Cancer Chemotherapy and Pharmacology最新文献

{"title":"Retraction Note: Long noncoding RNA GAS5 inhibits malignant proliferation and chemotherapy resistance to doxorubicin in bladder transitional cell carcinoma.","authors":"Hui Zhang, Yan Guo, Yongsheng Song, Chao Shang","doi":"10.1007/s00280-025-04758-9","DOIUrl":"https://doi.org/10.1007/s00280-025-04758-9","url":null,"abstract":"","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"30"},"PeriodicalIF":2.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HMGB1 assists the predictive value of tumor PD-L1 expression for the efficacy of anti-PD-1/PD-L1 antibody in NSCLC.","authors":"Kunihiko Funaishi, Kakuhiro Yamaguchi, Hiroki Tanahashi, Koji Kurose, Shinjiro Sakamoto, Yasushi Horimasu, Takeshi Masuda, Taku Nakashima, Hiroshi Iwamoto, Hironobu Hamada, Toru Oga, Mikio Oka, Noboru Hattori","doi":"10.1007/s00280-025-04751-2","DOIUrl":"10.1007/s00280-025-04751-2","url":null,"abstract":"<p><strong>Background: </strong>The expression of anti-programmed cell death ligand-1 (PD-L1) in tumors is widely used as a biomarker to predict the therapeutic efficacy of anti-programmed cell death-1(PD-1)/PD-L1 antibodies. However, the predictive accuracy of this method is limited. High-mobility group box 1 (HMGB1) is known to modulate cancer immunity. Therefore, we investigated the potential of circulatory HMGB1 in combination with PD-L1 expression to predict the efficacy of anti-PD-1/PD-L1 antibody monotherapy.</p><p><strong>Patients and methods: </strong>This multicenter retrospective study analyzed blood samples collected from 114 patients with non-small cell lung cancer (NSCLC) prior to anti-PD-1/PD-L1 antibody monotherapy at two university hospitals (Hiroshima University Hospital and Kawasaki Medical School Hospital) between December 2015 and October 2020. We evaluated the association of serum HMGB1 levels with tumor response and progression-free survival (PFS).</p><p><strong>Results: </strong>Serum HMGB1 levels were significantly higher in patients with complete or partial response than in those with stable or progressive disease. Using receiver operating characteristic analysis, the cut-off level of serum HMGB1 to predict tumor response was determined to be 3.83 ng/mL. PFS was significantly longer in the HMGB1^high group than that in the HMGB1^low group in the entire cohort (4.3 months vs. 2.3 months) and in patients with NSCLC with PD-L1 tumor proportion score (TPS) ≥ 50% (12.4 months vs. 4.4 months), but not in those with PD-L1 TPS < 50% or unknown.</p><p><strong>Conclusion: </strong>HMGB1 may serve as a predictive biomarker for the efficacy of anti-PD-1/PD-L1 antibody therapy in the patients with NSCLC, especially in those with PD-L1 TPS ≥ 50%.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"28"},"PeriodicalIF":2.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipidomic profiling of plasma from patients with multiple myeloma receiving bortezomib: an exploratory biomarker study of JCOG1105 (JCOG1105A1).","authors":"Masaki Ri, Shinsuke Iida, Kosuke Saito, Yoshiro Saito, Dai Maruyama, Arisa Asano, Suguru Fukuhara, Hideki Tsujimura, Kana Miyazaki, Shuichi Ota, Noriko Fukuhara, Eiju Negoro, Junya Kuroda, Shinichiro Yoshida, Eiichi Ohtsuka, Tsukamoto Norifumi, Takayuki Tabayashi, Nobuyuki Takayama, Toko Saito, Yasuhiro Suzuki, Yasuhiko Harada, Ishikazu Mizuno, Isao Yoshida, Masaki Maruta, Yasushi Takamatsu, Hiroo Katsuya, Makoto Yoshimitsu, Yosuke Minami, Keisuke Kanato, Wataru Munakata, Hirokazu Nagai","doi":"10.1007/s00280-025-04752-1","DOIUrl":"https://doi.org/10.1007/s00280-025-04752-1","url":null,"abstract":"<p><strong>Purpose: </strong>A comprehensive analysis of metabolites (metabolomics) has been proposed as a new strategy for analyzing liquid biopsies and has been applied to identify biomarkers predicting clinical responses or adverse events associated with specific treatments. Here, we aimed to identify metabolites associated with bortezomib (Btz)-related toxicities and response to treatment in newly diagnosed multiple myeloma (MM).</p><p><strong>Methods: </strong>Fifty-four plasma samples from transplant-ineligible MM patients enrolled in a randomized phase II study comparing two less-intensive regimens of melphalan, prednisolone and Btz (MPB) were subjected to the lipidomic profiling analysis. The amount of each lipid metabolite in plasma obtained prior to MPB therapy was compared to toxicity grades and responses to MPB therapy.</p><p><strong>Results: </strong>High levels of 7 phospholipids (4 lysophosphatidylcholines and 3 phosphatidylcholines) were observed in cases with Btz-induced ≥ grade 2 peripheral neuropathy (BiPN) (n = 11). In addition, low levels of 3 fatty acids (FAs)-FA (18:2), FA (18:1), and FA (22:6)-were observed in patients who developed severe skin disorders ≥ grade 2 (n = 10). No metabolite significantly associated with treatment response was identified.</p><p><strong>Conclusion: </strong>We conclude that levels of specific plasma lipid metabolites are associated with the severity of BiPN and skin disorders in patients with MM. These metabolites may serve as candidate biomarkers to predict Btz-induced toxicity in patients with MM before initiating Btz-containing therapy.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"29"},"PeriodicalIF":2.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase I trial of ATR inhibitor elimusertib with FOLFIRI in advanced or metastatic gastrointestinal malignancies (ETCTN 10406).","authors":"Anuradha Krishnamurthy, Hong Wang, John C Rhee, Diwakar Davar, Ryan H Moy, Lee Ratner, Susan M Christner, Julianne L Holleran, Joshua Deppas, Carina Sclafani, John C Schmitz, Steve Gore, Edward Chu, Christopher J Bakkenist, Jan H Beumer, Liza C Villaruz","doi":"10.1007/s00280-024-04745-6","DOIUrl":"https://doi.org/10.1007/s00280-024-04745-6","url":null,"abstract":"<p><strong>Background: </strong>ATR is an apical DDR kinase activated at damaged replication forks. Elimusertib is an oral ATR inhibitor and potentiates irinotecan in human colorectal cancer models.</p><p><strong>Methods: </strong>To establish dose and tolerability of elimusertib with FOLFIRI, a Bayesian Optimal Interval trial design was pursued. Starting elimusertib dose was 20 mg BID days 1, 2, 15 and 16 every 28-day cycle, combined with irinotecan (150 mg/m²) and 5-FU (2000 mg/m²).</p><p><strong>Results: </strong>The trial was stopped after 10 accruals, with four DLT across 4 dose levels including grade 3 febrile neutropenia, mucositis, nausea, vomiting and grade 4 neutropenia. The most common grade 3/4 adverse events were neutropenia, leukopenia, lymphopenia and mucositis. Based on significant toxicities the trial was stopped. PK data for 5-FU and irinotecan were unremarkable and did not account for DLTs. Among the six response evaluable patients, four had stable disease as their best response. Median PFS was 7 months. A first case of ATRi chemotherapy combination related AML (t-AML) was observed.</p><p><strong>Conclusions: </strong>The combination of elimusertib with FOLFIRI was associated with intolerable toxicity. Combination of ATR kinases with chemotherapies that target DNA replication may be associated with significant myelotoxicity. Ongoing ATRi trials should monitor for t-AML.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov id: </strong>NCT04535401.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"27"},"PeriodicalIF":2.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dihydropyrimidine enzyme activity and its effect on chemotherapy toxicity: importance of genetic testing.","authors":"Alexia Shamaei Zadeh, Danielle Roberts, Abby Williams, Deepali Pandey, John L Villano","doi":"10.1007/s00280-024-04740-x","DOIUrl":"https://doi.org/10.1007/s00280-024-04740-x","url":null,"abstract":"<p><strong>Purpose: </strong>Patients with partial or complete DPD deficiency have decreased capacity to degrade fluorouracil and are at risk of developing toxicity, which can be even life-threatening.</p><p><strong>Case: </strong>A 43-year-old man with moderately differentiated rectal adenocarcinoma on capecitabine presented to the emergency department with complaints of nausea, vomiting, diarrhea, weakness, and lower abdominal pain for several days. Laboratory findings include grade 4 neutropenia (ANC 10) and thrombocytopenia (platelets 36,000). Capecitabine is used as a component of first-line adjuvant therapy by approximately 2 million patients worldwide each year. Capecitabine is metabolized to fluorouracil via the enzyme dihydropyrimidine dehydrogenase (DPD). With worsening pancytopenia and diarrhea, genetic testing for DPD deficiency was sent. Prompt treatment with uridine triacetate was initiated for presumed DPD deficiency. Unfortunately, he passed away from an infectious complication and was later confirmed to have a heterozygous DPYD*2A mutation.</p><p><strong>Discussion: </strong>Our case demonstrates uneven testing guidelines for DPD prior to initiating 5-FU chemotherapy, appropriateness of treating with uridine triacetate, and analysis of next-generation sequencing (NGS) on tumor samples and co-incidentally obtaining germline DPD deficiency status. Our case also highlights the severe clinical impact of having DPD deficiency even with early uridine triacetate therapy.</p><p><strong>Conclusion: </strong>It is our recommendation to perform DPD deficiency in curative intent cancer treatment and this information can increasingly be obtained in standard tumor NGS profiling, a growing norm in medical oncology.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"26"},"PeriodicalIF":2.7,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WT161, a selective HDAC6 inhibitor, decreases growth, enhances chemosensitivity, promotes apoptosis, and suppresses motility of melanoma cells.","authors":"João Marcos Oliveira-Silva, Leilane Sales Oliveira, Carolina Berraut Chiminazo, Rafael Fonseca, Carlos Vinicius Expedito de Souza, Alexandre Ferro Aissa, Graziela Domingues de Almeida Lima, Marisa Ionta, Angel Mauricio Castro-Gamero","doi":"10.1007/s00280-024-04731-y","DOIUrl":"https://doi.org/10.1007/s00280-024-04731-y","url":null,"abstract":"<p><strong>Purpose: </strong>Histone deacetylase 6 (HDAC6) plays a critical role in tumorigenesis and tumor progression, contributing to proliferation, chemoresistance, and cell motility by regulating microtubule architecture. Despite its upregulation in melanoma tissues and cell lines, the specific biological roles of HDAC6 in melanoma are not well understood. This study aims to explore the functional effects and underlying mechanisms of WT161, a selective HDAC6 inhibitor, in melanoma cell lines.</p><p><strong>Methods: </strong>Cell proliferation was assessed using both 2D and 3D cell culture systems, including MTT assays, spheroid growth analyses, and colony formation assays. The interaction between WT161 and the chemotherapeutic agents temozolomide (TMZ) or dacarbazine (DTIC) was evaluated using the Chou-Talalay method. Apoptotic cell death was analyzed through flow cytometry, while migration, adhesion, and invasion assays were conducted to evaluate the motility capacities of melanoma cells. Western blot assays quantified α-tubulin acetylation (Lys40), PARP cleavage, and protein levels of β-catenin and E-cadherin.</p><p><strong>Results: </strong>WT161 significantly reduced cell growth in both 2D and 3D cultures, decreased clonogenic capacity, and showed synergistic interactions with TMZ and DTIC. The inhibitor also induced apoptotic cell death and enhanced TMZ-induced apoptosis. Additionally, WT161 reduced cell migration and invasion while increasing cell adhesion. These effects were linked to changes in β-catenin and E-cadherin levels, depending on the specific cell type evaluated.</p><p><strong>Conclusion: </strong>Our study underscores the pivotal role of HDAC6 in melanoma progression, establishing it as a promising therapeutic target. We provide the first comprehensive evidence of WT161's anti-melanoma effects, setting the stage for further research into HDAC6 inhibitors as a potential strategy for melanoma treatment.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"22"},"PeriodicalIF":2.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population pharmacokinetics and exposure-response analysis of durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer.","authors":"Aburough Abegesah, Do-Youn Oh, KyoungSoo Lim, Chunling Fan, Cecil Chen, Chong Kim, Julie Wang, Ioannis Xynos, Magdalena Zotkiewicz, Song Ren, Alex Phipps, Megan Gibbs, Diansong Zhou","doi":"10.1007/s00280-024-04743-8","DOIUrl":"https://doi.org/10.1007/s00280-024-04743-8","url":null,"abstract":"<p><strong>Purpose: </strong>Durvalumab in combination with gemcitabine/cisplatin has shown a favorable benefit-risk profile in the TOPAZ-1 study for advanced biliary tract cancers (BTC). This analysis evaluated the population pharmacokinetics (PopPK) of durvalumab, and exposure-response for efficacy and safety (ERES) of TOPAZ-1.</p><p><strong>Methods: </strong>The PopPK model for durvalumab was updated using data from 5 previously analysed studies and TOPAZ-1. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for exposure-response (ER) analysis related to efficacy and safety.</p><p><strong>Results: </strong>Consistent with previous analyses, the durvalumab pharmacokinetics in BTC followed a 2-compartment model with time-dependent clearance. The final population parameters were: CL, 0.298 L/day; V1, 3.42 L; V2, 1.99 L; Q, 0.452 L/day; and the time dependent clearance suggests that the clearance could decrease up to 39% over the time course of treatment. There were 111 patients (3.53%) with treatment-emergent ADA positive in the pooled group of 6 studies, and the exposure was comparable for ADA positive and negative patients. Covariates had minimal clinical impact on PopPK parameters. No significant associations were found between exposure and overall survival (OS), progression-free survival (PFS), using Cox proportional analysis (CPH). Logistic regression analysis indicated no significant relationship between the exposure and relevant adverse events measures of Grade 3 and higher treatment-related AE, Grade 3 and higher treatment-related AESI (AEs of special interest), or AE leading to treatment discontinuation.</p><p><strong>Conclusions: </strong>No dose adjustment for durvalumab is needed based on PopPK and ERES analyses. The analysis supports the TOPAZ-1 regimen for patients with advanced BTC.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"23"},"PeriodicalIF":2.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase I study of MLN4924 and belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.","authors":"Keri R Maher, Danielle Shafer, Dale Schaar, Dipankar Bandyopadhyay, Xiaoyan Deng, John Wright, Richard Piekarz, Michelle A Rudek, R Donald Harvey, Steven Grant","doi":"10.1007/s00280-024-04742-9","DOIUrl":"10.1007/s00280-024-04742-9","url":null,"abstract":"<p><strong>Purpose: </strong>Relapsed and/or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome continue to have a poor prognosis with limited treatment options despite advancements in rational combination and targeted therapies. Belinostat (an HDAC inhibitor) and Pevonedistat (a NEDD8 inhibitor) have each been independently studied in hematologic malignancies and have tolerable safety profiles with limited single-agent activity. Preclinical studies in AML cell lines and primary AML cells show the combination to be highly synergistic, particularly in high-risk phenotypes such as p53 mutant and FLT-3-ITD positive cells. Here, we present the safety, pharmacokinetics and pharmacodynamics of belinostat and pevonedistat in a dose escalation Phase I study in AML and High-Risk MDS.</p><p><strong>Methods: </strong>Eighteen patients (16 with AML, 2 with MDS) were treated at 5 dose levels (belinostat 800-1000 mg/m², pevonedistat 20-50 mg/m²). Safety and tolerability were assessed according to protocol defined dose limiting toxicities (DLTs). Correlative pharmacokinetic and pharmacodynamic analyses were performed.</p><p><strong>Results: </strong>No dose limiting toxicities were noted. Most Grade 3 or 4 toxicities were hematologic in nature. The best response was stable disease in four patients, and complete remission in one patient who qualified as an exceptional responder. Pharmakokinetic studies revealed no association between drug exposure and best response. Pharmacodynamic RT-PCR studies demonstrated post-treatment increases in several proteins, including quantitative increases in the oxidative stress protein NQO1, ferroptosis protein SLC7A11, and GSR, linked to glutathione metabolism and oxidative stress, as did the anti-oxidants SRXN1 and TXNRD1.</p><p><strong>Conclusions: </strong>Patterns of post-treatment changes in correlative pharmacodynamic parameters may suggest possible mechanistic changes in the DNA damage response, oxidative damage, and ferroptosis pathways. The combination of pevonedistat plus belinosat is safe in an adult relapsed and/or refractory AML/High-Risk MDS population with modest but notable activity in this heavily treated, high risk population. Our findings also raise the possibility that certain extremely poor prognosis AML patients may respond to a regimen combining two targeted agents that have little or no activity when administered individually.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov ID NCT03772925, first posted 12/12/2018; CTEP Identifier 10246.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"24"},"PeriodicalIF":2.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic exposure and treatment outcomes of lenvatinib in patients with renal cell carcinoma and differentiated thyroid carcinoma.","authors":"Marinda Meertens, Eline L Giraud, Esbar Hassan, Sybrand W J Zielhuis, Tiemen T Snels, Ingrid M E Desar, Janneke E W Walraven, Sofie Wilgenhof, Johannes V van Thienen, Jan Paul de Boer, Neeltje Steeghs, Nielka P van Erp, Alwin D R Huitema","doi":"10.1007/s00280-024-04746-5","DOIUrl":"https://doi.org/10.1007/s00280-024-04746-5","url":null,"abstract":"<p><strong>Purpose: </strong>After initial approval of lenvatinib for radioiodine-refractory differentiated thyroid cancer (DTC), it has also shown promising outcomes in among others metastatic renal cell carcinoma (mRCC). Given that trial populations typically do not represent routine clinical care populations, questions arise about how applicable trial outcomes are in clinical practice. This study aims to compare the pharmacokinetics (PK), toxicity patterns, and survival data of lenvatinib in a real-world cohort with DTC and mRCC to those observed in pivotal clinical trials.</p><p><strong>Materials and methods: </strong>Patients were included when diagnosed with DTC or mRCC, had received current or prior treatment with lenvatinib, and had at least one available lenvatinib plasma concentration measurement. A descriptive comparison was made between the baseline characteristics, PK data, toxicity and survival data in this real-world cohort and those described in the phase III trials.</p><p><strong>Results: </strong>Overall, 29 patients with mRCC and 35 patients with DTC were included. For mRCC, median time to treatment discontinuation (mTTD) was shorter than observed in the phase III trial (7.5 versus 11.0 months) with fewer dose-limiting toxicities, likely because 66% of the patients started with a reduced dose. mRCC patients were more pretreated and had a worse performance status than trial participants. This was resembled in overall lower PK exposure in mRCC patients. For DTC, mTTD was longer in our cohort (17.1 versus 13.8 months), with similar toxicity patterns and PK exposure as in the phase III trial.</p><p><strong>Conclusions: </strong>Our data suggests that patient characteristics and outcomes in routine clinical care deviate from clinical trials and show the need for alternative treatment strategies to manage tolerability to lenvatinib.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"25"},"PeriodicalIF":2.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting on the PI3K/mTOR: a potential treatment strategy for clear cell ovarian carcinoma.","authors":"Kewei Zheng, Guanqin Jin, Rui Cao, Yi Gao, Jing Xu, Ranran Chai, Yu Kang","doi":"10.1007/s00280-024-04748-3","DOIUrl":"10.1007/s00280-024-04748-3","url":null,"abstract":"<p><strong>Purpose: </strong>Ovarian clear cell carcinoma is a highly malignant gynecological tumor characterized by a high rate of chemotherapy resistance and poor prognosis. The PI3K/AKT/mTOR pathway is well-known to be closely related to the progression of various malignancies, and recent studies have indicated that this pathway may play a critical role in the progression and worsening of OCCC.</p><p><strong>Methods: </strong>In this study, we investigated the combined effects of WX390, a dual inhibitor of PI3K/mTOR, and cisplatin on OCCC through both in vitro and in vivo experiments to further elucidate their therapeutic effects.</p><p><strong>Results: </strong>WX390 significantly inhibited the proliferation of human OCCC cell lines ES2 and OVISE, while promoting apoptosis. Furthermore, the combination of WX390 with CDDP exhibited a synergistic effect, markedly increasing the sensitivity of OCCC cells to chemotherapeutic agents and significantly suppressing tumor growth in PDX models. Western blot and RNA-seq analyses revealed that WX390 robustly inhibited the PI3K/AKT/mTOR pathway, interrupt autophagy, altered cell cycle dynamics, and induced apoptosis.</p><p><strong>Conclusion: </strong>This study comprehensively assessed the efficacy of WX390 across multiple models of OCCC, laying a solid foundation for the development of new therapeutic strategies for this challenging malignancy.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"21"},"PeriodicalIF":2.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11723846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}