This project is focused on developing an innovative treatment modality for pancreatic cancer, which is one of the most lethal human malignancies. This treatment modality consists of two components: an innovative drug with enhanced efficacy, and imaging techniques that can non-invasively monitor treatment responses to assist physicians adjusting the therapeutic plan accordingly. We will evaluate the efficacy of the agent and the sensitivity of the imaging methods in multiple primary tumor models in mice. It has been recognized that a pancreatic tumor contains not only malignant cells but also supporting cells and connective tissues, which are referred to as stroma collectively. Stroma is known to promote cancer progression and spread, and has been identified as a therapeutic target to enhance pancreatic cancer therapy. Unfortunately, the progress of developing a stroma-targeted drug has been limited, and almost all of the testing drugs have failed in early human trials. The recent encouraging data with Abraxane (a taxane drug with an improved formulation) in human patients suggest that taxanes can be an effective stromal depleting agent to enhance pancreatic cancer treatment if the drug delivery efficiency is improved. We have thus created an innovative formulation for docetaxel (named Cellax), which selectively accumulate in tumors for sustained drug release and prolonged efficacy. In a mouse pancreatic tumor model, Cellax depleted most of the stroma and eventually eliminated the pancreatic tumors. We plan to further evaluate Cellax in 5 human primary tumor models that better represent the human disease, and also to investigate if the existing MRI techniques can monitor therapeutic response after Cellax therapy. 1. Evaluate Cellax in 5 primary models of pancreatic cancer. We will compare the efficacy of Cellax for inhibiting stroma and tumor growth compared to native docetaxel and Abraxane. The toxicity of these drugs will also be compared. We will also compare these treatments for their intratumoral drug delivery and effects on tumor cells and stromal cells separately to determine their mode-of-action and whether Cellax exhibits improved antitumor efficacy via enhanced anti-stromal activity. 2. Investigate if MRI techniques can monitor therapeutic response of Cellax. We will investigate if existing MRI techniques (magnetization transfer MRI and dynamic contrast enhanced MRI) can sensitively monitor tumor stromal depletion and tumor vascularity changes after Cellax therapy in 2 selected primary models of pancreatic cancer. If successful, these immediately translatable MR techniques will enable clinical monitoring of the response of stromal depletion therapy and timely adjustment of the treatment plan. The overall goal is to create an enhanced treatment modality to improve pancreatic cancer care.

Public Health Relevance

Pancreatic cancer remains one of the most deadly forms of malignancy, and the current standard of care only provides palliation or marginally improves survival. This project is aimed at developing a paired treatment modality composed of an innovative therapeutic agent and an imaging technology for non-invasive therapeutic monitoring to enhance pancreatic cancer care.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA176339-02
Application #
8692699
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Alley, Michael C
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ontario Institute for Cancer Research
Department
Type
DUNS #
City
Toronto
State
ON
Country
Canada
Zip Code
M5 0A3
Roy, Aniruddha; Bhattacharyya, Mousumi; Ernsting, Mark J et al. (2014) Recent progress in the development of polysaccharide conjugates of docetaxel and paclitaxel. Wiley Interdiscip Rev Nanomed Nanobiotechnol 6:349-68
Roy, Aniruddha; Murakami, Mami; Ernsting, Mark J et al. (2014) Carboxymethylcellulose-based and docetaxel-loaded nanoparticles circumvent P-glycoprotein-mediated multidrug resistance. Mol Pharm 11:2592-9
Hoang, Bryan; Ernsting, Mark J; Murakami, Mami et al. (2014) Docetaxel-carboxymethylcellulose nanoparticles display enhanced anti-tumor activity in murine models of castration-resistant prostate cancer. Int J Pharm 471:224-33