Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - ImPRESS (Imaging Perfusion Restrictions from Extracellular Solid Stress)

Teaser

For patients with brain tumors, some tumors are soft as jelly, while others are hard as stone. While the traditional diagnosis of these tumor types may be similar or even identical, the way they respond to anti-cancer therapy may be very different.The ImPRESS project will...

Summary

For patients with brain tumors, some tumors are soft as jelly, while others are hard as stone. While the traditional diagnosis of these tumor types may be similar or even identical, the way they respond to anti-cancer therapy may be very different.

The ImPRESS project will deliver new scientific knowledge on how a mechanical force, solid stress, caused by proliferating cancer cells and the extracellular matrix compress fragile blood vessels to the point that they no longer supply the tissue with nutrients and oxygen. This hypoxic microenvironment prevents drug delivery and promotes metastatic growth, which effectively makes tumors difficult to treat. Developing biomarkers that can measure how solid stress impair perfusion and promotes therapy resistance is essential for understanding the disease. ImPRESS will provide novel diagnostic insights into how potential treatment options may alleviate solid stress to revitalize conventional therapy and remove barriers for successful anti-cancer therapy.

The ImPRESS project main objective is to develop a novel imaging paradigm coined Restricted Perfusion Imaging (RPI) to reveal vascular restrictions in solid cancers caused by mechanical solid stress and use RPI to demonstrate that alleviating this force will repair the cancerous microenvironment and improve therapeutic response. While a new therapeutic drug may target a specific pathway with great success, most cancer treatments do not account for other components of the microenvironment that also regulate tumorigenesis. We hypothesize that using Magnetic Resonance Imaging (MRI) to measure how mechanical forces of the tumor microenvironment restrict perfusion and promotes treatment resistance will be critical for patient care. ImPRESS focus on brain cancers, a patient group with dismal prognosis and a cancer type where the proposed studies are expected to have especially appealing effects.

The ImPRESS project will generate imaging data from MRIs of adult patients with brain tumors, prior to, during, and after treatment with traditional cancer therapies with- and without additional drugs that aim to remove the mechanical forces of the tumor microenvironment. This data will include both conventional, anatomical images, as well as functional data on water diffusion, vascular hemodynamics, as well as tissue stiffness and force. This data will be used to derive aggregated measures of anatomical and functional status of the tissue, as well as the radiographic response to therapy and time of disease relapse.

Work performed

In the initial phase of the project we have obtained the necessarily study approvals (including ethics), as well as implemented and evaluated our proposed study imaging protocol at Oslo University Hospital (Oslo, Norway). The study protocol including vascular (perfusion) and mechanical (elastography) MRI is now operational and evaluated in both healthy volunteers and patients with brain tumors. This included comparing the MRI data with tissue samples of the patient taken during image-guided neurosurgery.

Moreover, using the new imaging protocol, we aim to test medications that could reduce the mechanical forces of the cancerous microenvironment. Retrospective meta-analyzes in humans have shown that a particular type of blood pressure medication, called angiotensin receptor blockers, may prolong the time before disease relapse, as well as prolong overall survival in cancer patients. Based on findings from animal studies, we believe this is due to an additional feature of these medicines that reduce the mechanical pressure in the cancerous tumor, improve perfusion and thus enhance the effect of traditional cancer treatment. Because this constitutes an \'off-label\' treatment in humans, we have now obtained all the required approvals to perform this study (clinicaltrials.gov identifier NCT03951142), set to start in the fall of 2019 in accordance with the project plan.

The ImPRESS project has published three peer-review manuscripts to date (please refer ‘Publications’). Of note, a recent paper in Nature Biomedical Engineering demonstrates, for the first time, how solid stress impacts the tissue surrounding brain tumors and contributes to neurological dysfunction. The study presents evidence in both pre-clinical models and patients’ data of increased compression and deformation of brain tissue around nodular tumors – those that continue growing as a single, well-defined mass - but not in infiltrative tumors, which instead invade surrounding tissues. Specifically, analysis of MRI data from 64 patients with brain tumors (glioblastoma) taken prior to any treatment was able to distinguish those with nodular tumors. These patients exhibited significantly worse neurologic function than did those with infiltrative tumors. The MRIs also revealed reduced vascular perfusion in healthy tissue surrounding the tumors of about half the tumors, and patients with reduced vascular perfusion around their tumors had greater neurologic impairment than did those in whom perfusion was unchanged.

The ImPRESS project has also presented data at several international conferences, including the annual meetings of the International Society for Magnetic Resonance in Medicine (ISMRM) and European Society of Neuroradiology (ESNR) in 2019. Finally, a range of non-scientific and non-peer-reviewed publications are presented, as well as relevant activities in social media (please refer ‘Dissemination & Communication Activities’).

Final results

Moving from the current targeted-drug-delivery approach to a make-drugs-reach-their-target approach constitutes a potential game-changer in the way we assess cancer treatment. There are no available diagnostic strategies for how to measure impaired vasculature from solid stress and mechanical forces in human cancers and therefore, the ImPRESS project goes beyond state-of-the-art by introduce a new paradigm for clinical cancer imaging.

Specifically, we have obtained new information on how mechanical forces affect tissues surrounding a brain tumor and potentially impairing neurological function. While the deformation of normal brain tissue by a growing tumor has been associated with greater disability and increased risk of death, the impact of specific patterns of tumor growth is not understood. By identifying characteristics of tumors most likely to impose solid stress, we describe a potential way of distinguishing patients with such tumors. In a pre-clinical model, we present data suggesting that the neuroprotective drug lithium may work as a relevant treatment strategy. Preservation of neurological function and maintaining patients’ quality of life are critical goals of brain tumor treatment. The results of our study support application of neuroprotection to patients with nodular brain tumors that compress surrounding tissues. Based on these promising results, we hypothesize similar effects will be observed by alleviating mechanical forces using angiotensin receptor blockers.

Moreover, based on preliminary data arising from the ImPRESS project, we have recently submitted a disclosure of invention (DOFI) to our hospitals’ technology transfer office (TTO) on the use of artificial intelligence (AI) for analyses of our MRI data. We believe AI presents great possibilities for improved analysis of diagnostic data and we therefore aim to pursue the added value of this innovation.

Website & more info

More info: https://www.ous-research.no/emblem/.