Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methlation inhibitor guadecitabine
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE90681 | GEO | 2017/01/01
SECONDARY ACCESSION(S): PRJNA355320
REPOSITORIES: GEO
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Project description:Germ cell tumors (GCTs) can be cured with cisplatin-based therapy, although a clinically significant number of patents are refractory and die of progressive disease. Based on preclinical studies indicating that refractory testicular GCTs are hypersensitive to hypomethylating agents (HMA), we conducted a phase I trial [NCT02429466] of the next-generation HMA guadecitabine (SGI-110) in combination with cisplatin in patients with recurrent, cisplatin-resistant GCTs. The primary endpoint was safety and toxicity including DLT and MTD. A total of 14 patients were enrolled. The majority of patients were heavily pretreated. MTD was determined to be 30 mg/m2 guadecitabine followed by cisplatin 100 mg/m2. DLTs were neutropenia and thrombocytopenia. Three patients had partial responses by RECIST criteria, two of these patients qualified as complete responses by serum tumor marker criteria with survival of 16 and 26 months. Three patients also had stable disease for an overall response rate of 23% and clinical benefit rate of 46%. Genome-wide analysis pre- and post-guadecitabine indicated dramatic and widespread global DNA demethylation in cell-free plasma samples including in the promoters of genes of cancer related pathways. In summary, the combination of guadecitabine followed by cisplatin was tolerable and demonstrated biological activity in patients with platinum refractory GCTs.
2020-12-25 | GSE152802 | GEO
Project description:Testicular germ cell tumors (TGCTs) are the most common cancers of young males. A substantial portion of TGCT patients are refractory to cisplatin. There are no effective therapies for these patients, many of whom die from progressive disease. Embryonal carcinoma (EC) are the stem cells of TGCTs. In prior in vitro studies we found that EC cells were highly sensitive to the DNA methyltransferase inhibitor, 5-aza deoxycytidine (5-aza). Here, as an initial step in bringing demethylation therapy to the clinic for TGCT patients, we evaluated the effects of the clinically optimized, second generation demethylating agent guadecitabine (SGI-110) on EC cells in an animal model of cisplatin refractory testicular cancer. EC cells were exquisitely sensitive to guadecitabine and the hypersensitivity was dependent on high levels of DNA methyltransferase 3B. Guadecitabine mediated transcriptional reprogramming of EC cells included induction of p53 targets and repression of pluripotency genes. As a single agent, guadecitabine completely abolished progression and induced complete regression of cisplatin resistant EC xenografts even at doses well below those required to impact somatic solid tumors. Low dose guadecitabine also sensitized refractory EC cells to cisplatin in vivo. Genome-wide analysis indicated that in vivo antitumor activity was associated with activation of p53 and immune-related pathways and the antitumor effects of guadecitabine were dependent on p53, a gene rarely mutated in TGCTs. These preclinical findings suggest that guadecitabine alone or in combination with cisplatin is a promising strategy to treat refractory TGCT patients.
| S-EPMC5356854 | biostudies-literature
Project description:Testicular germ cell tumors (TGCTs) can be treated with cisplatin-based therapy. However, a clinically significant number of cisplatin-resistant patients die from progressive disease as no effective alternatives exist. Curative cisplatin therapy results in acute and life-long toxicities in the young TGCT patient population providing a rationale to decrease cisplatin exposure. In contrast to genetic alterations, recent evidence suggests that epigenetics is a major driving factor for TGCT formation, progression, and response to chemotherapy. Hence, targeting epigenetic pathways with “epidrugs” is one potential relatively unexplored strategy to advance TGCT treatment beyond cisplatin. In this report, we demonstrate for the first time that targeting polycomb demethylases KDM6A and KDM6B with epidrug GSK-J4 can treat both cisplatin-sensitive and -resistant TGCTs. While GSK-J4 had minimal effects alone on TGCT tumor growth in vivo, it dramatically sensitized cisplatin-sensitive and -resistant TGCTs to cisplatin. We validated KDM6A/KDM6B as the target of GSK-J4 since KDM6A/KDM6B genetic depletion had a similar effect to GSK-J4 on cisplatin-mediated anti-tumor activity and transcriptome alterations. Pharmacologic and genetic targeting of KDM6A/KDM6B potentiated or primed the p53-dominant transcriptional response to cisplatin, with also evidence for basal activation of p53. Further, several chromatin modifier genes, including BRD4, lysine demethylases, chromodomain helicase DNA binding proteins, and lysine methyltransferases, were repressed with cisplatin only in KDM6A/KDM6B-targeted cells, implying that KDM6A/KDM6B inhibition sets the stage for extensive chromatin remodeling of TGCT cells upon cisplatin treatment. Our findings demonstrate that targeting polycomb demethylases is a new potent pharmacologic strategy for treating cisplatin resistant TGCTs that warrants clinical development.
2024-10-01 | GSE278498 | GEO
Project description:To clarify the mechanism of cisplatin resistance in testicular germ cell tumor (TGCT), cisplatin-resistant TGCT cells (N8R and G9R) were generated from parental NEC8 cells (N8P) and TGCT patient-derived cells (TGCT-PDC)(G9P), respectively, by culture in medium containing cisplatin. We used microarrays to detail the global programme of gene expression underlying cisplatin resistance and identified up- and down-regulated genes during this process.
2022-10-17 | GSE197347 | GEO
Project description:Guadecitabine is a second generation DNA methylation inhibitor with improved pharmacokinetics and clinical activity in relapsed/refractory AML (rrAML). Here we report genome-wide DNA methylation profiles in pre-treatment samples from 116 rrAML patients treated at therapeutic doses of guadecitabine in a phase I/II study. Response rate to guadecitabine was 22 % (16CR, 42 12CRi/CRp). There were no strong mutation or methylation predictors of response. Gene expression defined a subset of patients (~20%) that had (i) high DNMT3B and low CDKN2B, CTCF and CDA expression, (ii) enrichment for KRAS/NRAS mutations, (iii) frequent CpG island hypermethylation (iv) low LINE1 hypomethylation after treatment and (v) resistance to guadecitabine in both phase I (response rate 0 % vs 33 %, p=0.07) and phase II components of the study (response rate 5 % vs. 30 %, p=0.02). Multivariate analysis identified peripheral blood blasts and hemoglobin as predictors of response and cytogenetics, gene expression, RAS mutations and hemoglobin as predictors of survival. Thus, a subset of patients (∿ 20%) with rrAML are unlikely to benefit from single agent guadecitabine. In the remaining 80%, guadecitabine is a viable option with a median survival of ∿ 8 months and a three year survival rate of over 20%.
2019-08-06 | GSE112838 | GEO
Project description:A phase 1 study of guadecitabine plus cisplatin in platinum refractory germ cell tumors [Methylation]
| PRJNA640431 | ENA
Project description:We used DNA content-based flow cytometry to distinguish and isolate nuclei of clonal tumor populations from primary and metastatic refractory testicular germ cell tumors (TGCTs) tissues. We then interrogated each sorted tumor populationwith whole genome aCGH and next generation sequencing (NGS). we have explored the clonal basis of refractory TGCT by investigating distinct tumor populations that were present in each tumor. Notably this included resected primary tissues and treatment refractory metastases that arose after high dose chemotherapy. These results provide new knowledge regarding the role of clonal selection and selected genomic lesions in the resistance to chemotherapy in TGCT within this exceptional cohort.
2019-02-26 | GSE123464 | GEO
Project description:Clonal Analyses of Refractory Testicular Germ Cell Tumors
| PRJNA508792 | ENA
Project description:A greater understanding of the hypersensitivity and curability of testicular germ cell tumors (TGCTs) has the potential to inform strategies to sensitize other solid tumors to conventional chemotherapies. More than 80% of metastatic TGCT patients are cured with cisplatin-based chemotherapy. However, resistance can occur, which results in poor outcomes. The mechanisms of cisplatin hypersensitivity and resistance in these tumors and embryonal carcinoma (EC), the stem cells of TGCTs, remain largely undefined. To study the mechanisms of cisplatin acquired resistance we generated a large panel of independently derived, acquired resistant clones from three distinct parental EC models employing a protocol designed to match standard of care regimens of TGCT patients. Transcriptomics revealed highly significant alterations shared between resistant cells regardless of their parental origin. This included a highly significant enrichment of genes normally repressed by H3K27 methylation and the polycomb repressive complex 2 (PRC2) which correlated with a substantial decrease in global H3K27me3, H2AK119 ubiquitination and expression of BMI1. Importantly repression of H3K27 methylation with the EZH2 inhibitor GSK-126 conferred cisplatin resistance to parental cells while induction of H3K27 methylation with the histone lysine demethylase inhibitor GSK-J4 resulted in increased cisplatin sensitivity to resistant cells. A gene signature based on H3K27me gene enrichment was associated with an increased rate of recurrent/progressive disease in testicular cancer patients. Our data indicates that repression of H3K27 methylation may be a mechanism of cisplatin acquired resistance in TGCTs and that restoration of PRC2 complex function could be a viable approach to overcome treatment failure.
2019-11-11 | GSE129696 | GEO
Project description:Molecular basis of cisplatin resistance in testicular germ cell tumors
| PRJNA562689 | ENA