Cancer Chemotherapy and Pharmacology最新文献

{"title":"Irinotecan induces intestinal atrophy and compromises duodenal motility and mucosal permeability: in vivo and in vitro evaluations.","authors":"Nathalie Arendt, Tania Payo-Serafín, Hans Lennernäs, Femke Heindryckx, Markus Sjöblom","doi":"10.1007/s00280-026-04965-y","DOIUrl":"https://doi.org/10.1007/s00280-026-04965-y","url":null,"abstract":"<p><strong>Purpose: </strong>Intestinal toxicity is a major adverse effect of irinotecan (IRT) chemotherapy, and effective preventive treatments are lacking. This study evaluated the impact of IRT on (i) duodenal motility and mucosal barrier function, (ii) histopathological changes along the small intestine and colon, and (iii) faecal water content, to improve understanding of IRT-induced intestinal injury and support development of future therapeutic strategies.</p><p><strong>Methods: </strong>Anaesthetized Sprague-Dawley rats underwent in situ duodenal perfusion to quantify the effects of intravenous (i.v.) IRT on duodenal motility and blood-to-lumen clearance of ³H-mannitol (paracellular route). In separate experiments, intestinal toxicity was induced by intraperitoneal (i.p.) IRT. After 72 h, rats were sacrificed and the small intestine and colon collected for histopathological evaluation. Body weight and faecal water content were assessed. Additionally, the effects of IRT and its active metabolite SN-38 on cell viability were examined in HCT116 cells.</p><p><strong>Results: </strong>IRT (60 mg/kg, i.v.) markedly increased duodenal motility (+ 277%) and mucosal paracellular permeability (+ 85%) immediately after administration. At 72 h after administration, IRT (180-200 mg/kg, i.p.) reduced villus length in the duodenum (- 52%, - 45%) and jejunum (- 37%, - 33%), with no significant effect in the ileum, and increased jejunal crypt depth (+ 48%, + 41%). In addition, IRT (i.p.) elevated faecal water content (+ 19%, + 16%) and reduced body weight (- 10%, - 13%). In vitro, IRT and SN-38 decreased HCT116 viability in a concentration-dependent manner, with IC₅₀ values of 19.4 µM and 12.8 nM.</p><p><strong>Conclusion: </strong>IRT increases duodenal motility, disrupts mucosal barrier integrity, induces diarrhoea, and causes small-intestinal injury. SN-38 shows substantially higher cytotoxic potency. These findings provide mechanistic insight into IRT-induced intestinal toxicity and may inform development of strategies to mitigate gastrointestinal side effects in cancer patients.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149263035","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":"Biological frailty and chemotherapy dose intensity independently predict survival in older adults with Stage II-III colon cancer.","authors":"Ahmet Burak Ağaoğlu, Ferhat Ekinci, Mustafa Şahbazlar, Atike Pinar Erdogan","doi":"10.1007/s00280-026-04974-x","DOIUrl":"https://doi.org/10.1007/s00280-026-04974-x","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate the prognostic impact of chemotherapy dose intensity and frailty indices-including the laboratory-based Frailty Index (FI-Lab)-on survival in older adults with stage II-III colon cancer receiving adjuvant chemotherapy.</p><p><strong>Methods: </strong>This retrospective study included 94 patients aged ≥ 65 years with stage II (high-risk) or stage III colon cancer treated with adjuvant chemotherapy after curative surgery. Frailty was assessed using FI-Lab with a predefined cut-off of 0.25. Measures included the G8 geriatric screening tool, modified 5-item Frailty Index (mFI-5), and Charlson Comorbidity Index (CCI). Patients were categorised as optimal dose completed, optimal dose started with subsequent reduction, or not started at the optimal dose. Overall survival (OS) and disease-free survival (DFS) were analysed using Kaplan-Meier and Cox regression models.</p><p><strong>Results: </strong>With a median follow-up of 70 months, 28 recurrences (29.8%) and 22 deaths (23.4%) occurred. FI-Lab ≥ 0.25 independently predicted inferior OS (HR: 3.73; p = 0.023) and DFS (HR: 2.81; p = 0.029). G8, mFI-5, and CCI were not independently associated with survival. Dose initiation strategy was also independently associated with outcomes. Compared with the optimal dose completed group, patients not started at the optimal dose had worse OS (HR: 14.41; p = 0.011) and DFS (HR: 5.16; p = 0.013), whereas dose reduction after optimal initiation was not associated with survival.</p><p><strong>Conclusions: </strong>Laboratory-based frailty and initial dose intensity independently predicted survival in older adults receiving adjuvant chemotherapy for colon cancer. These findings support individualised treatment strategies integrating biological reserve and early treatment intensity.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243140","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":"Protective effect of N-acetylcysteine on oxaliplatin-induced peripheral neuropathy in colorectal cancer: a randomized controlled trial.","authors":"Zeyad K Hegazy, Sahar K Tawfik, Nehal M Elmashad","doi":"10.1007/s00280-026-04971-0","DOIUrl":"https://doi.org/10.1007/s00280-026-04971-0","url":null,"abstract":"<p><strong>Purpose: </strong>Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting adverse effect of FOLFOX chemotherapy in colorectal cancer (CRC) patients. We aimed to evaluate the protective effect of N-acetylcysteine (NAC) against OIPN. Additionally, we investigated its mechanistic effects on serum biomarkers including total antioxidant capacity (TAC), interleukin-6 (IL-6), and neurotensin.</p><p><strong>Methods: </strong>Forty-six patients with stage III or high-risk stage II CRC receiving adjuvant modified FOLFOX-6 chemotherapy were randomized in a 1:1 ratio to receive either oral NAC 1200 mg (effervescent tablets or granules) or placebo one hour before each oxaliplatin infusion for four cycles. Serum levels of TAC, IL-6, and neurotensin were measured before and after treatment. Neuropathy was assessed using the FACT/GOG-NTX-12 and NCI-CTCAE scales, and pain was estimated by using the Brief Pain Inventory-Short Form.</p><p><strong>Results: </strong>Neurotensin was significantly decreased in the NAC group compared to controls after treatment (P < 0.001), and was significantly lower post-treatment versus pre-treatment in the NAC group (P = 0.001). IL-6 was significantly reduced in the NAC group versus controls after treatment (P < 0.001), and significantly decreased post-treatment in both groups (P < 0.05). FACT/GOG-NTX-12 and NCI-CTCAE scores were significantly lower in the NAC group at the end of the first two cycles and at the end of treatment (P < 0.05). Pain interference, but not pain severity, was significantly reduced in the NAC group at both time points (P < 0.001).</p><p><strong>Conclusion: </strong>NAC administration during FOLFOX chemotherapy significantly reduced OIPN severity, pain interference, and serum levels of IL-6 and neurotensin, suggesting both clinical and mechanistic neuroprotective effects.</p><p><strong>Clinical registration: </strong>The study was is registered on ClinicalTrials.gov (ID: NCT07391163).</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243126","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":"Successful treatment with BrECADD in a patient with Dubin-Johnson syndrome and classic Hodgkin lymphoma: a case report.","authors":"Hishan Tharmaseelan, Christian Peter Jaworek, Peter Borchmann, Conrad-Amadeus Voltin, Martin Galler, Gareth J Veal, Louisa Lepkes, Björn Reusch, Clara Velmans, Christian Netzer, Wenyu Yang, Uwe Fuhr, Shelby Barnett","doi":"10.1007/s00280-026-04975-w","DOIUrl":"https://doi.org/10.1007/s00280-026-04975-w","url":null,"abstract":"<p><p>Dubin-Johnson syndrome (DJS) results from ABCC2/MRP2 mutations causing impaired biliary transport. MRP2 also mediates hepatic elimination of chemotherapeutic agents, yet no data exist on anthracycline-based chemotherapy in adult DJS patients. We report a 26-year-old male with advanced-stage classic Hodgkin lymphoma and DJS harboring a novel homozygous ABCC2 variant (c.2291G>A, p.Gly764Asp). After a pembrolizumab prephase, full-dose BrECADD was administered, and samples were taken for therapeutic drug monitoring (TDM), which demonstrated normal etoposide and doxorubicin pharmacokinetics. Complete metabolic remission was achieved without significant toxicity. This case demonstrates that TDM-guided, full-dose anthracycline-based chemotherapy is feasible in DJS.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243084","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":"Translational applications and clinical utility of organoids in ovarian cancer: a systematic review.","authors":"Reem ALzahrani, Maha Ali Alghadmi","doi":"10.1007/s00280-026-04973-y","DOIUrl":"https://doi.org/10.1007/s00280-026-04973-y","url":null,"abstract":"<p><strong>Background: </strong>Ovarian cancer remains the most lethal gynecological malignancy, largely due to late-stage diagnosis and the rapid emergence of platinum resistance. Traditional treatment selection relies on population-level guidelines that often fail to account for individual tumor heterogeneity. Patient-derived organoids have emerged as potential functional avatars for personalized therapy, providing a real-time read-out of tumor sensitivity.</p><p><strong>Methods: </strong>This systematic review synthesized data from 13 studies evaluating the feasibility, histological fidelity, and clinical concordance of ovarian cancer patient-derived organoids. Studies were assessed for quality using the Newcastle-Ottawa Scale and QUADAS-2.</p><p><strong>Results: </strong>A pooled analysis identified a mean success rate of 71% for obtaining patient-derived tumor organoids in early passages, with short-term assays showing high feasibility for immediate therapy guidance. Because the majority of the included studies relied on short-term cultures, these figures represent early-passage obtention rather than the true \"establishment\" of stable, cryopreservable lines that can be propagated beyond five passages. Indeed, a direct comparison of establishment rates for such long-term lines was precluded by the inconsistent reporting of total sample sizes (denominators) across the included publications-an important reporting gap that should be addressed in future studies. While 92.3% of studies reported high concordance between PDTO drug sensitivity and patient outcomes for platinum and PARP inhibitors, critical discordance in specific models suggests that growth robustness does not always guarantee predictive accuracy.</p><p><strong>Conclusion: </strong>PDOs represent a robust platform for functional drug screening within a clinically actionable 21-day window. To move into routine practice, the field requires standardized proficiency testing, harmonized reporting of establishment denominators, and the integration of complex stroma-containing models to better reflect the tumor microenvironment.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243147","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":"Longitudinal plasma phosphorylated neurofilament-heavy chain levels in oxaliplatin-induced peripheral neuropathy: a prospective multi-institutional exploratory study.","authors":"Yoshiharu Motoo, Katsunori Shinozaki, Masatomo Miura, Tsuyoshi Takagi, Shingo Ito, Naohisa Yoshida, Yoshinori Munemoto, Akihito Tsuji","doi":"10.1007/s00280-026-04959-w","DOIUrl":"10.1007/s00280-026-04959-w","url":null,"abstract":"<p><strong>Purpose: </strong>Reliable circulating biomarkers for chemotherapy-induced peripheral neuropathy (CIPN) remain lacking. Phosphorylated neurofilament-heavy chain (pNF-H) is an axon-oriented biomarker of neuroaxonal injury, but its clinical relevance in oxaliplatin-induced peripheral neuropathy has not been established. We evaluated the feasibility and longitudinal behavior of plasma pNF-H in patients receiving oxaliplatin-based chemotherapy.</p><p><strong>Methods: </strong>This prospective multi-institutional exploratory study included patients with unresectable or recurrent colorectal cancer receiving CapeOX plus bevacizumab as part of the NYX study, a randomised trial of ninjin'yoeito (NYT; TJ-108, Tsumura & Co., Tokyo, Japan), a twelve-ingredient Kampo herbal extract, at 9.0 g/day for 24 weeks in the NYT arm. Plasma samples were collected at baseline, at clinically assessed CIPN onset (follow-up 1), and at the time of neuropathy resolution, at cycle 9, or at discontinuation, whichever came first (follow-up 2). Plasma pNF-H concentrations were measured by enzyme-linked immunosorbent assay. CIPN was assessed using CTCAE version 5.0.</p><p><strong>Results: </strong>Thirty patients with evaluable plasma samples were included. Plasma pNF-H levels showed substantial inter-individual variability without a consistent temporal pattern. Compared with baseline and CIPN onset, plasma pNF-H levels at follow-up 2 were modestly but significantly increased. However, plasma pNF-H levels were not associated with the onset, severity, or persistence of clinically assessed CIPN.</p><p><strong>Conclusions: </strong>Although longitudinal plasma pNF-H measurement was technically feasible, pNF-H did not function as a clinically meaningful biomarker for oxaliplatin-induced peripheral neuropathy. These findings may reflect a pathophysiological mismatch between dorsal root ganglion neuronal cell body injury and the axon-oriented biological specificity of pNF-H.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13668949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179576","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":"Research and development of a multi-target HER2 inhibitor (CPD 1) and its mechanism and application in combating HER2-positive breast cancer.","authors":"Jianchao Pan, Wenqing Zhang, Xiang Yang","doi":"10.1007/s00280-026-04967-w","DOIUrl":"https://doi.org/10.1007/s00280-026-04967-w","url":null,"abstract":"<p><p>HER2-positive breast cancer, particularly in patients with central nervous system metastasis, presents significant clinical challenges due to limited treatment options and extremely poor prognosis. This paper reports the rational design, synthesis, and systematic evaluation of a novel multi-target HER2 inhibitor, CPD 1. CPD 1 retains potent and selective HER2 inhibitory activity while exhibiting additional ferroptosis-associated activity and functional P-glycoprotein-modulatory activity in vitro. In vitro studies demonstrate potent antiproliferative activity of CPD 1 against a panel of HER2-positive breast cancer cells (including PIK3CA mutant variants), exhibiting significantly superior IC₅₀ values compared to btucatinib. Its mechanism involves effective inhibition of the HER2/PI3K/AKT pathway alongside induction of lipid peroxidation and glutathione depletion. In vivo evaluations demonstrated dose-dependent inhibition of subcutaneous tumour growth and a significant reduction in brain metastatic lesion burden at the experimental endpoint. Pharmacokinetic studies demonstrated measurable total brain exposure of CPD 1, with a total brain-to-plasma partition coefficient (Kp, brain) of 0.52; unbound brain exposure was not determined. Furthermore, preliminary toxicological assessments did not show overt toxicity at the tested doses. In summary, CPD 1 combines potent HER2 inhibition with ferroptosis-associated activity demonstrated in vitro and measurable brain exposure in preclinical pharmacokinetic studies. These properties suggest its potential to address challenges associated with HER2-positive breast cancer and CNS metastases, warranting further investigation.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164121","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":"Antibody-drug conjugates in lung cancer: clinical development, therapeutic advances, and emerging challenges.","authors":"Yilin Zhao, Xiaoran Ma, Xiaozhen Liu, Li Yan","doi":"10.1007/s00280-026-04964-z","DOIUrl":"10.1007/s00280-026-04964-z","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) are designed to deliver cytotoxic agents directly to tumor cells by conjugating an antigen-specific monoclonal antibody with a potent payload. By recognizing tumor-associated antigens and undergoing intracellular processing, ADCs enhance antitumor activity while minimizing damage to normal tissues. This review focuses on the research progress of ADCs targeting non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), providing an in-depth analysis of their mechanisms of action, molecular design, and clinical efficacy, with particular emphasis on novel ADCs targeting HER2, TROP2, and DLL3. Despite challenges such as target specificity and drug resistance, clinical trial data demonstrate that ADCs exhibit significant therapeutic efficacy in the treatment of both NSCLC and SCLC. The article also discusses emerging strategies to overcome current limitations, including innovative linker technologies, development of bispecific ADCs, and exploration of combination treatment plans. Given that lung cancer is the leading cause of cancer-related mortality worldwide, ADCs technology holds promise for delivering breakthrough advances in improving therapeutic outcomes and alleviating the societal burden of the disease. With ongoing research into ADCs, future clinical applications may provide more precise and effective treatment options for patients with lung cancer.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167805","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":"Pharmacological targeting of xCT/system Xc- to modulate temozolomide sensitivity in glioma and glioblastoma preclinical models: a focused systematic review.","authors":"Sufyan Elhashani, Mohamed Elkawafi, Abdalmanam El Shekhi, Sanad Elrishe, Mahmoud A Aloriby","doi":"10.1007/s00280-026-04957-y","DOIUrl":"10.1007/s00280-026-04957-y","url":null,"abstract":"<p><strong>Background: </strong>Resistance to temozolomide (TMZ) remains a major barrier in glioblastoma treatment. The cystine/glutamate antiporter system Xc-, mainly through its xCT/SLC7A11 light-chain subunit, supports cystine uptake, glutathione synthesis and redox balance, making it a biologically plausible target for modifying TMZ response. This focused systematic review evaluated whether pharmacological xCT/system Xc--relevant inhibition enhances TMZ sensitivity in glioma/glioblastoma preclinical models.</p><p><strong>Methods: </strong>Searches were conducted in Web of Science, PubMed/MEDLINE and the Cochrane Library, with supplementary Google Scholar screening, and were completed on 30 April 2026. Reference lists of the included preclinical studies were also screened as a supplementary citation-chasing method. No lower publication-date restriction was applied. Eligible studies were primary preclinical studies using glioma/glioblastoma models, TMZ treatment, and TMZ combined with a pharmacological xCT/system Xc--relevant inhibitor or related intervention. Because the included studies differed in models, inhibitors, formulations, treatment conditions and outcome measures, findings were synthesised narratively.</p><p><strong>Results: </strong>Ten non-retracted preclinical studies were included. Free-drug Sulfasalazine/SSZ and erastin studies provided the most directly relevant pharmacological evidence, but their effects differed by cell model, concentration, treatment duration and outcome assay. Genetic SLC7A11 manipulation supported a relationship between xCT expression, redox regulation and TMZ response, but was not treated as equivalent to pharmacological inhibition. Recent TMZ/SSZ and TMZ/erastin delivery-platform studies produced antitumour effects in TMZ-resistant and orthotopic models; however, these findings also reflected altered circulation, BBB or tumour delivery, targeting and sustained release. Sorafenib/TMZ results were inconsistent and generally lacked direct xCT/SLC7A11 assessment.</p><p><strong>Conclusions: </strong>xCT/system Xc- targeting is a promising but preliminary preclinical strategy for modifying TMZ response. Evidence remains heterogeneous, model- and formulation-dependent, and insufficient to support clinical efficacy claims. Genetic SLC7A11 studies provide mechanistic support, while selected free-drug SSZ and erastin experiments provide limited pharmacological evidence; recent in-vivo findings are predominantly formulation-specific, and sorafenib evidence remains mixed and non-specific. Further target-engagement, pharmacokinetic, BBB, toxicity and orthotopic validation is required.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13652864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147146","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":"PROTACs in personalized and precision medicine: transforming targeted therapy with advances in selectivity and patient stratification.","authors":"Sanket Nagmoti, Eshita Kadam, Nikhil Sakle, Harshad Kapare, Pawan N Karwa","doi":"10.1007/s00280-026-04970-1","DOIUrl":"https://doi.org/10.1007/s00280-026-04970-1","url":null,"abstract":"<p><p>Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative therapeutic strategy that extends beyond conventional occupancy-driven pharmacology by enabling the selective degradation of disease-causing proteins through the ubiquitin-proteasome system (UPS). Unlike traditional small-molecule inhibitors that transiently suppress protein function, PROTACs catalytically eliminate target proteins, thereby offering sustained pharmacological effects and the potential to bypass selected resistance mechanisms associated with conventional target inhibition, and expanding the druggable proteome to include previously undruggable targets. These unique properties position PROTACs as a promising platform for personalized and precision medicine. This review comprehensively examines recent advances in PROTAC technology with a particular emphasis on therapeutic selectivity, biomarker-guided patient stratification, and clinical translation. We discuss the structural design and mechanistic principles of PROTACs, including ternary complex formation, E3 ligase recruitment, ubiquitination, and proteasomal degradation. Recent innovations such as reversible covalent PROTACs, macrocyclic PROTACs, photo-switchable degraders (PHOTACs), conditional PROTACs, and the expanding repertoire of E3 ligases are highlighted for their potential to improve tissue specificity and therapeutic precision. Furthermore, the integration of computational modelling, artificial intelligence, molecular docking, molecular dynamics simulations, multi-omics technologies, CRISPR-based functional screening, and patient-derived organoids is discussed as a framework for rational degrader design and individualized therapeutic decision-making. The review also explores emerging applications of PROTACs in oncology, neurodegenerative disorders, autoimmune diseases, and infectious diseases while addressing current challenges related to pharmacokinetics, drug delivery, resistance mechanisms, biomarker validation, and regulatory considerations. Finally, we discuss emerging nanotechnology-enabled delivery strategies, companion-diagnostic concepts, and patient-specific degrader development as potential approaches to address pharmacokinetic, delivery, and translational barriers, while emphasizing that most of these strategies remain preclinical or investigational. Collectively, this review highlights the growing role of PROTACs as next-generation therapeutics capable of bridging chemical biology with precision medicine, supporting the development of potentially selective, biomarker-informed, and individualized treatment strategies.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147579","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}