Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer-related mortality, with a five year survival less than 5%. The overwhelming majority of patients succumb to metastatic disease or tumor recurrence following apparently curative resection. Current treatment efforts in PDAC are focused almost entirely on reduction in "bulk" tumor size, rather than elimination of cells with tumor initiating and metastatic abilities. Research performed in our laboratory over the last funding cycle has identified a putative cancer stem cell (CSC) compartment in PDAC, delineated by high levels of expression of the enzyme aldehyde dehydrogenase. This minor subpopulation of ALDH "bright" cells is capable of self-renewal and tumor initiation, and is observed in elevated numbers in PDAC metastases. The ALDH "bright" cells are exquisitely dependent upon sustained Hedgehog (Hh) and Notch signals for their viability. Preferential elimination of the ALDH "bright" cells with small molecule Hh antagonists blocks systemic metastases and increases survival in PDAC preclinical models;conversely, gemcitabine enhances the relative proportion of ALDH "bright" cells, underscoring the pitfall of conventional anti-metabolite therapy. The current proposal will build upon these themes, by developing therapies that target the cellular compartment responsible for disease progression.
In Aim 1, we propose the first Phase II clinical trial of an orally bioavailable Hh antagonist in combination with gemcitabine in patients with advanced PDAC, with the primary objective of improving overall survival.
In Aim 2, we will study the emerging contribution Hh-dependent stromal responses to PDAC disease initiation and progression, including stromal interactions with the epithelial CSC compartment, using a newly developed conditional mouse model of Hh ligand misexpression.
In Aim 3, we will initiate a comprehensive preclinical trial with an orally bioavailable inhibitor of Notch signaling in spontaneously metastatic orthotopic xenograft model of PDAC, as a prelude to future clinical application. We anticipate that developing parallel and complementary therapeutic approaches against two critical developmental signaling pathways that sustain CSC viability in PDAC provides an unprecedented opportunity for ameliorating the dismal prognosis of this malignancy.
Pancreatic cancer is the fourth most common cause of death in the United States. The long-term objective of this proposal is to improve the dismal prognosis of pancreatic cancer by developing therapies that target metastatic disease and tumor recurrence, the two most important clinical parameters that determine survival. In order to address this objective, this proposal will conduct the first clinical trial of Hedgehog (Hh) antagonists in patients with advanced pancreatic cancer, explore the role of Hh-dependent epithelial stromal interactions in a new mouse model, and begin preclinical trials with a novel pharmacological inhibitor of the Notch pathway in preclinical models of pancreatic cancer.
|Takano, Shigetsugu; Reichert, Maximilian; Bakir, Basil et al. (2016) Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization. Genes Dev 30:233-47|
|San Lucas, F A; Allenson, K; Bernard, V et al. (2016) Minimally invasive genomic and transcriptomic profiling of visceral cancers by next-generation sequencing of circulating exosomes. Ann Oncol 27:635-41|
|Rajeshkumar, N V; Dutta, Prasanta; Yabuuchi, Shinichi et al. (2015) Therapeutic Targeting of the Warburg Effect in Pancreatic Cancer Relies on an Absence of p53 Function. Cancer Res 75:3355-64|
|Hu, Chaoxin; Dadon, Tikva; Chenna, Venugopal et al. (2015) Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models. Mol Cancer Ther 14:1532-9|
|Agarwal, Jasmin R; Wang, Qiuju; Tanno, Toshihiko et al. (2014) Activation of liver X receptors inhibits hedgehog signaling, clonogenic growth, and self-renewal in multiple myeloma. Mol Cancer Ther 13:1873-81|
|Streppel, M M; Lata, S; DelaBastide, M et al. (2014) Next-generation sequencing of endoscopic biopsies identifies ARID1A as a tumor-suppressor gene in Barrett's esophagus. Oncogene 33:347-57|
|Cowan, Robert W; Maitra, Anirban (2014) Genetic progression of pancreatic cancer. Cancer J 20:80-4|
|Nimmagadda, Sridhar; Pullambhatla, Mrudula; Lisok, Ala et al. (2014) Imaging Axl expression in pancreatic and prostate cancer xenografts. Biochem Biophys Res Commun 443:635-40|
|Streppel, Mirte Mayke; Pai, Shweta; Campbell, Nathaniel R et al. (2013) MicroRNA 223 is upregulated in the multistep progression of Barrett's esophagus and modulates sensitivity to chemotherapy by targeting PARP1. Clin Cancer Res 19:4067-78|
|Yabuuchi, Shinichi; Pai, Shweta G; Campbell, Nathaniel R et al. (2013) Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer. Cancer Lett 335:41-51|
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