Metabolic-imaging of human glioblastoma live tumors: A new precision-medicine approach to predict tumor treatment response early

Abstract

BackgroundGlioblastoma (GB) is the most severe form of brain cancer, with a 12-15 month median survival. Surgical resection, temozolomide (TMZ) treatment, and radiotherapy remain the primary therapeutic options for GB, and no new therapies have been introduced in recent years. This therapeutic standstill is primarily due to preclinical approaches that do not fully respect the complexity of GB cell biology and fail to test efficiently anti-cancer treatments. Therefore, better treatment screening approaches are needed. In this study, we have developed a novel functional precision medicine approach to test the response to anticancer treatments in organoids derived from the resected tumors of glioblastoma patients.MethodsGB organoids were grown for a short period of time to prevent any genetic and morphological evolution and divergence from the tumor of origin. We chose metabolic imaging by NAD(P)H fluorescence lifetime imaging microscopy (FLIM) to predict early and non-invasively ex-vivo anti-cancer treatment responses of GB organoids. TMZ was used as the benchmark drug to validate the approach. Whole-transcriptome and whole-exome analyses were performed to characterize tumor cases stratification.ResultsOur functional precision medicine approach was completed within one week after surgery and two groups of TMZ Responder and Non-Responder tumors were identified. FLIM-based metabolic tumor stratification was well reflected at the molecular level, confirming the validity of our approach, highlighting also new target genes associated with TMZ treatment and identifying a new 17-gene molecular signature associated with survival. The number of MGMT gene promoter methylated tumors was higher in the responsive group, as expected, however, some non-methylated tumor cases turned out to be nevertheless responsive to TMZ, suggesting that our procedure could be synergistic with the classical MGMT methylation biomarker.ConclusionsFor the first time, FLIM-based metabolic imaging was used on live glioblastoma organoids. Unlike other approaches, ex-vivo patient-tailored drug response is performed at an early stage of tumor culturing with no animal involvement and with minimal tampering with the original tumor cytoarchitecture. This functional precision medicine approach can be exploited in a range of clinical and laboratory settings to improve the clinical management of GB patients and implemented on other cancers as well.

Opportunities and challenges of 5G network technology toward precision medicine

“…Hence, the advent of technologies of growing "mini-organs," the so-called organoids are beneficial for drug screening to predict patient response to drug treatment. Various studies [92][93][94][95][96][97][98][99][100] are conducted using different approaches to bridge gaps between disease modeling organoids and precision medicine, as shown in Table 5.…”

Preclinical glioma models in neuro-oncology: enhancing translational research

“…The first study utilized a mass accumulation rate (MAR) assay on microfluidic devices to measure TMZ response based on subtle changes in the mass distributions of drug-exposed neurospheres compared to control samples [38]. The second study [39] employed an imaging method called FLIM (Fluorescence Lifetime Imaging Microscopy) using the intrinsic auto-fluorescence properties of Nicotinamide Adenine Dinucleotide Phosphate Hydrogen (NAD(P)H), a metabolic enzymatic cofactor associated with cellular metabolic state. Cancer cell metabolic status is known to be an early predictor of treatment response [40,41].…”

“…Two recent studies aimed to overcome these limitations by conducting functional drug susceptibility testing using patient-derived tumor samples. The first study [38] utilized GB patient-derived neurosphere models, while the second study [39] employed patient-derived organoid models known as glioblastoma explants (GB-EXPs). GB-EXPs are minimally handled, briefly cultured without animal involvement, and preserved without dissociation or passaging, thereby maintaining the parental cytoarchitecture.…”

Exploring Regorafenib Responsiveness and Uncovering Molecular Mechanisms in Recurrent Glioblastoma Tumors through Longitudinal In Vitro Sampling

“…In pursuit of addressing this pressing need, we have recently pioneered an ex vivo drug response functional precision medicine approach. This innovative methodology allows us to assess how tumor samples respond to various cancer treatments, enabling us to analyze tissue samples both prior to and after treatment [ 14 ]. This approach involves the use of an in vitro 3D organoid model derived from vital patient glioblastoma tissue (referred to as GB-EXPs).…”