Intertumoral heterogeneity in patient-specific drug sensitivities in treatment-naïve glioblastoma

Abstract

Background A major barrier to effective treatment of glioblastoma (GBM) is the large intertumoral heterogeneity at the genetic and cellular level. In early phase clinical trials, patient heterogeneity in response to therapy is commonly observed; however, how tumor heterogeneity is reflected in individual drug sensitivities in the treatment-naïve glioblastoma stem cells (GSC) is unclear. Methods We cultured 12 patient-derived primary GBMs as tumorspheres and validated tumor stem cell properties by functional assays. Using automated high-throughput screening (HTS), we evaluated sensitivity to 461 anticancer drugs in a collection covering most FDA-approved anticancer drugs and investigational compounds with a broad range of molecular targets. Statistical analyses were performed using one-way ANOVA and Spearman correlation. Results Although tumor stem cell properties were confirmed in GSC cultures, their in vitro and in vivo morphology and behavior displayed considerable tumor-to-tumor variability. Drug screening revealed significant differences in the sensitivity to anticancer drugs ( p < 0.0001). The patient-specific vulnerabilities to anticancer drugs displayed a heterogeneous pattern. They represented a variety of mechanistic drug classes, including apoptotic modulators, conventional chemotherapies, and inhibitors of histone deacetylases, heat shock proteins, proteasomes and different kinases. However, the individual GSC cultures displayed high biological consistency in drug sensitivity patterns within a class of drugs. An independent laboratory confirmed individual drug responses. Conclusions This study demonstrates that patient-derived and treatment-naïve GSC cultures maintain patient-specific traits and display intertumoral heterogeneity in drug sensitivity to anticancer drugs. The heterogeneity in patient-specific drug responses highlights the difficulty in applying targeted treatment strategies at the population level to GBM patients. However, HTS can be applied to uncover patient-specific drug sensitivities for functional precision medicine. Electronic supplementary material The online version of this article (10.1186/s12885-019-5861-4) contains supplementary material, which is available to authorized users.

A Proteotranscriptomic-Based Computational Drug-Repositioning Method for Alzheimer’s Disease

“…GBM showed a consistent strong correlation with AD among nine cancer types. GBM is characterized by a high degree of cellular and molecular heterogeneity both among patients and within the same patient (Skaga et al, 2019). AD is also a heterogeneous disease that is classified into three clinical stages including the preclinical, mild cognitive impairment, and dementia (Jack et al, 2018), and its neuropathology is highly variable (Whitwell et al, 2012).…”

Multiplex-inhibitor bead mass spectrometry reveals differential kinome signatures in newly diagnosed and recurrent glioblastoma

“…Upon tumor recurrence, exome sequencing has shown that many somatic mutations are not conserved and transcriptional subtype is often not maintained, suggesting a high degree of evolution from the initial tumor 19,43 . Additionally, drug sensitivity between patients varies widely 16 .…”

“…Given the heterogeneity among both GBM tumors and GBM cell populations, as well as their ability to rapidly acquire drug resistance, a one-size-fits-all treatment approach for recurrent GBM is not possible 16 . Unfortunately, differences in newly diagnosed and recurrent GBM tumors are difficult to differentiate based on mRNA levels alone, suggesting a need for further exploration of tumor signaling pathways.…”

Feasibility study of using high‐throughput drug sensitivity testing to target recurrent glioblastoma stem cells for individualized treatment

“…The intricate tumor heterogeneity at the cellular and molecular level in the treatment‐naïve GBM poses a substantial challenge for therapeutic progress on its own [11–14], but even more for treatment of the relapsed disease. Recent studies have described a longitudinal heterogeneity of tumor evolution following therapy, as the selection pressure exerted by standard treatment display tumor‐to‐tumor variability [15–18].…”

“…We have previously described the intertumoral heterogeneity in patient‐specific drug sensitivity patterns in the treatment‐naïve GBM [13]. However, the feasibility of translating automated drug sensitivity testing of a patient`s cancer cells ex vivo to individualized treatment in solid tumors is immature [28].…”