Trametinib for a child with refractory Rosai-Dorfman-Destombes disease harboring a novel somatic mutation in MAP2K1.

Rosai-Dorfman-Destombes disease (RDD) is a rare histiocytosis characterized by accumulation of S100 + , CD68 + , and CD1a- histiocytes, with emperipolesis. It occurs predominantly in black adolescents and young adults, but rarely in Japanese children. Recently, oncogenic mutations in mitogen-activated protein kinase (MAPK) pathway genes were reported in 30-50% of patients with RDD, and several studies have described treatment of adult patients with MAPK inhibitors. Here, we present the case of a Japanese boy with refractory RDD without signs of cardiofaciocutaneous (CFC) syndrome who harbored MAP2K1 p.Lys59del and responded to trametinib. The patient had lymph node, nasal cavity, kidney, upper respiratory tract, and intracranial involvement. RDD progressed after multi-agent chemotherapy, but responded to trametinib (0.025 mg/kg). Trametinib did not eliminate the mass lesions, but trametinib plus minimal prednisolone (0.1 mg/kg) resulted in a good outcome for more than 15 months, without significant adverse effects. MAP2K1 p.Lys59del has been described as a germline mutation in a patient with CFC syndrome, but not as a somatic mutation in patients with malignancies. Trametinib may be a promising drug for children with RDD that is refractory to multi-agent chemotherapy. Its long-term efficacy and safety alone and in combination with chemotherapy should be investigated.

Erratum: Combining peptide TNIIIA2 with all-trans retinoic acid accelerates N-Myc protein degradation and neuronal differentiation in MYCN-amplified neuroblastoma cells.

[This corrects the article on p. 434 in vol. 9, PMID: 30906641.].

Targeting FROUNT with disulfiram suppresses macrophage accumulation and its tumor-promoting properties.

Tumor-associated macrophages affect tumor progression and resistance to immune checkpoint therapy. Here, we identify the chemokine signal regulator FROUNT as a target to control tumor-associated macrophages. The low level FROUNT expression in patients with cancer correlates with better clinical outcomes. Frount-deficiency markedly reduces tumor progression and decreases macrophage tumor-promoting activity. FROUNT is highly expressed in macrophages, and its myeloid-specific deletion impairs tumor growth. Further, the anti-alcoholism drug disulfiram (DSF) acts as a potent inhibitor of FROUNT. DSF interferes with FROUNT-chemokine receptor interactions via direct binding to a specific site of the chemokine receptor-binding domain of FROUNT, leading to inhibition of macrophage responses. DSF monotherapy reduces tumor progression and decreases macrophage tumor-promoting activity, as seen in the case of Frount-deficiency. Moreover, co-treatment with DSF and an immune checkpoint antibody synergistically inhibits tumor growth. Thus, inhibition of FROUNT by DSF represents a promising strategy for macrophage-targeted cancer therapy.

Inactivation of beta1 integrin induces proteasomal degradation of Myc oncoproteins.

The MYC family oncogenes (MYC, MYCN, and MYCL) contribute to the genesis of many human cancers. Among them, amplification of the MYCN gene and over-expression of N-Myc protein are the most reliable risk factors in neuroblastoma patients. On the other hand, we previously found that a peptide derived from fibronectin, termed FNIII14, is capable of inducing functional inactivation in ß1-integrins. Here, we demonstrate that inactivation of ß1-integrin by FNIII14 induced proteasomal degradation in N-Myc of neuroblastoma cells with MYCN amplification. This N-Myc degradation by FNIII14 reduced the malignant properties, including the anchorage-independent proliferation and invasive migration, of neuroblastoma cells. An in vivo experiment using a mouse xenograft model showed that the administration of FNIII14 can inhibit tumor growth, and concomitantly a remarkable decrease in N-Myc levels in tumor tissues. Of note, the activation of proteasomal degradation based on ß1-integrin inactivation is applicable to another Myc family oncoprotein, c-myc, which also reverses cancer-associated properties in pancreatic cancer cells. Collectively, ß1-integrin inactivation could be a new chemotherapeutic strategy for cancers with highly expressed Myc. FNIII14, which is a unique pharmacological agent able to induce ß1-integrin inactivation, may be a promising drug targeting Myc oncoproteins for cancer chemotherapy.

Combining peptide TNIIIA2 with all-trans retinoic acid accelerates N-Myc protein degradation and neuronal differentiation in MYCN-amplified neuroblastoma cells.

Neuroblastoma is one of the common solid tumors of childhood. Nearly half of neuroblastoma patients are classified into the high-risk group, and their 5-year event-free survival (EFS) rates remain unsatisfactory in the range of 30-40%. High-risk neuroblastoma is characterized by amplification of the MYCN gene and excessive expression of its protein product, N-Myc. Because N-Myc is a transcription factor for various pro-proliferative proteins, the excessive expression causes aberrant or blocked neuronal differentiation during development of sympathetic nervous system, which is a central aspect of neuroblastoma genesis. The current main treatment for high-risk neuroblastoma is intensive chemotherapy using anti-cancer drugs that induce apoptosis in tumor cells, but intensive chemotherapy has another serious risk of long-lasting side effects, so-called "late effects", that occur many years after chemotherapy has ended. As a solution for such situation, differentiation therapy has been expected as a mild chemotherapy with a low risk of late effects, and an application of retinoic acid (RA) and its derivatives as treatment for high-risk neuroblastoma has long been attempted. However, the clinical outcome has not been sufficient with the use of retinoids, including all-trans retinoic acid (ATRA), mainly because of the inhibition of differentiation caused by N-Myc. In the present study, we succeeded in synergistically accelerating the ATRA-induced neuronal differentiation of MYCN-amplified neuroblastoma cells by combining a peptide derived from tenascin-C, termed TNIIIA2, which has a potent ability to activate ß1-integrins. Accelerated differentiation was caused by a decrease in N-Myc protein level in neuroblastoma cells after the combined treatment of TNIIIA2 with ATRA. That is, combination treatment using ATRA with TNIIIA2 induced proteasomal degradation in the N-Myc oncoprotein of neuroblastoma cells with MYCN gene amplification, and this caused acceleration of neuronal differentiation and attenuation of malignant properties. Furthermore, an in vivo experiment using a xenograft mouse model showed a therapeutic potential of the combination administration of ATRA and TNIIIA2 for high-risk neuroblastoma. These results provide a new insight into differentiation therapy for high-risk neuroblastoma based on N-Myc protein degradation.

Genome-wide association study of cervical cancer suggests a role for ARRDC3 gene in human papillomavirus infection.

The development of cervical cancer is initiated by human papillomavirus (HPV) infection and involves both viral and host genetic factors. Genome-wide association studies (GWAS) of cervical cancer have identified associations in the HLA locus and two loci outside HLA, but the principal genes that control infection and pathogenesis have not been identified. In the present study, we performed GWAS of cervical cancer in East Asian populations, involving 2609 cases and 4712 controls in the discovery stage and 1461 cases and 3295 controls in the follow-up stage. We identified novel-significant associations at 5q14 with the lead single nucleotide polymorphism (SNP) rs59661306 (P = 2.4 × 10-11) and at 7p11 with the lead SNP rs7457728 (P = 1.2 × 10-8). In 5q14, the chromatin region of the GWAS-significant SNPs was found to be in contact with the promoter of the ARRDC3 (arrestin domain-containing 3) gene. In our functional studies, ARRDC3 knockdown in HeLa cells caused significant reductions in both cell growth and susceptibility to HPV16 pseudovirion infection, suggesting that ARRDC3 is involved in the infectious entry of HPV into the cell. Our study advances the understanding of host genes that are responsible for cervical cancer susceptibility and guides future research on HPV infection and cancer development.

MicroRNA induction by copy number gain is associated with poor outcome in squamous cell carcinoma of the lung.

Copy number gains in cancer genomes have been shown to induce oncogene expression and promote carcinogenesis; however, their role in regulating oncogenic microRNAs (onco-miRNAs) remains largely unknown. Our aim was to identify onco-miRNAs induced by copy number gains in human squamous cell carcinoma (Sq) of the lung. We performed a genome-wide screen of onco-miRNAs from 245 Sqs using data sets from RNA-sequencing, comparative genomic hybridization, and the corresponding clinical information from The Cancer Genome Atlas. Among 1001 miRNAs expressed in the samples, 231 were correlated with copy number alternations, with only 11 of these being highly expressed in Sq compared to adenocarcinoma and normal tissues. Notably, miR-296-5p, miR-324-3p, and miR-3928-3p expression was significantly associated with poor prognosis. Multivariate analysis using the Cox proportional hazards model showed that miRNA expression and smoking were independent prognostic factors and were associated with poor prognosis. Furthermore, the three onco-miRNAs inhibited FAM46C to induce MYC expression, promoting proliferation of Sq cells. We found that copy number gains in Sq of the lung induce onco-miRNA expression that is associated with poor prognosis.

Ceritinib Treatment for Carcinomatous Meningitis with a Secondary Mutation at I1171T in Anaplastic Lymphoma Kinase.

The mechanisms underlying anaplastic lymphoma kinase (ALK) resistance have not been well investigated in clinical practice. We herein report the case of a lung cancer patient with carcinomatous meningitis who had an ALK I1171T resistance mutation revealed by direct DNA sequencing of the cerebrospinal fluid after treatment with cytotoxic chemotherapy, crizotinib, and alectinib. I1171T is considered to be sensitive to ceritinib. Although ceritinib was not effective initially, we chose ceritinib again after whole-brain radiotherapy and ventriculoperitoneal shunting. Although the response duration was short, spinal magnetic resonance imaging revealed a marked response. The identification of an acquired ALK resistance mutation will aid in choosing the optimum sequence therapy.

Clinical significance of the 2016 WHO classification in Japanese patients with gliomas.

In this study, we retrospectively compared the prognostic value of the 2016 WHO classification with the former classification in 387 patients with glioma treated at our institution. According to the new classification, diagnoses included oligodendroglioma with isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion (5.4%), anaplastic oligodendroglioma with IDH mutation and 1p/19q co-deletion (3.4%), diffuse astrocytoma IDH-mutated (3.9%), anaplastic astrocytoma IDH-mutated (2.8%), glioblastoma IDH-mutated (7.8%), glioblastoma IDH-wildtype (58.4%), diffuse midline glioma H3 K27M mutation (2.6%), oligodendroglioma NOS (1.3%), anaplastic oligodendroglioma NOS (0.8%), diffuse astrocytoma IDH-wildtype (2.8%), and anaplastic astrocytoma IDH-wildtype (10.9%). The prognoses of IDH-mutated astrocytomas clearly varied according to tumor grade. However, we identified no survival difference between IDH-wildtype anaplastic astrocytomas and glioblastomas; additionally, these tumors showed similar gene expression profiles. After exclusion of those without 1p/19q co-deletion, patients with oligodendroglial tumors showed excellent survival regardless of tumor grade. Our evaluation of chromosomal aberrations suggests that the MAPK/PI3K pathway plays a role in acquired malignancy of astrocytic tumors, whereas TP53 participates in tumorigenesis. We suspect the RB pathway also plays a role in tumorigenesis of IDH-mutated gliomas. The new WHO classification more clearly reflects the tumorigenesis of gliomas and improves the prognostic power of classification.

Genetic alterations in Japanese extrahepatic biliary tract cancer.

Biliary tract cancer (BTC) is one of the most devastating types of malignant neoplasms worldwide. However, the mechanisms underlying the development and progression of BTC remain unresolved. BTC includes extrahepatic bile duct carcinoma (EBDC), gallbladder carcinoma (GBC) and ampulla of Vater carcinoma (AVC), named according to the location of the tumor. Although genetic alterations of intrahepatic cholangiocarcinoma have been investigated, those of EBDC, GBC and AVC have not yet been fully understood. The present study analyzed somatic mutations of 50 cancer-associated genes in 27 Japanese BTC cells, including: 11 EBDC, 14 GBC and 2 AVC. Next-generation sequencing using an Ion AmpliSeq Cancer Panel identified a total of 44 somatic mutations across 14 cancer-associated genes. Among the 44 mutations, 42 were judged as pathological mutations. Frequent mutations were identified in tumor protein 53 (TP53) (14/27), SMAD family member 4 (SMAD4) (6/27), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA) (6/27), and Kirsten rat sarcoma (KRAS) (6/27); no significant differences were identified between EBDC and GBC tissues. Notably, the frequency of the PIK3CA mutation was higher when compared with previous reports. This result may suggest that the activation of the PIK3CA-protein kinase B signaling pathway, in addition to the abrogation of p53, SMAD4 and RAS mitogen-activated protein kinase may have a crucial role in the carcinogenesis of Japanese BTC. These findings may be useful for the development of personalized therapies for BTC.

Panel of autoantibodies against multiple tumor-associated antigens for detecting gastric cancer.

Gastric cancer is the second leading cause of cancer death in the world, and effective diagnosis is extremely important for good outcome. We assessed the diagnostic potential of an autoantibody panel that may provide a novel tool for the early detection of gastric cancer. We analyzed data from patients with gastric cancer and normal controls in test and validation cohorts. Autoantibody levels were measured against a panel of six tumor-associated antigens (TAAs) by ELISA: p53, heat shock protein 70, HCC-22-5, peroxiredoxin VI, KM-HN-1, and p90 TAA. We assessed serum autoantibodies in 100 participants in the test cohort. The validation cohort comprised 248 participants. Autoantibodies to at least one of the six antigens showed a sensitivity/specificity of 49.0% (95% confidence interval [CI], 39.2-58.8%)/92.4% (95% CI, 87.2-97.6%), and 52.0% (95% CI, 42.2-61.8%)/90.5% (95% CI, 84.8-96.3%) in the test and validation cohorts, respectively. In the validation cohort, no significant differences were seen when patients were subdivided based on age, sex, depth of tumor invasion, lymph node metastasis, distant metastasis, peritoneal dissemination, or TNM stage. Patients who were positive for more than two antibodies in the panel tended to have a worse prognosis than those who were positive for one or no antibody. Measurement of autoantibody response to multiple TAAs in an optimized panel assay to discriminate patients with early stage gastric cancer from normal controls may aid in the early detection of gastric cancer.

The influence of carmustine wafer implantation on tumor bed cysts and peritumoral brain edema.

The development of perifocal edema and tumor bed cyst has been reported after implantation of biodegradable carmustine wafers for the treatment of malignant gliomas. We retrospectively evaluated these changes in a series of patients; 19 consecutive patients with malignant glioma who received carmustine wafer implantation at our hospital from January 2013 through July 2013, and 28 patients who underwent surgery prior to our institution's initiation of carmustine wafer implantation, as historical controls. The volume of the tumor bed cyst and perifocal edema was calculated on MRI acquired at four time points: ⩽72hours after surgery for baseline, and at 1-4, 5-8, and 9-12weeks after surgery. The volume of the tumor bed cyst in the wafer group increased significantly relative to the control group at all time points (p=0.04). Opening of the ventricle was inversely correlated with enlargement of the tumor bed cyst in the wafer group (p=0.04). The change in the volume of perifocal edema in the wafer group was not significantly different (p=0.48), but exhibited a considerable increase in patients with anaplastic oligodendroglioma relative to glioblastoma patients in the wafer group (p=0.01). We demonstrated significant enlargement of the tumor bed cyst volume after carmustine wafer implantation, as well as the development of marked perifocal edema in patients with anaplastic oligodendroglioma.

NY-ESO-1 autoantibody as a tumor-specific biomarker for esophageal cancer: screening in 1969 patients with various cancers.

BACKGROUND: Although serum NY-ESO-1 antibodies (s-NY-ESO-1-Abs) have been reported in patients with esophageal carcinoma, this assay system has not been used to study a large series of patients with various other cancers. PATIENTS AND METHODS: Serum samples of 1969 cancer patients [esophageal cancer (n = 172), lung cancer (n = 269), hepatocellular carcinoma (n = 91), prostate cancer (n = 358), gastric cancer (n = 313), colorectal cancer (n = 262), breast cancer (n = 365)] and 74 healthy individuals were analyzed using an originally developed enzyme-linked immunosorbent assay system for s-NY-ESO-1-Abs. The optical density cut-off value, determined as the mean plus three standard deviations for serum samples from the healthy controls, was fixed at 0.165. Conventional tumor markers were also evaluated in patients with esophageal carcinoma. RESULTS: The positive rate of s-NY-ESO-1-Abs in patients with esophageal cancer (31 %) was significantly higher than that in the other groups: patients with lung cancer (13 %), patients with hepatocellular carcinoma (11 %), patients with prostate cancer (10 %), patients with gastric cancer (10 %), patients with colorectal cancer (8 %), patients with breast cancer (7 %), and healthy controls (0 %). The positive rate of s-NY-ESO-1-Abs was comparable to that of serum p53 antibodies (33 %), squamous cell carcinoma antigen (36 %), carcinoembryonic antigen (26 %), and CYFRA 21-1 (18 %) and gradually increased with the tumor stage. CONCLUSIONS: The positive rate of s-NY-ESO-1-Abs was significantly higher in patients with esophageal cancer than in patients with the other types of cancers. On the basis of its high specificity and sensitivity, even in patients with stage I tumors, s-NY-ESO-1-Abs may be one of the first choices for esophageal cancer.

Sendai virus-mediated expression of reprogramming factors promotes plasticity of human neuroblastoma cells.

Neuroblastoma (NB) is the most common extracranial solid tumor that originates from multipotent neural crest cells. NB cell populations that express embryonic stem cell-associated genes have been identified and shown to retain a multipotent phenotype. However, whether somatic reprogramming of NB cells can produce similar stem-cell like populations is unknown. Here, we sought to reprogram NB cell lines using an integration-free Sendai virus vector system. Of four NB cell lines examined, only SH-IN cells formed induced pluripotent stem cell-like colonies (SH-IN 4F colonies) at approximately 6 weeks following transduction. These SH-IN 4F colonies were alkaline phosphatase-positive. Array comparative genomic hybridization analysis indicated identical genomic aberrations in the SH-IN 4F cells as in the parental cells. SH-IN 4F cells had the ability to differentiate into the three embryonic germ layers in vitro, but rather formed NBs in vivo. Furthermore, SH-IN 4F cells exhibited resistance to cisplatin treatment and differentiated into endothelial-like cells expressing CD31 in the presence of vascular endothelial growth factor. These results suggest that SH-IN 4F cells are partially reprogrammed NB cells, and could be a suitable model for investigating the plasticity of aggressive tumors.

NCYM promotes calpain-mediated Myc-nick production in human MYCN-amplified neuroblastoma cells.

NCYM is a cis-antisense gene of MYCN and is amplified in human neuroblastomas. High NCYM expression is associated with poor prognoses, and the NCYM protein stabilizes MYCN to promote proliferation of neuroblastoma cells. However, the molecular mechanisms of NCYM in the regulation of cell survival have remained poorly characterized. Here we show that NCYM promotes cleavage of MYCN to produce the anti-apoptotic protein, Myc-nick, both in vitro and in vivo. NCYM and Myc-nick were induced at G2/M phase, and NCYM knockdown induced apoptotic cell death accompanied by Myc-nick downregulation. These results reveal a novel function of NCYM as a regulator of Myc-nick production in human neuroblastomas.

Functional interplay between MYCN, NCYM, and OCT4 promotes aggressiveness of human neuroblastomas.

Neuroblastoma is a pediatric solid tumor that originates from embryonic neural crest cells. The MYCN gene locus is frequently amplified in unfavorable neuroblastomas, and the gene product promotes the progression of neuroblastomas. However, the molecular mechanisms by which MYCN amplification contributes to stem cell-like states of neuroblastoma remain elusive. In this study, we show that MYCN and its cis-antisense gene, NCYM, form a positive feedback loop with OCT4, a core regulatory gene maintaining a multipotent state of neural stem cells. We previously reported that NCYM is co-amplified with the MYCN gene in primary human neuroblastomas and that the gene product promotes aggressiveness of neuroblastoma by stabilization of MYCN. In 36 MYCN-amplified primary human neuroblastomas, OCT4 mRNA expression was associated with unfavorable prognosis and was correlated with that of NCYM. The OCT4 protein induced both NCYM and MYCN in human neuroblastoma cells, whereas NCYM stabilized MYCN to induce OCT4 and stem cell-related genes, including NANOG, SOX2, and LIN28. In sharp contrast to MYCN, enforced expression of c-MYC did not enhance OCT4 expression in human neuroblastoma cells. All-trans retinoic acid treatment reduced MYCN, NCYM, and OCT4 expression, accompanied by the decreased amount of OCT4 recruited onto the intron 1 region of MYCN. Knockdown of NCYM or OCT4 inhibited formation of spheres of neuroblastoma cells and promoted asymmetric cell division in MYCN-amplified human neuroblastoma cells. These results suggest that the functional interplay between MYCN, NCYM, and OCT4 contributes to aggressiveness of MYCN-amplified human neuroblastomas.

Frequency of brain metastases in non-small-cell lung cancer, and their association with epidermal growth factor receptor mutations.

BACKGROUND: The brain is a frequent site of metastases from non-small-cell lung cancer (NSCLC). We analyzed the frequency of brain metastases (BMs) from NSCLC in the era of magnetic resonance images, and evaluated the correlation between epidermal growth factor receptor (EGFR) mutations and BMs among East Asian patients. METHODS: Frequency, number, and size of BMs, and survival of 1,127 NSCLC patients were retrospectively reviewed. Mutation status of EGFR was evaluated in all cases, and its association with BMs was statistically evaluated. RESULTS: EGFR mutations were found for 331 cases (29.4 %). BM was the cause of primary symptoms for 52 patients (4.6 %), and found before initiation of treatment for 102 other patients (9.1 %); In addition to these 154 patients, 107 patients (9.5 %) developed BMs, giving a total of 261 patients (23.2 %) who developed BMs from 1,127 with NSCLC. BM frequency was higher among EGFR-mutated cases (31.4 %) than EGFR-wild cases (19.7 %; odds ratio: 1.86; 95 % confidence interval (CI) 1.39-2.49; P < 0.001). BMs from EGFR-mutated NSCLC were small, but often became disseminated. EGFR mutations accounted for 39.9 % of BMs, but patient survival after BMs was significantly longer for EGFR-mutated cases than for EGFR-wild cases (hazard ratio: 2.23; 95 % CI 1.62-3.10; P < 0.001). CONCLUSIONS: Patients with EGFR-mutated NSCLC were more likely to develop BMs, but apparently also survived longer after BMs.

Phase 2 trial of hypofractionated high-dose intensity modulated radiation therapy with concurrent and adjuvant temozolomide for newly diagnosed glioblastoma.

PURPOSE/OBJECTIVES: To assess the effect and toxicity of hypofractionated high-dose intensity modulated radiation therapy (IMRT) with concurrent and adjuvant temozolomide (TMZ) in 46 patients with newly diagnosed glioblastoma multiforme (GBM). METHODS AND MATERIALS: All patients underwent postsurgical hypofractionated high-dose IMRT. Three layered planning target volumes (PTVs) were contoured. PTV1 was the surgical cavity and residual tumor on T1-weighted magnetic resonance images with 5-mm margins, PTV2 was the area with 15-mm margins surrounding the PTV1, and PTV3 was the high-intensity area on fluid-attenuated inversion recovery images. Irradiation was performed in 8 fractions at total doses of 68, 40, and 32 Gy for PTV1, PTV2, and PTV3, respectively. Concurrent TMZ was given at 75 mg/m(2)/day for 42 consecutive days. Adjuvant TMZ was given at 150 to 200 mg/m(2)/day for 5 days every 28 days. Overall and progression-free survivals were evaluated. RESULTS: No acute IMRT-related toxicity was observed. The dominant posttreatment failure pattern was dissemination. During a median follow-up time of 16.3 months (range, 4.3-80.8 months) for all patients and 23.7 months (range, 12.4-80.8 months) for living patients, the median overall survival was 20.0 months after treatment. Radiation necrosis was diagnosed in 20 patients and was observed not only in the high-dose field but also in the subventricular zone (SVZ). Necrosis in the SVZ was significantly correlated with prolonged survival (hazard ratio, 4.08; P=.007) but caused deterioration in the performance status of long-term survivors. CONCLUSIONS: Hypofractionated high-dose IMRT with concurrent and adjuvant TMZ altered the dominant failure pattern from localized to disseminated and prolonged the survival of patients with GBM. Necrosis in the SVZ was associated with better patient survival, but the benefit of radiation to this area remains controversial.

Temozolomide suppresses MYC via activation of TAp63 to inhibit progression of human glioblastoma.

Glioblastoma multiforme (GBM) is a highly invasive and chemoradioresistant brain malignancy. Temozolomide (TMZ), a DNA-alkylating agent, is effective against GBM and has become the standard first-line drug. However, the mechanism by which TMZ regulates the progression of GBM remains elusive. Here, we demonstrate that TMZ targets TAp63, a p53 family member, inducing its expression to suppress the progression of human GBM. High levels of TAp63 expression in GBM tissues after TMZ treatment was an indicator of favourable prognosis. In human GBM cells, TMZ-induced TAp63 directly repressed MYC transcription. Activation of this TAp63-MYC pathway by TMZ inhibited human GBM progression both in vitro and in vivo. Furthermore, downregulation of MYC mRNA levels in recurrent GBMs after TMZ treatment correlated with better patient survival. Therefore, our results suggest that the TAp63-mediated transcriptional repression of MYC is a novel pathway regulating TMZ efficacy in GBM.