Year: 2020
Type: article
Abstract: Given the high prevalence of brain metastasis in EGFR-mutant NSCLC patients (up to 40%), blood-brain barrier (BBB) permeability is increasingly considered an important property of EGFR tyrosine kinase inhibitors (EGFR-TKIs) to maximize patient benefit. First- and second-generation EGFR-TKIs, such as gefitinib, erlotinib, and afatinib, have shown some activity against brain metastatic disease in the clinic, but ultimately disease progression occurs. The lack of BBB permeability of first-generation EGFR-TKIs is believed to be one of the reasons for their limited efficacy in the treatment of brain metastases, mainly due to the fact that all EGFR-TKIs in humans are efflux transporter substrates.1 Osimertinib is a potent and selective EGFR-TKI of both sensitizing and T790M-resistance mutations. In this study, published online in October in Clinical Cancer Research, Colclough et al2 examined the level of brain penetration for 16 irreversible and reversible EGFR-TKIs using multiple in vitro and in vivo BBB preclinical models. In vitro osimertinib was the weakest substrate for human BBB efflux transporters (efflux ratio 3.2). In vivo rat free brain to free plasma ratios (Kpuu) showed osimertinib to have the most BBB penetrance (0.21) compared with the other TKIs (Kpuu ≤0.12). PET imaging in cynomolgus macaques demonstrated osimertinib as the only TKI amongst those tested to achieve significant brain penetrance (Cmax% ID 1.5, brain/blood Kp 2.6). Desorption electrospray ionization mass spectroscopy (DESI-MS) images of brains from mouse PC9 macrometastases models showed osimertinib readily distributes across both healthy brain and tumor tissue. Comparison of osimertinib to the poorly BBB-penetrant afatanib in a mouse PC9 model of subclinical brain metastases showed that only osimertinib has a significant effect on rate of brain tumor growth. These preclinical experiments indicate that osimertinib can achieve significant exposure in the brain compared with the other EGFR-TKIs and support the ongoing clinical evaluation of osimertinib for the treatment of EGFR-mutant brain metastasis. In this regard, osimertinib has shown promising CNS activity in recent phase III trials (FLAURA and AURA3).3,4 In the FLAURA trial, patients with brain metastases treated with osimertinib showed a 52% risk reduction in disease progression or death compared to standard-of-care EGFR-TKIs that have poor BBB permeability. Furthermore, fewer patients in the osimertinib arm experienced disease progression due to the development of new CNS lesions compared with patients in the comparator arm (12% vs. 30%). The latter observation suggests osimertinib may offer a benefit in preventing or controlling early disease progression. Moreover, this work demonstrates the link between low in vitro transporter efflux ratios and increased brain penetrance in vivo, supporting the use of in vitro transporter assays as an early screen in drug discovery. New trials on osimertinib in brain metastases are ongoing. Indoleamine-pyrrole 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are enzymes that catalyze the first and rate-limiting step in the kynurenine pathway. IDO is also an essential part of the immune system, and the IDO 1 and 2 enzymes contribute to immune evasion in cancer. The inhibition of IDO has shown promise in preclinical studies and was postulated to reverse tumor-derived immunosuppression.1 To date, IDO1 inhibitors have failed to demonstrate a benefit in clinical trials.2 In part, this failure may be due to the lack of patient stratification based on IDO1 expression; however, other pathways may drive resistance to IDO1 inhibitors. A recent publication in Cell reported that the aryl hydrocarbon receptor (AHR)-activating enzyme interleukin 4 (IL4)-induced gene 1 (IL4I1) might be instrumental in this process.3 AHR is a ligand-activated transcription factor that enables cells to adapt by sensing changes in the environment, such as diet, microbiome, and cellular metabolism. Cancers express high levels of IDO1, taking advantage of tryptophan catabolite-mediated AHR activation. The IL4I1 gene may play a role in cancer immune suppression, as it is expressed in tumor-associated macrophages and may suppress T cell responses. To identify new mediators of AHR activation in human tumors, the authors assessed the association of metabolic enzymes beyond IDO with expression of AHR target genes. The authors developed a signature that enables detection of AHR activity, irrespective of cell type or ligand. Using the AHR signature, they assessed whether the expression of IDO1 or TDO2 is associated with AHR activity. The AHR signature, derived by natural language processing, revealed that across 32 tumor entities, IL4I1 associated more frequently with AHR activity than IDO1 or TDO2, previously recognized as the main tryptophan-catabolic enzymes. Interestingly, glioblastoma and low-grade glioma patients with high compared to low IL4I1 expression showed a 2.3-fold and 3.3-fold higher risk of death, respectively. The high IL4I1-expressing gliomas had elevated AHR activity, with a strong association of IL4I1 with AHR activity and glioma survival outcomes. The authors reported that AHR-driven motility contributes to the malignant properties of glioma. The authors also observed that this pathway is associated with suppression of adaptive immunity and an inferior survival in glioma patients. The authors remarked that immune checkpoint blockade induces IDO1 and IL4I1. However IDO1 inhibitors do not block IL4I1, and this may explain why IDO1 inhibitors, to date, have been ineffective in human trials. IL4I1 inhibition may represent a new therapeutic opportunity to reverse immunosuppression in gliomas and other cancers. Integrated molecular profiling continues to clarify the biological features of isocitrate dehydrogenase (IDH)-mutant gliomas, along with their distinctions from IDH-wild type counterparts. The vast majority of IDH-mutant gliomas arise supratentorially, with frequent frontal lobe involvement. However, a small subset of IDH-mutant astrocytomas arise in the posterior fossa, brainstem, and spinal cord. In a recent Acta Neuropathologica article, Banan et al. report the molecular characterization of the largest cohort of infratentorial IDH-mutant astrocytomas to date.1 Their profiled samples included 43 tumors from 42 patients that were paired with a similarly sized (N = 50) set of supratentorial IDH-mutant astrocytomas. The authors found that only 24% of IDH-mutant infratentorial astrocytomas harbored the IDH1 R132H mutation, with so-called “non-canonical” mutations in IDH1 and IDH2 predominating. This finding was in sharp contrast to supratentorial counterparts, for which IDH1 R132H was present in the overwhelming majority of cases. Moreover, absent expression of α-thalassemia mental retardation X-linked (ATRX) was seen in less than half of infratentorial tumors compared with ~94% of supratentorial cases. Infratentorial tumors also demonstrated a stronger male sex predominance and had lower rates of MGMT promoter methylation. Next-generation panel sequencing revealed isolated instances of H3 K27M mutations co-occurring with IDH mutations in aggressive infratentorial astrocytomas. Interestingly, no promoter mutations in the telomerase reverse transcriptase (TERT) locus were discovered, contrasting with the near absolute mutual exclusivity arrangement with ATRX deficiency seen in supratentorial variants. Global methylation profiling delineated a distinct signature for infratentorial IDH-mutant astrocytomas, made apparent when gliomas were examined separately from other primary brain tumors. While no methylation distinctions emerged within supra- and infratentorial groups with regard to precise anatomical localization, some clustering was evident by tumor grade for both variants. Finally, infratentorial IDH-mutant astrocytomas demonstrated an intermediate level of aggressiveness between those of supratentorial IDH-mutant astrocytomas (more favorable) and diffuse midline gliomas with H3 K27M mutation (less favorable). This work is significant in that it establishes a novel and clinically distinct subgroup of IDH-mutant astrocytoma involving infratentorial sites, and its reporting is timely given the imminent release of the revised WHO 2021 classification of primary brain tumors. DIPG carrying a H3K27M mutation have a bad prognosis and are in urgent need of effective treatment options. To understand the molecular underpinnings of the disease, Chung et al1 employed a multi-OMIC strategy using genetically engineered immortalized murine neural stem cells and patient-derived H3K27M tumor cells. The analyses confirmed the finding that H3K27M leads to a decrease of H3K27me3, a chromatin mark for inactive genes, and an increase of the opposite mark H3K27ac. This change, also found at neural stem cell genes, has been associated with the incapability of the cells to differentiate. The evaluation of H3K27M-associated gene expression, proteome, and metabolome concordantly indicated profound changes in the cell metabolism associated with upregulation of glycolysis and TCA cycle metabolism. The metabolite α-ketoglutarate (αKG) was strongly upregulated, which may explain the observed global chromatin demethylation by αKG-dependent demethylases such as KDM6A/B. The metabolism-related transporter gene SLC2A3 and several of the glycolytic enzymes, including HK2 and GLUD1/2 (encodes GDH), displayed high expression in H3K27M tumors as compared with H3WT or H3G34R/V tumors. In accordance, comparison of H3.3K27M vs. H3.3WT NSC by chromatin immunoprecipitation sequencing (ChIP-seq) revealed an increased level of the activating chromatin mark H3K4me3, and exclusion of H3K27me3 at the promoters of SLc2a3 and Hk2, Glud1, and Idh1 in the H3.3K27M NSC. From these observations, the authors concluded increased glycolysis and TCA cycle metabolism. The comparisons of1H magnetic resonance spectroscopy (1H MRS) revealed increased levels of glutamine (Gln) and citrate (Cit) in H3K27M as compared with H3WT brainstem tumors that may contribute to enhanced αKG production supported by the experimental evidence provided in the study. Most interestingly, the αKG dependency represents a potential vulnerability. Targeting GDH, HK2, or Gln metabolism (glutamine antagonist) that are elements in the pathway for αKG production, the authors show inhibition of proliferation of H3K27M tumor cells in vitro and in vivo. This effect was associated with increase of global H3K27me3. The fact that H3K27M and IDH1/2 mutations are mutually exclusive in glioma,2 and the opposite role of αKG in the epigenetic deregulation of the respective tumors, led the authors to investigate IDH1 in this context. Higher protein levels of IDH1 were detected in H3K27M tumors than H3WT. Targeting IDH1, or expressing IDH1 R132H, or treating with the oncometabolite 2 hydroxyglutarate (D-2HG) had an inhibitory effect on proliferation of H3K27M cells and increased H3K27me3, but had a slighter effect on H3WT tumor cells. Together with complementary experiments the authors concluded that H3.3K27M and IDH1 R132H are synthetic lethal. Taken together, these novel insights into the metabolomic reprogramming mediated by H3K27M indicates αKG-dependent vulnerabilities that may afford novel treatment strategies. Several potential targets (HK2, IDH1, GDH, glutamine metabolism) have been identified and successfully tested in in vitro and in vivo models of H3K27M. Moreover, the treatment efficacy may be followed non-invasively in patients by high-resolution1H MRS of the metabolite concentrations.
Source: Neuro-Oncology
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4206314508