Pancreas cancer is the fourth leading cause of cancer mortality in the United States, with very few effective therapeutic options. The median survival rate for resectable tumors is only 2 years, and systemic chemotherapy with gemcitabine only offers a modest survival benefit. The main characteristic of pancreas tumors that makes chemotherapy treatment difficult is the extensive stromal desmoplasia, which decreases blood perfusion, increases the intratumoral pressure and impedes the delivery of chemotherapy. Disrupting the stromal barrier would both increase perfusion and permeabilize the tumor, enhancing penetration of chemotherapy. In our initial grant period we successfully demonstrated that mechanical disruption of the stroma using pulsed high intensity focused ultrasound (pHIFU)-induced cavitation resulted in enhanced penetration of doxorubicin by up to 4.5-fold. These results were obtained in an in vivo genetically engineered mouse model (KPC mouse) of pancreatic ductal adenocarcinoma, using an optimized ultrasound-guided pHIFU small animal treatment system. The KPC model, unlike xenograft or subcutaneous models, closely recapitulates the genetic mutations, clinical symptoms and histopathology found in human pancreatic cancer. These results are readily translatable to patient treatment. In this renewal application we propose to evaluate the tumor response and survival of KPC mice treated with pHIFU and systemic administration of gemcitabine. We will then develop a new ultrasound-guided pHIFU clinical system that incorporates Bubble Doppler imaging algorithms to enable monitoring of pHIFU therapy. The system will be designed, fabricated and characterized following FDA guidelines. The main paradigm shift compared to the small animal studies is the design of ultrasound transducers that produce less focused, lower frequency (sub-MHz) HIFU beams that affect larger tissue areas and may have a different physical mechanism of cavitation nucleation compared to high- frequency, highly focused transducers used previously. We hypothesize that this change will: 1) shorten treatment duration; 2) provide deeper penetration depth; 3) allow the use of lower pHIFU pressure amplitudes and therefore improve safety. The other major innovation of this proposal is the further development of a unique cavitation mapping technique, discovered by our group during the initial grant period and termed Bubble Doppler, which enables ultrasound-based monitoring of pHIFU therapy in real-time. We will complete preclinical evaluation of the feasibility and safety of pHIFU treatments using Bubble Doppler monitoring in porcine pancreas in a series of acute and short term survival studies. In parallel, a clinical trial using this therapy device will be designed. All relevant reports will be compiled to apply for an investigational device exemption (IDE) to US FDA to conduct a clinical trial in patients with pancreatic cancer.

Public Health Relevance

Pancreas cancer is expected to become the second deadliest cancer in the United States by 2020. Current standard of care only offers a modest survival benefit due to extensive fibrous matrix, which impedes chemotherapy delivery. The proposed work will benefit public health by bringing to clinical translation the promising new technology of ultrasound-guided pulsed HIFU for enhancing the penetration of chemotherapeutic drugs into pancreatic tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA154451-07
Application #
10135659
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tandon, Pushpa
Project Start
2020-04-01
Project End
2022-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Farr, Navid; Wang, Yak-Nam; D'Andrea, Samantha et al. (2018) Hyperthermia-enhanced targeted drug delivery using magnetic resonance-guided focussed ultrasound: a pre-clinical study in a genetic model of pancreatic cancer. Int J Hyperthermia 34:284-291
Farr, Navid; Wang, Yak-Nam; D'Andrea, Samantha et al. (2017) Noninvasive characterization of pancreatic tumor mouse models using magnetic resonance imaging. Cancer Med 6:1082-1090
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Zhou, Yufeng; Wang, Yak-Nam; Farr, Navid et al. (2016) Enhancement of Small Molecule Delivery by Pulsed High-Intensity Focused Ultrasound: A Parameter Exploration. Ultrasound Med Biol 42:956-63
Li, Tong; Wang, Yak-Nam; Khokhlova, Tatiana D et al. (2015) Pulsed High-Intensity Focused Ultrasound Enhances Delivery of Doxorubicin in a Preclinical Model of Pancreatic Cancer. Cancer Res 75:3738-46
Li, Tong; Khokhlova, Tatiana; Maloney, Ezekiel et al. (2015) Endoscopic high-intensity focused US: technical aspects and studies in an in vivo porcine model (with video). Gastrointest Endosc 81:1243-50
Li, Tong; Chen, Hong; Khokhlova, Tatiana et al. (2014) Passive cavitation detection during pulsed HIFU exposures of ex vivo tissues and in vivo mouse pancreatic tumors. Ultrasound Med Biol 40:1523-34
Li, Tong; Khokhlova, Tatiana D; Sapozhnikov, Oleg A et al. (2014) A new active cavitation mapping technique for pulsed HIFU applications--bubble Doppler. IEEE Trans Ultrason Ferroelectr Freq Control 61:1698-708
Khokhlova, Tatiana; Li, Tong; Sapozhnikov, Oleg et al. (2013) The use of twinkling artifact of Doppler imaging to monitor cavitation in tissue during high intensity focused ultrasound therapy. Proc Meet Acoust 19:

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