Pancreatic cancer is now the 4th leading cause of cancer death in the United States. Despite some recent advances in systemic therapy, survival remains dismal in large part due to the aggressive nature of this disease and its propensity for early metastasis. Thus, there is a critical need to define new therapeutic targets that can more effectively block tumor growth and spread. To define new ways to approach cancer therapy we have focused on stem cell signals that are hijacked to drive cancer initiation, propagation, and recurrence. Using this approach we previously identified the stem cell fate determinant Musashi (Msi) as critically required for progression of hematologic malignancies. Importantly, we have recently found that Msi is highly expressed in pancreatic cancer cells in both mouse models of the disease and in primary patient samples. Further, our preliminary studies indicate that Msi inhibition functionally blocks the growth of pancreatic cancer cell lines as well as patient samples in vitro and in xenografts. These data have led us to hypothesize that pancreatic cancer growth and propagation is critically dependent on Msi. We will test this by determining 1) whether Msi expression marks cancer stem cells, cells with preferential capacity for pancreatic cancer cell propagation, 2) whether Msi is necessary for propagation of pancreatic cancer in genetically engineered mouse models, and 3) whether Msi is necessary for human pancreatic cancer propagation in primary patient-derived xenografts. These studies will help define whether Msi is a key regulator of pancreatic cancer and if it may be an effective target for therapy.

Public Health Relevance

Pancreatic cancer is now the 4th leading cause of cancer death in the United States; despite some recent advances in systemic therapy, survival remains dismal in large part due to the aggressive nature of this disease and its propensity for early metastasis. Our preliminary studies suggest that the regulatory factor Musashi is required for pancreatic cancer growth and propagation. The studies proposed in this application are critical to defining the role of Msi in pancreatic cancer, and whether it may serve as a therapeutic target to contain, impair, or resolve pancreatic tumor growth.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA186043-03
Application #
9210060
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
2015-02-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$341,565
Indirect Cost
$121,200
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Fox, Raymond G; Lytle, Nikki K; Jaquish, Dawn V et al. (2016) Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma. Nature 534:407-11
Kwon, Hyog Young; Bajaj, Jeevisha; Ito, Takahiro et al. (2015) Tetraspanin 3 Is Required for the Development and Propagation of Acute Myelogenous Leukemia. Cell Stem Cell 17:152-64