Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and invasive cancer, with a median survival of 6 months and a 5-year survival rate of 6%. Although recent advances have been made in the understanding of PDAC development, effective therapies are lacking. At the time of diagnosis, less than 15% of patients qualify for surgery due to the presence of locally advanced disease and micrometastases. Here, we consider an alternative paradigm in which ultrasound therapy (ablation or hyperthermia) of the primary tumor is combined with systemic drug delivery particles and immunotherapy that can effectively treat remaining primary tumor and metastases. We hypothesize that ultrasound therapy of pancreatic cancer, performed in combination with delivery of gemcitabine nanoparticles (squalene-gemcitabine nanoassemblies (Sq-Gem-NAs)) and immunotherapy, can effectively and safely treat pancreatic cancer. We recently demonstrated 50 fold enhancement of delivery of nanoparticles to the ablated margin in tumor models that span epithelial cancer and highly invasive mesenchymal phenotypes. We further demonstrated enhanced survival combining hyperthermia with drug and immunotherapy; we extend the result in preliminary data to show complete regression of systemic cancer. We also demonstrate the synthesis of squalene-gemcitabine conjugates and their self-assembly as nanoparticles. Squalene-gemcitabine conjugation is known to extend the circulation of the intact drug and the conjugate has greater efficacy than free drug in resistant cancers. Further, we have synthesized a positron emission tomography chelator conjugated to squalene to be used to assess the pharmacokinetics and biodistribution of the particles with and without ultrasound therapy. Such particles can be targeted to pancreatic cancer and can be long circulating or temperature sensitive. The combination of an immune adjuvant (CpG) with a checkpoint inhibitor (aPD-1) is incorporated and response shown to be enhanced by ultrasound therapy.
Our specific aims are therefore to: 1) fabricate and characterize Sq-Gem-NAs and Sq- BAT conjugates and evaluate their self-assembly with other lipids, 2) determine the biodistribution of Sq-Gem NAs with and without plectin-1 targeted moieties and ultrasound in both healthy mice and mice with PDAC tumors and 3) compare the therapeutic response of PDAC mice treated with the Sq-Gem-NAs and ultrasound and immunotherapy protocols. Both ablation and hyperthermia ultrasound protocols will be evaluated.

Public Health Relevance

We propose to develop squalene-gemcitabine nanoassemblies (Sq-Gem-NAs) and combine their administration with ultrasound-mediated treatment of pancreatic cancer and immunotherapy. We have demonstrated locally curative and systemically curative protocols for other cancers based on such a combination and will evaluate the potential to eliminate pancreatic tumors with this approach.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA210553-03
Application #
9657580
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Redmond, George O
Project Start
2016-07-01
Project End
2021-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Stanford University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Kakwere, Hamilton; Ingham, Elizabeth S; Allen, Riley et al. (2018) Unimicellar hyperstars as multi-antigen cancer nanovaccines displaying clustered epitopes of immunostimulating peptides. Biomater Sci 6:2850-2858
Tucci, Samantha T; Seo, Jai W; Kakwere, Hamilton et al. (2018) A Scalable Method for Squalenoylation and Assembly of Multifunctional 64Cu-Labeled Squalenoylated Gemcitabine Nanoparticles. Nanotheranostics 2:387-402
Seo, Jai Woong; Tavaré, Richard; Mahakian, Lisa M et al. (2018) CD8+ T-Cell Density Imaging with 64Cu-Labeled Cys-Diabody Informs Immunotherapy Protocols. Clin Cancer Res 24:4976-4987
Ilovitsh, Asaf; Ilovitsh, Tali; Foiret, Josquin et al. (2018) Simultaneous Axial Multifocal Imaging using a Single Acoustical Transmission: a Practical Implementation. IEEE Trans Ultrason Ferroelectr Freq Control :
Chavez, Michael; Silvestrini, Matthew T; Ingham, Elizabeth S et al. (2018) Distinct immune signatures in directly treated and distant tumors result from TLR adjuvants and focal ablation. Theranostics 8:3611-3628
Ilovitsh, Tali; Ilovitsh, Asaf; Foiret, Josquin et al. (2018) Acoustical structured illumination for super-resolution ultrasound imaging. Commun Biol 1:
Ilovitsh, Tali; Ilovitsh, Asaf; Foiret, Josquin et al. (2018) Enhanced microbubble contrast agent oscillation following 250?kHz insonation. Sci Rep 8:16347
Ilovitsh, Tali; Ilovitsh, Asaf; Foiret, Josquin et al. (2018) Imaging beyond ultrasonically-impenetrable objects. Sci Rep 8:5759
Foiret, Josquin; Zhang, Hua; Ilovitsh, Tali et al. (2017) Ultrasound localization microscopy to image and assess microvasculature in a rat kidney. Sci Rep 7:13662
Kakwere, Hamilton; Ingham, Elizabeth S; Allen, Riley et al. (2017) Toward Personalized Peptide-Based Cancer Nanovaccines: A Facile and Versatile Synthetic Approach. Bioconjug Chem 28:2756-2771

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