Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and invasive cancer, with a mediansurvival of 6 months and a 5-year survival rate of 6%. Although recent advances have beenmade in the understanding of PDAC development, effective therapies are lacking. At the time ofdiagnosis, less than 15% of patients qualify for surgery due to the presence of locally advanceddisease and micrometastases. Here, we consider an alternative paradigm in which ultrasoundtherapy (ablation or hyperthermia) of the primary tumor is combined with systemic drug deliveryparticles and immunotherapy that can effectively treat remaining primary tumor and metastases.We hypothesize that ultrasound therapy of pancreatic cancer, performed in combination withdelivery of gemcitabine nanoparticles (squalene-gemcitabine nanoassemblies (Sq-Gem-NAs))and immunotherapy, can effectively and safely treat pancreatic cancer. We recentlydemonstrated 50 fold enhancement of delivery of nanoparticles to the ablated margin in tumormodels that span epithelial cancer and highly invasive mesenchymal phenotypes. We furtherdemonstrated enhanced survival combining hyperthermia with drug and immunotherapy; weextend the result in preliminary data to show complete regression of systemic cancer. We alsodemonstrate the synthesis of squalene-gemcitabine conjugates and their self-assembly asnanoparticles. Squalene-gemcitabine conjugation is known to extend the circulation of theintact 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 beused to assess the pharmacokinetics and biodistribution of the particles with and withoutultrasound therapy. Such particles can be targeted to pancreatic cancer and can be longcirculating or temperature sensitive. The combination of an immune adjuvant (CpG) with acheckpoint inhibitor (aPD-1) is incorporated and response shown to be enhanced by ultrasoundtherapy. 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 thebiodistribution of Sq-Gem NAs with and without plectin-1 targeted moieties and ultrasound inboth healthy mice and mice with PDAC tumors and 3) compare the therapeutic response ofPDAC mice treated with the Sq-Gem-NAs and ultrasound and immunotherapy protocols. Bothablation and hyperthermia ultrasound protocols will be evaluated.
|Effective start/end date||7/1/16 → 6/30/21|
- National Institutes of Health: $636,467.00