Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a dismal therapeutic outcome. This interdisciplinary study aims to develop a new Positron Emission Tomography (PET) assay for patient stratification, which could lead to more efficacious and better tolerated personalized therapies for PDAC. Therapeutic responses to gemcitabine (GEM), the most frequently used chemotherapeutic agent in PDAC, are observed in less than 10% of patients. Amongst proposed reasons for GEM's suboptimal efficacy in PDAC two suggested mechanisms have emerged as leading candidates: (i) suboptimal drug delivery to PDAC tumor cells because of a poorly vascularized and dense tumor-associated stroma and (ii) inefficient uptake and/or conversion of the prodrug GEM to its active, cytotoxic metabolites by the PDAC tumor cells. In support of the former mechanism, new stromal depleting (SD) therapies, such as Abraxane and pegylated hyaluronidase improve GEM delivery to tumor cells, extending survival in preclinical models, and, in the case of Abraxane, in patients. GEM could be used more effectively for PDAC therapy if companion diagnostics are developed to measure if the addition of a SD agent enhances intratumoral GEM delivery and its conversion to therapeutically active metabolites in tumor cells. This proposal will test the hypothesis that a new GEM analog PET probe 1-L-(2-Deoxy-2,-18Fluoro-Arabinofuranosyl) Cytosine (18F-L-FAC) developed by UCLA investigators can be used to determine (1) the shortest schedule of SD agents required to increase GEM delivery to tumor cells, and (2) the efficiency both of intratumoral GEM accumulation and activation by tumor cells in PDAC patients.
In Aim 1, PET will be used to determine, in preclinical models, the shortest schedule of stromal depleting therapy required to induce detectable changes in tumor probe (18F-L-FAC) and drug (GEM) delivery.
Aim 2 proposes study to determine the accuracy of 18F-L-FAC PET measures of intra-tumoral GEM delivery and metabolism in PDAC patients treated with SD therapies. The expected outcome is a new PET assay to identify PDAC patients who are likely responders to GEM administered in combination with SD therapies. This assay will address a currently unmet clinical need in pancreatic cancer management since alternatives to GEM/Abraxane, albeit considerably more toxic for patients, are now available.

Public Health Relevance

Oncologists now face the challenging decision of how to best treat pancreatic cancer given the recent FDA approval of the gemcitabine/Abraxane combination and the emergence of new chemotherapeutic regimens. To address this unmet clinical need and enable a more personalized approach to pancreatic cancer treatment, we will develop a new non-invasive companion biomarker to gemcitabine/Abraxane which will allow the identification of patients who are likely responders to this combination at the beginning of their therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA187678-01
Application #
8750786
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Farahani, Keyvan
Project Start
2014-08-18
Project End
2019-07-31
Budget Start
2014-08-18
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$518,617
Indirect Cost
$181,853
Name
University of California Los Angeles
Department
Pharmacology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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