Inhibition of pleiotrophin to combat pancreatic cancer metastasis

Project Summary
Pancreatic ductal adenocarcinoma (PDA) is projected to become the second leading cause of
cancer-related deaths in the United States by the year 2030 unless significant progress is made
on improving therapy for this disease. The current 5-year survival rate is ~12%, showing a
modest increase over the last 30 years. Although chemotherapy response rates are improving,
these systemic therapies only provide minimal survival advantage. In addition, PDA is largely
resistant to immunotherapy. Metastasis, a common event in PDA patients, limits the utility of
surgical resection, the most effective therapeutic strategy for PDA. Understanding factors that
contribute PDA progression and metastasis has the potential to reveal novel therapeutic targets.
Recently, we have shown that an embryonic neurotrophic factor, Pleiotrophin (PTN), marks
successful lung metastases in mouse pre-clinical breast cancer models. Consequently, blocking
PTN, pharmacologically or genetically, reduces metastasis and sensitizes metastatic breast
cancer to checkpoint blockade and chemotherapy. The current proposal seeks to determine
whether PTN inhibition is therapeutically efficacious in preclinical models of PDA. PTN is
expressed in PDA and is associated with disease progression. However, there have only been
limited efforts to perturb PTN function in models of PDA. We have the tools to address the
therapeutic utility of targeting PTN in robust models of PDA. This proposal is directly responsive
to PAR-22-2216 which calls for applications focused on novel strategies to enhance the
effectiveness of chemotherapy and or immune therapy. Success in completing the aims of the
project will nominate PTN as a new potential target for the treatment of PDA.

Grant Number: 1R21CA286348-01A1
NIH Institute/Center: NIH
Principal Investigator: Rolf Brekken