IMAGINE: Imaging molecular mechanisms of angiogenesis in glioma-associated neovasculature

Glioblastoma is one of the deadliest forms of cancer, and there is an urgent and unmet need to improve treatment strategies. A significant challenge is that glioblastomas are heterogeneous; therefore future treatment advances must be tailored to each patients’ unique and specific molecular features. Such patient-specific and personalized treatment approach requires precise and accurate imaging diagnostics. In this study, we will use advanced imaging techniques such as Positron Emission Tomography (PET), computed tomography (CT), and Magnetic Resonance Imaging (MRI) to measure molecular features of the cancer cells and the microenvironment. More specifically, these imaging techniques will provide knowledge on a new cancer therapy at Oslo University Hospital (OUH), aiming to reduce the unwanted pressure from a growing tumor. We aim to use this knowledge to predict which patients who will be benefit from this new treatment regimen, and hopefully get one step closer to becoming truly personalized medicine. The PET/CT exams include use of a radioactive tracer know as prostate-specific membrane antigen (PSMA). PSMA is believed to play an important functional role in tumor angiogenesis, and shown to exhibit robust expression (=PET signal) in the vasculature of many solid tumors, including brain tumors with a permeable vasculature (such as glioblastoma). The combination of PSMA PET/CT and MRI allows us to understand what drives vascular growth and restrictions in cancer, and how the tumor vasculature responds to therapy. In the first year of patient recruitment (from October 2020), the patient accrual was severely challenged by COVID-19 and its aftermath. However, since September 2021, the study has been in an active recruitment phase. To date, we have included and scanned six patients with glioblastoma on PET/CT and MRI. The patient cohort is part of our ongoing clinical trial («ImPRESS», ClinicalTrials.gov NCT03951142). Moreover, we have also included six patients with brain metastases from lung cancer. A part of this patient group is recruited from the main study «ImPRESS» clincial trial. According to our study protocol, each patient underwent two PET/CT examinations; first at baseline, then 2 weeks after start of treatment for the glioblastoma patient cohort, and first at baseline, then three months after start of treatment for the lung cancer patients with brain metastases cohort. A key aim of the project is to ensure image data of high quality. We have therefore conducted a phantom study to determine the accurate reconstruction parameters for the advanced study-specific imaging protocol. The results from this study were published in EJNMMI Physics October 2023. We have also focused on a quantitative assessment of the clinical PET and MR data, and the preliminary results from this analysis were presented at the European Association of Nuclear Medicine (EANM) annual meeting in October 2022. This work continues as we gather more data. Finally, we are currently developing methods for assessing and quantifying tissue vasculature as observed on the MR images. This has led to a range of published works (please refer results section).

Glioblastoma is one of the deadliest forms of cancer and the primary goal of treatment is simply to decelerate tumor growth. Still, after decades of research, standard-of-care for these brain tumors only includes surgery, radiotherapy and chemotherapy. A significant challenge of therapy is reduced penetration of anti-cancer drugs from a dysfunctional and impaired tumor vasculature. Oslo University Hospital (OUH) is currently spearheading an international effort to identify and alleviate impaired perfusion directly in brain cancer patients by targeting the abnormal physical forces of the tumor microenvironment. Using a safe and affordable anti-hypertensive medicine, an angiotensin II receptor blocker (ARB), we will remove the physical barriers of the extracellular matrix that prevent anti-cancer drugs from reaching their target. However, glioblastomas are notoriously heterogeneous, and we hypothesize that a specific physical, vascular and metabolic 'signature' is required for ARBs to have an impact on treatment. Intriguingly, the natural interplay of these mechanisms in patients may only be assessed by in vivo imaging and we therefore build on current efforts by performing a clinical imaging study using a novel Positron Emission Tomography (PET) tracer in combination with Magnetic Resonance Imaging (MRI). This study will reveal the unique and patient-specific signature of the cancers' microenvironment and bring current treatments options one step closer to becoming truly personalized medicine.