A Phase 2 Multi-arm, Open Label Study to Assess the Safety and Efficacy of EP0057 in Combination With Olaparib in Defined Populations of Patients With Relapsed Advanced Gastric Cancer and Small Cell Lung Cancer

The aim of EP0057 - 202 is to assess the safety and efficacy of EP0057 in combination with Olaparib (a PARP inhibitor) in two cancers where there is a high unmet need: extensive stage small cell lung cancer (SCLC) and ATM-negative gastric cancer (GC).
EP0057-202 is a non-comparative, multi-arm, multi-centre, open label, Phase 2 study to determine the efficacy, safety, and tolerability of EP0057 in combination with olaparib (an approved PARP inhibitor) in defined patient populations with relapsed* GC and SCLC.
*(see Eligibility Criteria for definition of "relapse" for each tumour type/population) The treatment cohorts will open sequentially at the Sponsor's discretion and patients may be enrolled into each cohort concurrently.
EP0057 is an investigational nanoparticle-drug conjugate administered intravenously. The rationale for developing EP0057 is to enable selective entry of EP0057 into tumour tissue and as a result create preferential accumulation of EP0057, and therefore of the payload Camptothecin, to translate into maximum tumour cell killing.

开始日期2023-04-01

申办/合作机构

Ellipses Pharma Ltd.

EUCTR2020-003083-98-GB / Unknown status临床2期

A Phase 2 study to evaluate the safety and efficacy of EP0057 in combination with Olaparib in advanced ovarian cancer patients who have: Cohort 1 – platinum resistant disease and are PARP inhibitor naïve; Cohort 2 – had at least 2 prior lines of therapy which must include at least 1 line of platinum-based chemotherapy followed by PARP inhibitor maintenance

开始日期2020-12-16

申办/合作机构

Ellipses Pharma Ltd.

100 项与 TOP1 x HIF-1α 相关的临床结果

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100 项与 TOP1 x HIF-1α 相关的转化医学

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0 项与 TOP1 x HIF-1α 相关的专利（医药）

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项与 TOP1 x HIF-1α 相关的文献（医药）

2014-01-01·Molecular Cancer Therapeutics2区 · 医学

The Natural Inhibitor of DNA Topoisomerase I, Camptothecin, Modulates HIF-1α Activity by Changing miR Expression Patterns in Human Cancer Cells

2区 · 医学

Article

作者: Fornari, Francesca ; Gramantieri, Laura ; Marinello, Jessica ; Bertozzi, Davide ; Capranico, Giovanni ; Manzo, Stefano G.

AbstractDNA topoisomerase I (Top1) inhibition by camptothecin derivatives can impair the hypoxia-induced cell transcriptional response. In the present work, we determined molecular aspects of the mechanism of camptothecin's effects on hypoxia-inducible factor-1α (HIF-1α) activity in human cancer cells. In particular, we provide evidence that low concentrations of camptothecin, without interfering with HIF-1α mRNA levels, can reduce HIF-1α protein expression and activity. As luciferase assays demonstrated the involvement of the HIF-1α mRNA 3′ untranslated region in camptothecin-induced impairment of HIF-1α protein regulation, we performed microarray analysis to identify camptothecin-induced modification of microRNAs (miRNA) targeting HIF-1α mRNA under hypoxic-mimetic conditions. The selected miRNAs were then further analyzed, demonstrating a role for miR-17-5p and miR-155 in HIF-1α protein expression after camptothecin treatments. The present findings establish miRNAs as key factors in a molecular pathway connecting Top1 inhibition and human HIF-1α protein regulation and activity, widening the biologic and molecular activity of camptothecin derivatives and the perspective for novel clinical interventions. Mol Cancer Ther; 13(1); 239–48. ©2013 AACR.

2012-05-01·Gene Expression Patterns4区 · 生物学

Differential subcellular localization of DNA topoisomerase-1 isoforms and their roles during Caenorhabditis elegans development

4区 · 生物学

Article

作者: Sejin Lee ; Sarah E. Hollis ; Myon-Hee Lee ; Udaya Sree Datla ; Eunsuk Kim ; Jinsun Ryu ; Hey Rim Jung ; Chris Li ; Dong Seok Cha ; Myeongwoo Lee ; Kyuhyung Kim

DNA topoisomerase-1 (TOP-1) resolves the topological problems associated with DNA replication, transcription and recombination by introducing temporary single-strand breaks in the DNA. Caenorhabditis elegans TOP-1 has two isoforms, TOP-1α and TOP-1β. TOP-1β is broadly localized to the nuclei of many cells at all developmental stages and concentrated in nucleoli in embryo gut and oogenic cells. However, TOP-1α is specifically localized to centrosomes, neuronal cells, excretory cells and chromosomes of germ cells in embryonic and larval stages. Reporter gene analysis also shows that top-1 transcription is highly activated in several sensory neurons, speculating the possible role of TOP-1α in neuronal development. From RNA interference (RNAi) experiments, we demonstrated that C. elegans TOP-1 is required for chromosomal segregation, germline proliferation and gonadal migration, which are all correlated with the expression and activity of TOP-1. Therefore, our findings may provide an insight into a new role of TOP-1 in development of multicellular organisms.

2010-12-01·Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

Dissecting the transcriptional functions of human DNA topoisomerase I by selective inhibitors: Implications for physiological and therapeutic modulation of enzyme activity

Review

作者: Jessica Marinello ; Giovanni Capranico ; Laura Baranello

Camptothecin is a selective inhibitor of DNA topoisomerase I, and has effective antitumor activity. Recently, camptothecin has been shown to activate the transcription of low-abundance antisense RNAs at the HIF-1α gene locus in human cancer cells in a Topoisomerase I-dependent manner. The activation of antisense transcription is likely due to sustained drug interference with transcription regulation mechanisms leading to a more open chromatin conformation and de-repression/activation of antisense transcription. Camptothecin readily inhibits Topoisomerase I in cells, and the enzyme inhibition activates transcriptional Cdk (Cdk9 and/or Cdk7) activity leading to the hyperphosphorylation of the CTD of the largest subunit of RNA polymerase II (RNAP II). This results in an alteration of RNAP II regulation with specific effects at transcription levels. Thus, the findings have documented that camptothecin can interfere with specific transcription regulatory steps, impairing the balance of cellular antisense and sense transcripts at the HIF-1α gene locus. That may have a considerable impact on cancer therapy development particularly for non-responsive human tumors.