Molecular imaging in the development of a novel treatment paradigm for glioblastoma (GBM): an integrated multidisciplinary commentary

Highlights

• Molecular imaging (MI) plays a key part in identifying glioblastoma (GBM) therapies against multiple cancer hallmarks.

• Functional magnetic resonance imaging (MRI) has potential as a predictive biomarker for antiangiogenics.

• Application of novel positron emission tomography (PET) approaches supports development of GBM-targeted therapies.

• Implementation of MI in gene therapy protocols supports improved clinical outcome.

• GBM cancer stem cell (CSC) targeted drug discovery platforms should comprise sensitive MI approaches.

Current therapeutic strategies against glioblastoma (GBM) have failed to prevent disease progression and recurrence effectively. The part played by molecular imaging (MI) in the development of novel therapies has gained increasing traction in recent years. For the first time, using expertise from an integrated multidisciplinary group of authors, herein we present a comprehensive evaluation of state-of-the-art GBM imaging and explore how advances facilitate the emergence of new treatment options. We propose a novel next-generation treatment paradigm based on the targeting of multiple hallmarks of cancer evolution that will heavily rely on MI.

Introduction

Based on estimations, 23 000 men and women (55% of this number being men) will be diagnosed with a primary brain or other nervous system malignancy this year in the USA, with 13 700 men and women succumbing to these diseases [1]. Glioma is the most common primary central nervous system (CNS) tumour. Widespread infiltration of surrounding tissue, the presence of necrotic tissue and/or angiogenic activity characterise the most malignant form termed glioblastoma (GBM) grade IV [2]. The standard of care for treatment of GBM consists of neurosurgical tumour resection and concomitant chemotherapy and radiotherapy (RT) followed by adjuvant chemotherapy. The most widely implemented treatment regimen has been developed by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group, and is often referred to as the ‘Stupp protocol’. In a randomised trial including almost 600 patients improved overall survival was clearly demonstrated in patients who received a combined modality treatment of temozolomide (TMZ) chemotherapy in conjunction with concomitant RT followed by adjuvant or maintenance TMZ for six cycles (TMZ/RT → TMZ), compared with patients who received only RT as the initial treatment but might have received TMZ chemotherapy at recurrence [3]. Nevertheless, despite the emergence of novel treatment strategies in recent years (discussed in detail below), survival rates for GBM patients continue to be low. According to the National Cancer Institute median survival for patients with GBM is 15 months from time of diagnosis [1].

Development of novel therapeutics with anti-GBM activity remains a crucial and challenging objective. Targeting a single ‘cancer hallmark’ [4] is unlikely to elicit significant benefit in patients presenting with advanced malignancies. Thus, developing molecular targeted drugs that concomitantly impact several GBM survival pathways/cancer hallmarks is likely to represent a new horizon within the field. However, notwithstanding the validity of this objective, the average cost of developing a drug within the healthcare space has increased to an average of US$ 1.3 billion over several years with sustained investment required over a period of no less than ten years. This is none more evident than in the oncology space, where molecular targeted therapies (in the context of the evolution of a personalised treatment paradigm) comprise a significant sector of the market.

Reducing the drug development time-line through implementation of molecular imaging (MI) strategies during preclinical and clinical development phases would significantly reduce the burden of cost. MI can improve the efficiency of drug screening and can be used to interrogate drug pharmacokinetics and biodistribution, thus markedly reducing time and costs required for the development of a new drug. Moreover, identification of MI biomarkers yielding spatial and temporal information could also provide surrogate clinical endpoints. Crucially, imaging of key biological processes that underpin the classical cancer hallmarks [4] (e.g. angiogenesis, invasion, proliferation) might provide a more robust mechanistic assessment of newly emergent molecular targeted therapeutics that represent a cornerstone of personalised medicine. This is of note when one considers that chronic treatment with targeted therapies results in disease stabilisation rather than the tumour shrinkage more evident in response to cytotoxic therapies. As such, classical gross anatomical imaging of tumour lesions can no longer provide optimal therapeutic follow up; what is currently required are imaging modalities that enable sensitive assessment of drug effects at the level of specific targeted molecular features and/or biological pathways.

MI optimises, streamlines and refines the drug development process. The advantages of implementing a MI strategy during the preclinical and clinical development stages are clearly illustrated in terms of translational research in primary brain tumours. The disease represents particular challenges towards development of novel therapeutics, because drugs must be amenable to crossing the blood–brain barrier (BBB), notwithstanding BBB breakdown during the disease process, and should efficiently compromise the key processes of tumour angiogenesis, invasion and cell proliferation. The ability to monitor drug effects on these key biological processes in real time will play a key part in elucidating the next generation of molecular targeted anti-GBM therapeutics. Within the context of the current review, we have, for the first time, gathered a multidisciplinary team harnessing expertise in cell biology, preclinical modelling, neurosurgery, MI and neuro-oncology to assess the role played by MI critically in the development of a state-of-the-art next-generation anti-GBM therapeutic paradigm that will seek to target multiple cancer hallmarks.