Joe Durand

Research Mentor:

Dr. Albert Baldwin

Clinical Co-mentor:

Dr. William Kim, MD

Home Department Genetics
Project Description

Pancreatic ductal adenocarcinoma has one of the highest mortality rates of any cancer. The lack of early detection, the high metastatic potential, and the resistance to chemotherapy all contribute to poor prognosis. The K-ras gene is mutated in approximately 70-90 percent of pancreatic cancers, more than any other solid neoplasm. Mutant K-ras is also strongly linked with the development and progression of other cancers, including adenocarcinomas of the lung and colon (Bos et al., 1990). Unfortunately, therapies directly targeting oncogenic Ras in vivo remain unsuccessful (Saxena et al., 2008); therefore, a better understanding of Ras biology and its downstream oncogenic effectors is fundamental in discovering new and more efficient therapies.

In the majority of K-ras-driven tumors, the NF-kB transcription factor is constitutively active, and contributes to cell survival and chemoresistance. Our lab has shown that knocking out the p65/RelA canonical NF-kB subunit in a mouse lung tumor model significantly reduced tumor development and grade (Basseres et al., 2010). Another study showed that the IKK-related kinase TBK1, involved in a non-canonical NF-kB pathway, was selectively essential in cells that expressed mutant/oncogenic K-ras (Barbie et al., 2009). GSK-3 (glycogen synthase kinase-3) is required for cell survival in pancreatic cancer cells expressing K-Ras (Ougolkov et al., 2005), and seems to regulate NF-kB activation through each of the distinct pathways (canonical and non-canonical) in pancreatic cancer cells (Bang and Cogswell, unpublished).

Previous studies achieved significant, but not complete, growth/survival inhibition when individual components of the IKK/NF-kB signaling pathway were inhibited. Therefore, we hypothesize that Ras-driven cancer is characterized by the activation of multiple, distinct NF-kB pathways and that simultaneous inhibition of both the canonical and non-canonical NF-kB pathways will be a more efficient method to decrease tumor growth and selectively induce death of cells expressing oncogenic K-ras. Because of the critical function of NF-kB signaling in Ras-mediated oncogenesis, it is imperative that we gain a better understanding of this pathway. Further investigation will undoubtedly lead to the development of more efficient NF-kB inhibitory drugs for future use as targeted therapies for the treatment of patients with defined mutations in K-ras.