Year: 2017
Type: article
Abstract: Efforts to effectively target glioblastoma (GBM) with designer drugs depend heavily on a detailed understanding of its unique underlying biology. In this setting, the importance of metabolic pathways and the transcriptional networks they regulate is increasingly recognized. A recent publication in Proceedings of the National Academy of Sciences by Gujar et al. describes an investigation into the role of nicotinamide adenine dinucleotide (NAD+) and its regulatory network in the pathogenesis of GBM. In particular, the report focuses on nicotinamide phosphoribosyltransferase (NAMPT), the enzyme mediating the rate-limiting step in NAD+ synthesis. While NAD+ had previously been implicated in transcriptional control, chromatin structure, and cancer biology, its precise function in GBM remained obscure. Using data from TCGA and REMBRANDT, the authors demonstrated that NAMPT was overexpressed in GBM, and indeed all gliomas, relative to normal brain, and that higher levels were associated with unfavorable prognosis. Pharmacologic inhibition or genetic knockdown of NAMPT in patient-derived glioma stem cells (GSCs) hampered self-renewal in vitro and xenograft growth in vivo. NAMPT inhibition also promoted cell death and decreased proliferation in GSCs. The authors went on to examine the consequences of NAMPT inhibition on gene expression. Using two independent computational approaches, with the first also incorporating TCGA data, they identified E2F2 as a master regulator of the NAD+-dependent transcriptional network GBM. Moreover, knockdown of E2F2 decreased GSC self-renewal and proliferation and overexpression mitigated the effects of NAMPT inhibition, indicating E2F2 and NAMPT exist in an epistatic relationship. Exploring the consequences of this interaction further, the authors found that E2F2 knockdown decreased levels of the helix-loop-helix ID (inhibitor of differentiation) proteins by way of direct transcriptional regulation. IDs have been implicated in several studies to date as mediators of self-renewal and tumorigenicity in GBM. Finally, the authors addressed the clinical relevance of the NAMPT-E2F2-ID axis by demonstrating that NAMPT inhibition increased responsiveness of GSCs to ionizing radiation. This study established intriguing connections between metabolic pathways and disease-relevant transcriptional networks that mediate important biological phenotypes in GBM. In doing so it invites the development of novel therapeutic approaches. Despite its relative rarity, atypical teratoid/rhabdoid tumor (ATRT) is among the most dreaded diagnoses in pediatric neuro-oncology. While some progress has been made with multi-agent chemotherapy regimens, particularly in patients over three years old,1 ATRT is highly resistant to existing therapies and is usually rapidly lethal. There is thus a dire need to better understand this cancer to improve therapeutic options. At the genetic level, ATRT is fairly homogeneous and simple—marked only by biallelic loss of the SMARCB1/INI1 gene on chromosome 22, a component of the SWI/SNF chromatin-remodeling complex. SMARCB1 is also lost in other rare pediatric rhabdoid tumors outside the CNS as well as in rare adult tumors. This is a tumor suppressor not readily druggable, but there is some hope for synthetic lethal approaches that have been identified with targets such as Aurora Kinase A and EZH2.2,3 Further therapeutic leverage may be gained from profiling ATRT at levels other than the genomic, and exciting recent reports have done just that. A study from 2015 identified two transcription-based subgroups of ATRT, one with a neurogenic signature and one with a mesenchymal signature.4 An important new report by the same group integrates epigenomic profiling with genomic profiling, not only deepening our biological understanding of ATRT but suggesting possible new therapeutic approaches to the identified subgroups.5 Torchia et al. assembled an extremely large sample set for this profiling, gathering 191 ATRT tumors and 10 ATRT cell lines. ATRT samples were profiled at multiple levels, including whole-genome sequencing, high-resolution analysis for copy number alterations, and RNA-sequencing with gene expression and methylation studies. Three subgroups were identified that had differences in their epigenomic, transcriptional, and genetic profiles—including in their SMARCB1 genotypes. Two of the groups were similar, however, and most of the subsequent studies combined them. With their relatively large (given the rarity of ATRT) set of ATRT cell lines, the authors were also able to assess the responses of the subgroups to a panel of small-molecule inhibitors. One group was marked by greater expression of markers for the Notch pathway and the other of the BMP pathway, with greater sensitivity of the subgrouped cell lines to the corresponding inhibitors. Notably, one of the subgroups was particularly sensitive to inhibitors that blocked PDGFR signaling, and this was found to correlate with decreased methylation of a PDGFRB-associated enhancer and higher expression of PDGFRB. While the identification of ATRT subgroups sensitive to Notch, BMP, or PDGFR inhibition could well be extremely valuable, further therapeutic insights may yet be gleaned from these extensive studies. It will be important to compare the efficacy of the agents in the growing pipeline of potential ATRT therapies against each other in light of these newly identified subgroups, and combinations of these agents should also be preclinically assessed. With this report and other promising recent findings on ATRT, there is finally real hope for therapeutic breakthroughs against this lethal cancer. The development of endocrine dysfunction in long-term survivors of childhood tumors involving the brain or incorporating cranial radiotherapy is well recognized. Commonly affecting the hypothalamic-pituitary axis (HPA), these disorders can adversely affect growth, sexual development, and overall health; many are rectifiable with timely diagnosis and treatment. While children with tumors involving the pituitary region usually receive endocrinological evaluation starting early in their course, evaluation of other pediatric brain tumor patients is less standardized and often does not begin until the transition to long-term follow-up care five years after diagnosis. To assess the prevalence and clinical features of early endocrine dysfunction in this patient population, Clement and colleagues undertook a nationwide medical record-based retrospective cohort study in the Netherlands. They excluded craniopharyngiomas and pituitary tumors and captured 718 cases (an estimated 98.6% of Dutch pediatric brain tumor patients) over an 11-year period. In this population, 25% developed at least one endocrine disorder; half of affected patients had multiple disorders. The 5-year cumulative incidence was 21%. The median time to diagnosis of the first endocrine disorder was 2.2 years, and 87% of patients with HPA dysfunction developed it within five years of tumor diagnosis. The most common disorders were GH deficiency (13%), precocious puberty (12%), TSH deficiency (9%), and thyroidal hypothyroidism (6%). As more than one-third of the cohort never underwent endocrinological evaluation, these figures may represent an underestimate of the true incidence. For example, 6% of the cohort had linear growth > 2 standard deviations below the norm despite not carrying a diagnosis of GH deficiency. Clinical factors strongly influenced risk of developing endocrinopathy. HPA dysfunction was associated with radiotherapy, suprasellar and infratentorial tumor location, hydrocephalus, and to a lesser extent younger age and longer follow-up. Thyroid dysfunction was strongly associated with the use of craniospinal radiation for medulloblastoma; similarly, hypergonadotropic hypogonadism was strongly associated with craniospinal radiotherapy. Hydrocephalus was particularly a risk factor for precocious puberty. Patients whose tumor was not suprasellar and who did not receive radiotherapy had a very low risk of endocrinopathy; only 6 of 145 who underwent endocrine evaluation were found to have pituitary dysfunction. While the study’s retrospective nature, lack of standardization of endocrinological evaluation, and absence of evaluation in 36% of patients represent limitations, these findings emphasize the importance of regular assessment of endocrine function in pediatric brain tumor patients beginning no later than when active treatment is ended. Tumor location, the use of radiotherapy, and hydrocephalus are factors that may be useful for endocrinopathy risk stratification in survivors of pediatric brain tumors. Patient-derived chimeric antigen receptor (CAR) T cell therapy has shown efficacy in leukemia by targeting CD19 on B cells. The efficacy of the CAR T cell approach, however, has been more elusive in solid cancers possibly because of limited infiltration into solid tumors and the immunosuppressive tumor microenvironment. Achieving a sufficient intratumoral concentration is particularly challenging for brain tumors. In a single patient with a recurrent multifocal GBM (MGMT methylated, IDHR132H wildtype), Brown et al demonstrated a transient response using a CAR T cell engineered to target the glioma antigen IL13Rα2. To overcome some of the limitations with CAR T cells in solid tumors, the team modified the CAR T cells to include 4-1BB co-stimulation and a mutated IgG4-Fc linker to reduce off target Fc receptor interactions (IL13BBζ-CAR T cells). At the time of recurrence, the patient underwent resection of 3 of the recurrent tumors which allowed for placement of a catheter into 1 of the resected tumor beds. IL13BBζ-CAR T cells were then infused into the cavity weekly. While this locally treated site remained under control, new disease appeared at distant sites so the authors shifted to intraventricular infusions of IL13BBζ-CAR T cells. After 16 cycles of treatment, the patient no longer required steroids and a complete response as determined by RANO criteria was achieved. There are several interesting insights to be learned from this single case report that will need to be further evaluated in more patients. First, a CR was achieved despite heterogeneous expression of the target, IL13Rα2, in tumor tissue suggesting possible re-activation of the immune system - activation was suggested as there were increases in endogenous immune cells and cytokines within the CSF. Second, local delivery was not effective in controlling disease and intraventricular delivery was needed. Most of this particular patient’s disease appeared to be leptomeningeal so more work will need to be done to clarify penetration of CAR T cells into parenchymal tumors when the treatment is given intraventricularly. Third, toxicity was minimal with no reported grade 3 or 4 toxicities. Finally, the accumulation of CAR T cells in CSF during later cycles was less than earlier cycles which the authors attribute to decreasing tumor burden. Unfortunately, the patient recurred 228 days after the first CAR T cell infusion and the authors are exploring reasons why but suggest one reason is decreased IL13Rα2 expression. Overall, this approach is promising and is being explored in clinical trials with other targets (ex. EGFRvIII) so we will hopefully have more information to confirm if this single patient case report is a harbinger of more effective treatments for this challenging disease. Gadgeel et al. present a pooled analysis of CNS response to the ALK inhibitor, alectinib, in patients with ALK-positive non-small cell lung cancer. The analysis was performed by aggregating two prior phase II studies and evaluating response in the CNS in patients with baseline brain metastases (BM). Importantly, eligibility mandated that patients with BM entering these trials were (1) neurologically stable, i.e. asymptomatic by clinical examination; (2) not on corticosteroids; and (3) if previously treated with radiotherapy (RT) were radiographically stable in brain. Of the 136 patients with BM, 50 (37%) had measurable CNS disease as defined by RECIST. The remaining 86 (63%) patients had non-measurable disease in brain. Seventy percent of patients in both categories had prior RT and represented the previously treated and stable BM population. Only 41 (30%) patients, 16 patients in the measurable and 25 in the non-measurable disease category, had untreated BM and therefore represented occult asymptomatic BM. These two categories of BM (history of stable treated BM and occult asymptomatic BM) were the subject of analysis. There are, however, two other categories of patients with BM – those with prior BM treatment and disease progression in the CNS and those with symptomatic BM – not evaluated in the current study. These two groups of patients are most often treated with local CNS-directed therapy (surgery, RT, or combination). Lastly, there is the group of patients with no BM by history or baseline brain imaging who remain at risk for the development of brain metastases. Adjudicating response in BM previously treated with RT and stable both neurologically and by CNS imaging is challenging, notwithstanding the long interval between RT and entry onto the alectinib studies. This contrasts with the group of patients without prior CNS therapy and occult asymptomatic BM in which there is no confounding treatment effect in determining response to alectinib. By RECIST response guidelines, lesions previously treated with RT and radiographically stable are non-target non-measurable lesions and assessable only for disease progression. Therefore, duration of response in brain is probably most meaningful as a response index as is the incidence of progression in the CNS, i.e. disease failure in brain. With regards to the former, duration of response to alectinib was similar to that seen in patients with no BM at baseline. As previously noted in the EMELIA breast cancer trial and reported in the current study, the incidence of progression in the CNS varies by the presence or absence of BM at baseline, with nearly a three-fold higher failure rate in the brain in patients with baseline BM. Other measures used to determine clinical benefit in the brain, though not used in the current study, include CNS-specific quality-of-life instruments, assessing neurocognitive function (impaired in essentially all patients with BM), and time to CNS salvage therapy. With the considerable, unmet therapeutic need in patients with BM, using CNS-penetrant targeted agents in cancers with actionable mutations is not only rational but appropriate in selected patients.
Source: Neuro-Oncology
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4253462527