Pancreatic ductal adenocarcinoma (PDA) is an unusually lethal disease with the highest 1-year and 5- year mortality rates of any cancer. An inability to detect the disease early together with multiple mechanisms of intrinsic resistance to chemical and radiotherapies contribute to the extreme lethality of PDA. Compounding the challenge in developing effective targeted therapies against pancreas cancer is the high degree of both numerical (aneuploidy) and structural (non-reciprocal translocations) chromosomal instability. The robust fibroinflammatory response, or desmoplasia, that accompanies and chronicles disease progression presents additional challenges to treating the disease, while also providing novel potential targets and approaches to combating PDA. We have recently characterized a number of critical elements of the desmoplastic reaction in pancreas cancer and the mechanisms by which these components promote and sustain nascent neoplasms. These components include tumor- associated macrophages, stromal fibroblasts and multiple types of immunosuppressive cells that invade and surround precursor ductal lesions from the earliest stages of preinvasive disease;a dense stromal collagen and proteoglycan matrix that appears to suppress angiogenesis and compromise tumor vascularity;and extremely high intratumoral fluid pressures. Thus, the delivery, diffusion and convection of small molecules are all critically limited by the stromal environment and together these various factors conspire to create a sanctuary for pancreas cancer progression. In this proposal, we will investigate first the ability of distinct interventions to disrupt the stromal matrix and improve perfusion in pancreas cancer to enhance the delivery and efficacy of chemotherapeutic agents. We will also test the ability of combining strategies directed against the stromal and epithelial compartments to make a clinically significant impact against this lethal disease.

Public Health Relevance

Pancreas cancer kills every patient it afflicts and is now the fourth leading cause of cancer-related deaths in this country with a rising incidence and unabated mortality. We have developed genetically engineered animal models of pancreas cancer that have exposed unique points of vulnerability for the development of new treatments. We propose a systematic program of investigation to target the fibrotic stromal reaction in pancreas cancer as the basis for new treatment strategies against this highly resistant disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA161112-04
Application #
8699699
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2011-09-22
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98109
DuFort, Christopher C; DelGiorno, Kathleen E; Carlson, Markus A et al. (2016) Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase. Biophys J 110:2106-19
DuFort, Christopher C; DelGiorno, Kathleen E; Hingorani, Sunil R (2016) Mounting Pressure in the Microenvironment: Fluids, Solids, and Cells in Pancreatic Ductal Adenocarcinoma. Gastroenterology 150:1545-1557.e2
Stromnes, Ingunn M; Schmitt, Thomas M; Hulbert, Ayaka et al. (2015) T Cells Engineered against a Native Antigen Can Surmount Immunologic and Physical Barriers to Treat Pancreatic Ductal Adenocarcinoma. Cancer Cell 28:638-52
Whittle, Martin C; Izeradjene, Kamel; Rani, P Geetha et al. (2015) RUNX3 Controls a Metastatic Switch in Pancreatic Ductal Adenocarcinoma. Cell 161:1345-60
Whittle, Martin C; Hingorani, Sunil R (2015) Disconnect between EMT and metastasis in pancreas cancer. Oncotarget 6:30445-6
Hingorani, Sunil R (2015) Intercepting Cancer Communiques: Exosomes as Heralds of Malignancy. Cancer Cell 28:151-3
Stromnes, Ingunn M; Greenberg, Philip D; Hingorani, Sunil R (2014) Molecular pathways: myeloid complicity in cancer. Clin Cancer Res 20:5157-70
Stromnes, Ingunn M; Brockenbrough, J Scott; Izeradjene, Kamel et al. (2014) Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut 63:1769-81
Stromnes, Ingunn M; DelGiorno, Kathleen E; Greenberg, Philip D et al. (2014) Stromal reengineering to treat pancreas cancer. Carcinogenesis 35:1451-60
DelGiorno, Kathleen E; Carlson, Markus A; Osgood, Ryan et al. (2014) Response to Chauhan et Al.: interstitial pressure and vascular collapse in pancreas cancer-fluids and solids, measurement and meaning. Cancer Cell 26:16-7

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