KUGEL LAB -- Kugel Lab

WELCOME TO THE KUGEL LAB

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is one of the most lethal of all human malignancies, responsible for hundreds of thousands of deaths annually. Combination chemotherapy remains the standard of care for patients with PDAC, which continues to carry a prognosis of less than one year. Thus, there is an urgent need to improve our understanding of PDAC pathogenesis and to leverage that understanding toward better therapeutic options.

Our current model proposes that the acquisition of a series of genetic alterations results in a stepwise progression through increasingly dysplastic precursor lesions, or pancreatic intraepithelial neoplasias (PanINs), toward invasive and finally metastatic PDAC. Initiating events identified in early PanIN lesions (PanIN I) include mutations and/or amplification in the KRAS oncogene, present in >90% of PDAC/PanINs, followed by inactivation of TP53 in higher grade lesions (PanIN III). However, this fundamental model of PDAC pathogenesis, which is recapitulated in genetically engineered mouse models (GEMMs), has failed to identify either critical pathways that may be effectively targeted in the clinic or relevant molecular subsets for improved prognosis and stratification of patients toward a more effective therapy. In preliminary studies, we have discovered and characterized a major new subset of PDAC, driven by expression of the loss of the NAD+-dependent histone deacetylase SIRT6 and reciprocal upregulation of the oncofetal RNA-binding protein LIN28B (Kugel, et al. Cell 2016). Based on this important finding, our laboratory aims to use our diverse panel of pancreatic cancer model systems to elucidate the molecular underpinnings that control tumor initiation, progression and metastasis and identify innovative therapeutic strategies to combat this new subset of PDAC.

Specifically, our laboratory will focus on two major areas:

  1. Epigenetic Reprogramming of Pancreatic Cancer
  2. Developmental Pathways in Pancreatic Cancer