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<p>Metastatic, drug-resistant ovarian cancer is the deadliest form of gynecological cancer afflicting women globally, with &gt; 49% relapse rate following initial diagnosis, surgery and treatment. High-grade serous ovarian cancer is the most diagnosed type of ovarian cancer. In the USA, 21,000 patients are diagnosed annually, with &gt; 50% of patients succumbing to the disease due to metastasis and treatment resistance. The mainstay treatment for ovarian cancer is platinum-based chemotherapy, such as cisplatin or carboplatin and in combination with a taxane (paclitaxel/docetaxel). However, patients often become resistant to it, due to the pervasive oncogenic signal driving cancer drug resistance. One such oncogene is c-MYC. 30–60% of high-grade serous and drug-resistant (paclitaxel and carboplatin) ovarian cancer overexpress c-MYC, leading to progressive disease and mortality. Herein, it was shown that the novel c-MYC mRNA drug 3’UTRMYC1-18 achieved a dose-dependent titratable downregulation of the c-MYC mRNA with a half-maximal inhibitory concentration superior to the standard-of-care drugs, and with anti-cancer migration and viability properties. By using patient-derived xenograft (PDX) in-vivo, it was shown that the c-MYC mRNA drug significantly inhibited ovarian cancer through the downregulation of c-MYC, programmed death-ligand 1, paired box gene 8 and p21. This drug provides a novel therapy to target drug-resistant ovarian cancer cells.</p> Graphical Abstract <p>Aggressive metastatic ovarian cancer cells with c-MYC, PD-L1, PAX8 and p21 upregulation were treated with 3’UTRMYC1-18. The destabilized 3’UTRMYC1-18 recognizes multiple exons on the target c-MYC mRNA. During translation, the ribosome stalls in-frame on the destabilized c-MYC mRNA, which triggers the EXOSC4-PELO and RNA exosome complex to degrade the c-MYC transcript, leading to the downregulation of the c-MYC-PD-L1-PAX8-p21 complex and, in turn, to the inhibition of the ovarian cancer cells. PD-L1, programmed death-ligand 1; PAX8, paired box gene 8; EXOSC4, exosome component 4; PELO, Pelota MRNA surveillance and ribosome rescue factor. </p> <p></p>

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In vivo inhibition of c-MYC in the metastatic drug-resistant ovarian cancer cells down regulates the c-MYC-PD-L1-PAX8-p21 to achieve therapeutic efficacy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月10日

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  • Queenie Chen,
  • Jigme P. Dorji,
  • Sandali G. Perera,
  • Petvy Li,
  • Fizza Aijaz,
  • Linda C. Ihuoma,
  • Hiroshi Matsui,
  • Chidiebere U. Awah

摘要

Metastatic, drug-resistant ovarian cancer is the deadliest form of gynecological cancer afflicting women globally, with > 49% relapse rate following initial diagnosis, surgery and treatment. High-grade serous ovarian cancer is the most diagnosed type of ovarian cancer. In the USA, 21,000 patients are diagnosed annually, with > 50% of patients succumbing to the disease due to metastasis and treatment resistance. The mainstay treatment for ovarian cancer is platinum-based chemotherapy, such as cisplatin or carboplatin and in combination with a taxane (paclitaxel/docetaxel). However, patients often become resistant to it, due to the pervasive oncogenic signal driving cancer drug resistance. One such oncogene is c-MYC. 30–60% of high-grade serous and drug-resistant (paclitaxel and carboplatin) ovarian cancer overexpress c-MYC, leading to progressive disease and mortality. Herein, it was shown that the novel c-MYC mRNA drug 3’UTRMYC1-18 achieved a dose-dependent titratable downregulation of the c-MYC mRNA with a half-maximal inhibitory concentration superior to the standard-of-care drugs, and with anti-cancer migration and viability properties. By using patient-derived xenograft (PDX) in-vivo, it was shown that the c-MYC mRNA drug significantly inhibited ovarian cancer through the downregulation of c-MYC, programmed death-ligand 1, paired box gene 8 and p21. This drug provides a novel therapy to target drug-resistant ovarian cancer cells.

Graphical Abstract

Aggressive metastatic ovarian cancer cells with c-MYC, PD-L1, PAX8 and p21 upregulation were treated with 3’UTRMYC1-18. The destabilized 3’UTRMYC1-18 recognizes multiple exons on the target c-MYC mRNA. During translation, the ribosome stalls in-frame on the destabilized c-MYC mRNA, which triggers the EXOSC4-PELO and RNA exosome complex to degrade the c-MYC transcript, leading to the downregulation of the c-MYC-PD-L1-PAX8-p21 complex and, in turn, to the inhibition of the ovarian cancer cells. PD-L1, programmed death-ligand 1; PAX8, paired box gene 8; EXOSC4, exosome component 4; PELO, Pelota MRNA surveillance and ribosome rescue factor.