SoNoCT

Research and Innovation Foundation, HORIZON EUROPE – 2nd OPPORTUNITY, OPPTY-ERC/1122/0001, Title: “Combining Normalization and Sonopermeation strategies to re-engineer tumor mechanics in Pancreatic Cancer”, €100.000,  May 2023-April 2024, Acronym: SoNoCT

Project details

Fellow: Fotios Mpekris

Principal Investigator: Fotios Mpekris/ Triantafyllos Stylianopoulos

Project ID: OPPTY-ERC/1122/0001

Total Funding: €100,000

Call for proposal: HORIZON EUROPE – 2nd OPPORTUNITY

Funding scheme: THE RESEARCH AND INNOVATION FOUNDATION PROGRAMMES FOR RESEARCH, TECHNOLOGICAL DEVELOPMENT AND INNOVATION “RESTART 2016 – 2020”

Coordinated in: Cyprus (University of Cyprus)

From May 2023 – April 2024

Overview of the project

Inefficient delivery of cellular and molecular medicines to solid tumors can reduce dramatically the efficacy of treatment and thus, affect negatively the quality of life and survival of cancer patients. This can explain in large part why standard therapies many times fail to treat specific cancer types, even though these therapies are potent enough to eradicate cancer cells in an in vitro system. In highly desmoplastic cancers, such as types of pancreatic cancer, interactions among cancer cells, stromal cells, and the fibrotic extracellular matrix (i.e., excess deposition of collagen and hyaluronan) result in the accumulation of intratumoral mechanical forces that are exerted on tumor blood vessels, causing vessel compression. Indeed, in pancreatic ductal adenocarcinomas an estimated 80% of tumor blood vessels are compressed or totally collapsed leading to reduced tumor blood flow and drug delivery, and rendering tumors hypo-perfused and hypoxic. Impaired blood supply and hypoxia help cancer cells evade the immune system and increase their invasive and metastatic potential. Particularly, hypo-perfusion can reduce the number of immune cells that infiltrate into the tumor, while hypoxia renders tumor microenvironment (TME) immunosuppressive and attenuates the killing potential of effector immune cells. Furthermore, in pancreatic cancers the vessels are considered to be moderately permeable, which along with hypo-perfusion could explain the failure of most nanomedicine and immunotherapies to treat pancreatic tumors in the clinic.

Normalization of the TME is a therapeutic strategy to restore these abnormalities of the TME in order to improve perfusion, oxygenation and delivery of medicines. It is based on the use of low dose of approved drugs with anti-fibrotic properties (e.g., TGFβ inhibitors) to alleviate mechanical forces and decompress tumor vessels. The successful clinical translation of this strategy with the use of the common anti-hypertensive drug losartan as a TME normalization agent to improve therapeutic outcomes in locally advanced pancreatic cancer patients highlights the promise of this new therapeutic strategy. However, preclinical data suggest that losartan and other normalization agents that we have tested have failed to fully restore blood vessel functionality and blood flow in almost half of the vessels remains compromised. Ultrasound-mediated drug delivery with microbubbles (MBs) is another strategy that could noninvasively enhance perfusion and thus, the transport of therapeutic agents to targeted tumors via sonopermeation. Sonopermeation aims to form transient pores in cell membranes and open the intercellular junctions of the endothelial cells that form the vessels. As MBs flow in the tumor vasculature, the interaction of ultrasound waves with MBs may cause bubbles' oscillation increasing locally tumor vessel’s permeability facilitating a better transport for medicines in tumor tissues and allowing for selective and effective uptake by cancer cells. It is clear, however, that in highly desmoplastic tumors with abundant collapsed vessels, MBs will not be able to effectively and uniformly delivered to the tumor leading to failure or compromised efficacy of this therapeutic strategy. 

Our hypothesis is that for optimal treatment efficacy in pancreatic tumors that have compressed vessels, the two strategies have to be combined so that TME normalization (ketotifen) will decompress the vessels and sonopermeation will make endothelial cells more permeable leading overall to increased drug delivery.

To test our hypothesis, we propose to carry out in vivo studies in orthotopic pancreatic tumor models and employ 1) ketotifen as TME normalization agent and 2) sonopermeation to further improve tumor perfusion.

Research Objectives

Research Objective 1: Test the ability of ketotifen with sonopermeation to normalize tumor microenvironment and improve drug delivery.