FORCE - Functional imaging Of vascular Restrictions in CancEr

For patients with brain tumors, some tumors are soft as jelly, while others are almost as hard as stone. While the traditional diagnosis and treatment plan of these tumor types is similar or even identical, the way they respond to anti-cancer therapy may be very different. Since only about half the cancer patients who receive a typical anti-cancer drug benefit and the others mostly suffer the side effects, knowing whether a patient's tumor is responding to a drug can bring us one step closer to truly personalized medicine – and tailoring therapies to the patients who will benefit and not waste precious time on treatments that will be ineffective. The FORCE project has delivered new scientific knowledge on how a mechanical force, solid stress, caused by proliferating cancer cells and the extracellular matrix compress or remodulate 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 hard to treat. The FORCE project main objective was to develop a novel imaging paradigm to reveal vascular restrictions in solid brain cancers caused by mechanical solid stress and use imaging to demonstrate that alleviating this force in patients with cancer will repair the cancerous microenvironment and improve therapeutic response. In the initial phase of FORCE, we obtained all required study approvals (including ethics) and implemented and evaluated our imaging protocol including vascular (perfusion) and mechanical (elastography) MRI at Oslo University Hospital (OUS), Oslo, Norway. The protocol is now operational and evaluated in both healthy volunteers and patients with brain tumors. A key result is a novel analysis method for quantification of tumor-induced tissue deformations from structural MRI by estimating so-called tissue displacement maps. The process of tumor recurrence involves changes in the tissue microenvironment weeks or even months before they are observed on conventional MRIs. Our MR elastography (MRE) setup has been used to quantify the hypothesized inverse relationship between MRE-based tissue stiffness and perfusion in brain. For patients with glioblastoma, this work also included a comparison of the MRI data with tissue samples of the patients taken during image-guided neurosurgery. By performing full molecular characterization (total RNA sequencing, mass spectroscopy for proteomics and lipidomics, and nuclear MR of polar metabolites), FORCE has identified the genetic mechanisms that govern tissue stiffness within glioblastoma and confirmed that this genetic signature has a significant impact on survival by use of an independent dataset. As a second phase of FORCE, we initiated a clinical trial (EudraCT Number: 2018-003229-27, clinicaltrials.gov NCT03951142) in the fall of 2019 to test whether losartan, an angiotensin receptor II blocker, could reduce the mechanical forces of the cancerous microenvironment. We designed an open-label, blinded assessor, single center, multi-dose, individual-randomized stepped-wedge trial on losartan with three indications in patients with brain cancers (‘ImPRESS – FORCE’). For most of the FORCE project period, the world-wide outbreak of COVID-19 continued to play a major factor for delay in the recruitment and maintenance of most clinical trials, including ours. Following this unavoidable delay, the clinical trial for the main treatment arm (patients with newly diagnosed glioblastoma) is in the final recruitment phase and estimated to meet the target study population in late 2022 or early 2023. To date, the FORCE participants has published over thirty peer-review manuscripts in relationship with the project, as well as four book chapters and two PhD thesis are now submitted for public defence. Of note, a 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 ‘pushing’ tumors, but not in infiltrative tumors. Finally, per project deliverables, the FORCE team hosted (as local organiser) an international session on mechanical imaging during the annual meeting of the European Society for NeuroRadiology (ESNR) in Oslo in the fall of 2019. Results of the FORCE project have also presented data at several international conferences throughout the project period, including the annual meetings of the International Society for Magnetic Resonance in Medicine (ISMRM) and the American Society of Neuroradiology (ASNR). A range of non-scientific and non-peer-reviewed publications are presented, as well as relevant activities in social media.

FORCE-prosjektet har bidratt til å endre tankesettet for hvordan pasienter med hjernekreft diagnostiseres og behandles på Oslo Universitetssykehus (OUS). Bildemetodene vi har utviklet i prosjektet gjør at vi i dag kan måle mekaniske krefter i- og omkring svulsten med magnetisk resonans (MR). Dette har ikke vært mulig tidligere. Effekten av denne innføringen er at behandlende lege kan bedre forstå hvordan svulsten vokser i hjernen, samt å forberede kirurgen på hva som venter under en operasjon. Her kan MR-bildene blant annet gi informasjon om hvordan svulsten påvirker omkringliggende hjernevev, hvilket kan ha stor betydning for hvor vanskelig og tidkrevende en operasjon vil være. Evnen til å måle mekaniske kreften med MR-bilder gjør også at vi kan måle hvordan pasienter responderer på medikamentell behandling som har som mål å redusere slike forhøyede og uønskede mekaniske krefter. Videre har FORCE-studien ført til oppstart av en annen klinisk avbildningsstudie på OUS ('IMAGINE', 2020-2024) hvor vi bruker positron emission tomography (PET) og et radioaktivt preparat ‘prostata spesifikt membran-antigen (PSMA). Selv om navnet tilsier annet, så virker PSMA også for hjernekreft, hvor preparatet tas opp i kreftsvulsten der hvor det er nydannelse av blodårer (såkalt angiogenese). Samspillet mellom angiogenese og mekaniske krefter i en hjernesvulst er svært sammensatt, og kombinasjonen av PET og MR gjør oss derfor i stand til å få helt ny viten om kreftsvulsten funksjon – og hvordan dette påvirker behandlingsrespons. En annen gevinst basert på resultater fra FORCE er en nylig innsendt patentsøknad (Januar 2022) hvor vi bruker avansert bildeanalyse og kunstig intelligens til å måle svært nøyaktig hvordan en kreftsvulst utvikler seg på MR-bilder over tid. Her kan vi både se hvor mye-, hvor fort-, og i hvilken retning kreftsvulsten vokser. Metoden gjør at vi kan fange opp endringer på MR-bildene opptil flere måneder før de samme endringene synes med dagens tradisjonelle bildemetoder. Formidlingsplanen til FORCE har fokusert på å presentere resultater i fagfelle-vurderte publikasjoner med høy synlighet, og med åpen tilgang. Dette inkluderer også deling av innsamlede forskningsdata (MR-bilder) for gjenbruk av andre. Vi har også utviklet såkalte MR-sekvenser (opptaksteknikker) for både blodstrømsavbildning og MR elastografi (stivhetsmålinger). Disse teknikkene vil bli delt med fagfeltet når de er ferdig testet og validert. I samme ånd har vi også utviklet en åpen datamodell hvor brukeren kan simulere naturtro tumorvekst slik den kan fremstå på MR-bildene (www.cancer-sim.com). Til slutt har FORCE bidratt til å utvide forskningsnettverket til prosjektdeltagerne - og her fått muligheten til å delta som partner i Europeiske forskningssøknader og inngå i dedikerte fagnettverk. Kunnskapen og resultatene fra FORCE har også muliggjort videre forskningsstøtte blant annet fra Forskningsrådet (‘MATRIX’, ‘TrackGrowth’) og fra Helse Sør-Øst (‘CHRONOS’).

The FORCE project main objective is to establish - for the first time in humans - a novel, functional imaging paradigm to reveal vascular restrictions in cancers caused by a non-fluid physical force; solid stress. By identifying and manipulating this force we will enhance drug delivery and improve patient survival. The mechanisms of conventional, anti-angiogenic and immuno-stimulant treatments are among the most-studied facets of cancers. However, pre-clinical data showing that proliferating tumor cells and a fibrous material known as the extracellular matrix can squeeze vessels shut and prevent drug delivery has only recently emerged. The FORCE project is based on the following observations; (I) pre-clinical work suggests that therapies targeting the matrix building blocks, collagen and hyaluronan, enhance drug delivery by decompressing tumor vessels; (II) matrix-induced compression of vessels are not proved in humans in vivo; and (III) there are currently no options to measure the response and effectiveness of matrix-depleting therapies in cancer patients. FORCE will conduct a comprehensive series of innovative studies in brain cancer patients to answer three critical questions: (Q1) Can our novel MR imaging methods of vascular architecture identify impaired perfusion from solid stress? (Q2) Does the level of matrix stiffness scale with vessel compression in humans and not just in pre-clinical animal models? (Q3) Do matrix-depleting drugs improve the delivery of concomitant cancer therapies in humans, and ultimately, patient survival? The FORCE project holds a unique position to answer these questions by our extensive experience with functional imaging in humans and unrivaled multidisciplinary and international infrastructure. With successful delivery, the FORCE results will have a direct impact on patient outcome and establish a functional imaging paradigm that will pave the way for new scientific knowledge on how to perfect matrix-depleting therapies.