre, called KPC). To explore PTEN-Long’s ability to enter various tissues we performed pharmacokinetic and pharmacodynamic experiments. We also utilized a surgical biopsy technique to obtain paired pre- and post-treatment tumor samples. These experiments demonstrated that PTEN-Long is able to alter canonical PTEN/PI3K signaling within pancreatic tumor tissues. Finally, we treated PTEN deficient mice (K-rasLSL.G12D/+; PTENFlox/+; PdxCre) with PTEN-Long in an attempt to model the therapeutic response of the ~5% of human pancreatic tumors that are genetically PTEN null. Longitudinal ultrasound imaging of the first of these mice suggests that these mice have more significant and prolonged regressions compared to KPC mice following PTEN-Long treatment. This abstract is also presented as Poster A86. Citation Format: Roshan Ara Ahmed, Benjamin Hopkins, Carmine Palermo, Steve A. Sastra, Zachary Rapp, Ramon Parsons, Kenneth P. Olive. PTEN-Long and gemcitabine combination treatment as a therapeutic for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr PR14.

PTEN deficiency facilitates gemcitabine efficacy in cancer by modulating the phosphorylation of PP2Ac and DCK

“…This open-label, single-arm, phase 2 clinical trial was conducted at the Eastern Hepatobiliary Surgery Hospital (EHBH), Shanghai, and enrolled 98 patients with advanced iCCA between 1 October 2017 and 1 June 2021 (cohort 1). Biopsy specimens obtained from each patient were subjected to morphological and pathological examinations, including hematoxylin and eosin and immunohistochemistry (IHC) staining for cytokeratin 19 and PTEN. Patients initially received a GEM plus cisplatin (GP) or GEM plus oxaliplatin (GEMOX) regimen, and the therapeutic efficacy was evaluated every 2 months (fig.…”

“…Although some studies have reported the relationship between PTEN expression and GEM response, the conclusions are inconsistent and even contrary among different cancer types and different laboratories. Some studies indicate that PTEN acts as a tumor suppressor to limit the phosphatidylinositol 3-kinase (PI3K)-AKT pathway; thus, PTEN loss may render cancer cells resistant to GEM by activating the AKT pathway (16)(17)(18)(19)(20). Conversely, other studies indicate that PTEN has no discernible impact on GEM efficacy (21) or that low expression of PTEN is correlated with better responses to GEM-combined therapy (22).…”