<p>Intrahepatic cholangiocarcinoma (iCCA) is an epithelial malignancy arising from intrahepatic biliary tract, characterised by a dismal prognosis with limited therapeutic alternatives.<span><sup>1</sup></span> The standard first-line treatment for patients with unresectable iCCA includes gemcitabine-based chemotherapy and immunotherapy. However, the objective response rate (ORR) of first-line treatment is below 30%, and there is currently insufficient evidence to support the use of second-line chemotherapy.<span><sup>2, 3</sup></span> This underscores an urgent need to identify novel therapeutic targets and effective drugs for iCCA.</p><p>Our previous research has demonstrated that phosphatase and tension homolog (PTEN), a tumour suppressor which counteracts phosphatidylinositol 3-kinase (PI3K)–AKT signalling, is frequently mutated or deleted in iCCA.<span><sup>4</sup></span> We established a spontaneous iCCA model in mice through liver-specific PTEN disruption and Kras activation, highlighting the crucial role of PTEN in iCCA tumourigenesis.<span><sup>5</sup></span> Importantly, we identified PTEN as a pivotal regulator of both the lysosomal and proteasomal systems, which are essential for maintaining cellular proteostasis in CCA cells. PTEN drives lysosome biogenesis and acidification through its protein phosphatase activity, which dephosphorylates transcription factor EB (TFEB) at Ser211, thereby regulating exosome secretion and iCCA metastasis.<span><sup>6</sup></span> Simultaneously, PTEN inhibits proteasomal transcription via its lipid phosphatase activity in a BACH1/MAFF-dependent manner.<span><sup>7</sup></span> Consequently, PTEN deficiency enhances protein synthesis and proteasomal activity, creating a dependency on the proteasome for iCCA cell growth and survival. Therefore, targeting the proteasome machinery by inhibitor bortezomib induces more apoptosis in PTEN-deficient iCCA cells.</p><p>We subsequently conducted a clinical trial (NCT03345303) to assess whether PTEN-deficient iCCA patients could benefit from bortezomib treatment after failure of first-line chemotherapy, investigating PTEN as a potential biomarker for proteasome inhibition. This open-label, single-arm, phase II clinical trial was conducted at the Eastern Hepatobiliary Surgery Hospital, Shanghai. A total of 130 advanced iCCA patients were screened for PTEN expression and 16 were enrolled and treated with single-agent bortezomib. Among the intent-to-treat cohort (<i>n</i> = 16), the ORR was 18.75% (three out of 16), and the disease control rate (DCR) was 43.75% (seven out of 16). Notably, three patients did not undergo efficacy assessment, resulting in more favourable outcomes in the per-protocol (PP) cohort (<i>n</i> = 13), which demonstrated an ORR of 23.08% and a DCR of 53.85%. The median progression-free survival (PFS) was 3.6 months, and median overall survival (OS) was 9.6 months in the PP cohort. To our knowledge, the primary efficacy endpoint of our trail, the
{"title":"Drug repurposing: Bortezomib in the treatment of PTEN-deficient iCCA","authors":"Shi-jia Dai, Tian-yi Jiang, Zhen-gang Yuan","doi":"10.1002/ctd2.70004","DOIUrl":"https://doi.org/10.1002/ctd2.70004","url":null,"abstract":"<p>Intrahepatic cholangiocarcinoma (iCCA) is an epithelial malignancy arising from intrahepatic biliary tract, characterised by a dismal prognosis with limited therapeutic alternatives.<span><sup>1</sup></span> The standard first-line treatment for patients with unresectable iCCA includes gemcitabine-based chemotherapy and immunotherapy. However, the objective response rate (ORR) of first-line treatment is below 30%, and there is currently insufficient evidence to support the use of second-line chemotherapy.<span><sup>2, 3</sup></span> This underscores an urgent need to identify novel therapeutic targets and effective drugs for iCCA.</p><p>Our previous research has demonstrated that phosphatase and tension homolog (PTEN), a tumour suppressor which counteracts phosphatidylinositol 3-kinase (PI3K)–AKT signalling, is frequently mutated or deleted in iCCA.<span><sup>4</sup></span> We established a spontaneous iCCA model in mice through liver-specific PTEN disruption and Kras activation, highlighting the crucial role of PTEN in iCCA tumourigenesis.<span><sup>5</sup></span> Importantly, we identified PTEN as a pivotal regulator of both the lysosomal and proteasomal systems, which are essential for maintaining cellular proteostasis in CCA cells. PTEN drives lysosome biogenesis and acidification through its protein phosphatase activity, which dephosphorylates transcription factor EB (TFEB) at Ser211, thereby regulating exosome secretion and iCCA metastasis.<span><sup>6</sup></span> Simultaneously, PTEN inhibits proteasomal transcription via its lipid phosphatase activity in a BACH1/MAFF-dependent manner.<span><sup>7</sup></span> Consequently, PTEN deficiency enhances protein synthesis and proteasomal activity, creating a dependency on the proteasome for iCCA cell growth and survival. Therefore, targeting the proteasome machinery by inhibitor bortezomib induces more apoptosis in PTEN-deficient iCCA cells.</p><p>We subsequently conducted a clinical trial (NCT03345303) to assess whether PTEN-deficient iCCA patients could benefit from bortezomib treatment after failure of first-line chemotherapy, investigating PTEN as a potential biomarker for proteasome inhibition. This open-label, single-arm, phase II clinical trial was conducted at the Eastern Hepatobiliary Surgery Hospital, Shanghai. A total of 130 advanced iCCA patients were screened for PTEN expression and 16 were enrolled and treated with single-agent bortezomib. Among the intent-to-treat cohort (<i>n</i> = 16), the ORR was 18.75% (three out of 16), and the disease control rate (DCR) was 43.75% (seven out of 16). Notably, three patients did not undergo efficacy assessment, resulting in more favourable outcomes in the per-protocol (PP) cohort (<i>n</i> = 13), which demonstrated an ORR of 23.08% and a DCR of 53.85%. The median progression-free survival (PFS) was 3.6 months, and median overall survival (OS) was 9.6 months in the PP cohort. To our knowledge, the primary efficacy endpoint of our trail, the","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}