Periodic Reporting for period 4 - ImPRESS (Imaging Perfusion Restrictions from Extracellular Solid Stress)
Período documentado: 2022-07-01 hasta 2023-03-31
Even the perfect cancer drug must reach its target to have an effect. The ImPRESS project has delivered new scientific knowledge on how a mechanical force, solid stress, caused by proliferating cancer cells and the extracellular matrix degrade and remodel fragile blood vessels to the point that they no longer can sufficiently supply the tissue with nutrients and oxygen. This chaotic and hypoxic microenvironment prevents drug delivery and promotes metastatic growth, which effectively makes tumors difficult to treat. Developing diagnostic biomarkers that can measure how solid stress impair perfusion and promotes therapy resistance is essential for understanding neoplastic disease. ImPRESS has provided novel diagnostic insights into how potential treatment options may alleviate mechanical forces in cancer to revitalize conventional therapy as well as remove barriers for successful immunotherapy.
While the traditional diagnosis and treatment plan for patients with these tumor types is similar or even identical, the way the patients respond to anti-cancer therapy may be very different. Only about half the cancer patients who receive a typical anti-cancer drug benefit while the others mainly suffer the side effects. Identifying patients who will benefit will also prevent non-responding patients to lose precious time on treatments that will have little or no effect.
The ImPRESS project overall objective was to develop a novel imaging paradigm to reveal vascular restrictions in solid cancers caused by mechanical forces and use imaging to demonstrate that alleviating this force in patients with cancer will repair the cancerous microenvironment and improve therapeutic response. ImPRESS has focused on brain cancers, a patient group with dismal prognosis and a cancer type where the proposed studies are expected to have especially appealing effects.
Our conclusions from the actions are as follows:
• Magnetic resonance imaging (MRI) can identify impaired tissue perfusion in human tumors and peri-tumoral tissue in vivo
• We have develop a novel longitudinal MRI analysis technique capable of tracking how tumor tissue properties change as a function of natural growth or treatment.
• We have implement MR Elastography for clinical use at Oslo Universitetssykehus HF to confirm an association between upregulated mechanical forces and vascular restrictions in patients with brain cancer.
• We have validated our MRI-based findings of mechanical forces with image-guided tissue sampling and histopathological analysis of extracellular matrix status.
• We have performed a clinical trial using the angiotensin II receptor inhibitor losartan in glioblastoma patients to assess changes in vascular function and mechanical force.
• We have provided evidence that losartan reduces intra-cranial edema and thus the need for immuno-suppressive steroids in brain cancer to boost the therapeutic effects of immunotherapy.
While the traditional diagnosis and treatment plan for patients with these tumor types is similar or even identical, the way the patients respond to anti-cancer therapy may be very different. Only about half the cancer patients who receive a typical anti-cancer drug benefit while the others mainly suffer the side effects. Identifying patients who will benefit will also prevent non-responding patients to lose precious time on treatments that will have little or no effect.
The ImPRESS project overall objective was to develop a novel imaging paradigm to reveal vascular restrictions in solid cancers caused by mechanical forces and use imaging to demonstrate that alleviating this force in patients with cancer will repair the cancerous microenvironment and improve therapeutic response. ImPRESS has focused on brain cancers, a patient group with dismal prognosis and a cancer type where the proposed studies are expected to have especially appealing effects.
Our conclusions from the actions are as follows:
• Magnetic resonance imaging (MRI) can identify impaired tissue perfusion in human tumors and peri-tumoral tissue in vivo
• We have develop a novel longitudinal MRI analysis technique capable of tracking how tumor tissue properties change as a function of natural growth or treatment.
• We have implement MR Elastography for clinical use at Oslo Universitetssykehus HF to confirm an association between upregulated mechanical forces and vascular restrictions in patients with brain cancer.
• We have validated our MRI-based findings of mechanical forces with image-guided tissue sampling and histopathological analysis of extracellular matrix status.
• We have performed a clinical trial using the angiotensin II receptor inhibitor losartan in glioblastoma patients to assess changes in vascular function and mechanical force.
• We have provided evidence that losartan reduces intra-cranial edema and thus the need for immuno-suppressive steroids in brain cancer to boost the therapeutic effects of immunotherapy.
ImPRESS has generated imaging data from magnetic resonance imaging (MRI) of adult patients with primary (glioblastoma) and secondary (metastases) brain tumors, prior to, during, and after treatment with traditional cancer therapies with- and without drugs that aim to remodel the mechanical forces of the tumor microenvironment. The MRI exam is now operational at Oslo Universitetssykehus HF, including conventional and functional imaging of water diffusion, vascular hemodynamics, and tissue stiffness and force. The protocol is evaluated in both healthy volunteers and patients with brain tumors.
ImPRESS has also performed a clinical trial (EudraCT Number: 2018-003229-27, clinicaltrials.gov NCT03951142) to test whether losartan, an angiotensin receptor II blocker, could manipulate the mechanical forces of the cancerous microenvironment. Because our clinical trial constitutes an 'off-label' treatment in humans, 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. In compliance with good clinical practice, this study has made use of the full clinical trial engine at our hospital, including a full time study nurse; a dedicated project coordinator; primary care physicians; a dedicated study statistician; a dedicated study monitor whose job is to perform risk analyses and source data verifications; contracts with hospital pharmacies; biobank setup and management; radiologic services (reporting), material transfer agreements (international collaborations), electronic case report forms (eCRF), and an independent safety committee. Also, our project management committee has maintained an efficient clinical study logistics pipeline, procedures for rapid safety reporting, a dedicated and automatic MRI analysis pipeline, and safe data storage and reporting.
Please refer the Major Achievements section for main results and their exploitation and dissemination.
To date, the ImPRESS project participants has published over thirty peer-review manuscripts in relationship with the project, as well as four book chapters and several associated PhD theses.
The ImPRESS project has also presented data at several international conferences, a range of non-scientific and non-peer-reviewed publications are presented, as well as relevant activities in social media.
ImPRESS has also performed a clinical trial (EudraCT Number: 2018-003229-27, clinicaltrials.gov NCT03951142) to test whether losartan, an angiotensin receptor II blocker, could manipulate the mechanical forces of the cancerous microenvironment. Because our clinical trial constitutes an 'off-label' treatment in humans, 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. In compliance with good clinical practice, this study has made use of the full clinical trial engine at our hospital, including a full time study nurse; a dedicated project coordinator; primary care physicians; a dedicated study statistician; a dedicated study monitor whose job is to perform risk analyses and source data verifications; contracts with hospital pharmacies; biobank setup and management; radiologic services (reporting), material transfer agreements (international collaborations), electronic case report forms (eCRF), and an independent safety committee. Also, our project management committee has maintained an efficient clinical study logistics pipeline, procedures for rapid safety reporting, a dedicated and automatic MRI analysis pipeline, and safe data storage and reporting.
Please refer the Major Achievements section for main results and their exploitation and dissemination.
To date, the ImPRESS project participants has published over thirty peer-review manuscripts in relationship with the project, as well as four book chapters and several associated PhD theses.
The ImPRESS project has also presented data at several international conferences, a range of non-scientific and non-peer-reviewed publications are presented, as well as relevant activities in social media.
Moving from the current targeted-drug-delivery approach to a make-drugs-reach-their-target approach constitutes a potential game-changer in how we assess cancer treatment. There are no available diagnostic strategies for how to measure impaired vasculature from mechanical forces in human brains and therefore, the ImPRESS project has moved beyond state-of-the-art by introducing a new paradigm for clinical neuroimaging.
Our beyond state-of-the-art setup for MRI elastography (MRE) has received much attention and now constitutes an integral part of our pre-operative imaging protocol for patients with meningioma. This includes the ability to assess and predict the degree of meningioma–brain adhesion, where a contemporary and ongoing MRI study led by our team uses scorings during surgery as the reference gold standard. The expected results of this study are estimated in 2023. This meningioma patient cohort is also a valid control group to patients with infiltrative gliomas.
Based on the experiences from our published work in Clinical Cancer Research (2020), the ImPRESS team initiated in 2020 a clinical imaging study (‘IMAGINE’, 2020-2024) using a Positron Emission Tomography (PET) tracer, named Prostate Specific Membrane Antigen (PSMA), for use in combination with MRI in patients with glioblastoma and brain metastases from lung cancer. Because reports show that only about half of all glioblastoma patients express significant and consistent PSMA activity, targeting PSMA by PET will help reveal how losartan modulates the vascular microenvironment in vivo.
A disclosure-of-invention (DOFI) from ImPRESS now translated into a full patent application submitted in the start of 2022 and currently under examiners review. In this context, we believe artificial intelligence presents great possibilities for improved analysis of diagnostic data and we therefore aim to pursue the added value of this innovation.
Our beyond state-of-the-art setup for MRI elastography (MRE) has received much attention and now constitutes an integral part of our pre-operative imaging protocol for patients with meningioma. This includes the ability to assess and predict the degree of meningioma–brain adhesion, where a contemporary and ongoing MRI study led by our team uses scorings during surgery as the reference gold standard. The expected results of this study are estimated in 2023. This meningioma patient cohort is also a valid control group to patients with infiltrative gliomas.
Based on the experiences from our published work in Clinical Cancer Research (2020), the ImPRESS team initiated in 2020 a clinical imaging study (‘IMAGINE’, 2020-2024) using a Positron Emission Tomography (PET) tracer, named Prostate Specific Membrane Antigen (PSMA), for use in combination with MRI in patients with glioblastoma and brain metastases from lung cancer. Because reports show that only about half of all glioblastoma patients express significant and consistent PSMA activity, targeting PSMA by PET will help reveal how losartan modulates the vascular microenvironment in vivo.
A disclosure-of-invention (DOFI) from ImPRESS now translated into a full patent application submitted in the start of 2022 and currently under examiners review. In this context, we believe artificial intelligence presents great possibilities for improved analysis of diagnostic data and we therefore aim to pursue the added value of this innovation.