Molecular Cancer Therapeutics最新文献

{"title":"DS-3939a: A TA-MUC1-directed Antibody-Drug Conjugate with Broad Anti-Tumor Activity.","authors":"Kohei Takano, Mayuko Yukiura, Kazuki Takahashi, Michiko Kitamura, Hiroko Okuno, Yoshinobu Shiose, Kokichi Honda, Kazunori Oyama, Makiko Yamada, Wataru Obuchi, Kazuyoshi Kumagai, Ken Sakurai, Riki Goto, Akiko Zembutsu, Takashi Kagari, Yuki Abe, Toshinori Agatsuma","doi":"10.1158/1535-7163.MCT-24-0666","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0666","url":null,"abstract":"<p><p>Tumor-associated mucin-1 (TA-MUC1) is a glycoform of the MUC1 protein that is aberrantly glycosylated and is primarily observed in cancer cells. TA-MUC1 is highly expressed in various human epithelial cancers, making it an attractive target for cancer therapies. Here, we describe the development of DS-3939a, a novel TA-MUC1-targeting antibody-drug conjugate (ADC) that utilizes the potent DNA topoisomerase I inhibitor, DXd, and evaluation of its pharmacological activity in preclinical in vitro and in vivo models. Immunohistochemistry of clinical tumor tissue microarrays of various cancer types exhibited positive staining for TA-MUC1 in a number of samples, with a particularly high positive rate in bladder, lung, and breast cancers. In vitro profiling of DS-3939a confirmed that it could specifically bind to TA-MUC1 and inhibit growth of TA-MUC1-positive cancer cells by inducing DNA damage and apoptosis. DS-3939a also exhibited significant anti-tumor effects in multiple TA-MUC1-positive cell line-derived and patient-derived xenograft models. Moreover, DS-3939a elicited strong tumor regression in several xenograft models even following treatment with other cytotoxic ADCs, likely through its efficient payload delivery. Overall, these data provide evidence for the potential utility of DS-3939a for the treatment of TA-MUC1-expressing tumors and support the rationale for the ongoing phase I/II clinical study (NCT05875168).</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting tumor-infiltrating immune cells for targeted alpha therapy in gliomas: Optimization of [225Ac]Ac-DOTA-αCD11b dosing through PET-imaging.","authors":"Ambika P Jaswal, Anders Josefsson, Angel G Cortez, Abhinav Bhise, Bo Li, Chaim T Sneiderman, Sarah R Vincze, Michal Nisnboym, Joseph D Latoche, Kathryn E Day, Robert S Edinger, Itay Raphael, Lora H Rigatti, Wilson B Edwards, Gary Kohanbash, Jessie R Nedrow","doi":"10.1158/1535-7163.MCT-24-0996","DOIUrl":"10.1158/1535-7163.MCT-24-0996","url":null,"abstract":"<p><p>Myeloid cells are key mediators of immunosuppression and treatment resistance in primary brain tumors including glioblastoma (GBM). This study aims to eradicate CD11b+ immunosuppressive cells at the tumor site to enhance overall survival in a model of GBM using an α-emitting radiopharmaceutical therapy (αRPT) targeted to tumor-associated myeloid cells (TAMCs) as a monotherapy or in combination with immune checkpoint inhibitors (ICI). An anti-CD11b (αCD11b) antibody was modified for radiolabeling with diagnostic (89Zr) or therapeutic (225Ac) radioisotopes. Initial PET-imaging and biodistribution studies using 89Zr-αCD11b found an antibody concentration of ~5 mg/kg of αCD11b (100-µg) was effective to saturate on-target/off-site sinks, such as the spleen, but effective at increasing tumor accumulation. The estimated maximum tolerable activity (eMTA) of 225Ac-αCD11b was determined by biodistribution and dosimetry studies, including the free in vivo generated decay daughters. The dose limiting tissue was the bone marrow and an eMTA (~0.55 kBq, 100-µg) was determined. The therapeutic efficacy of 225Ac-αCD11b was evaluated by survival studies, as both a monotherapy and in combination with ICI. Combinational therapy resulted in increased survival in the GBM model as compared to the monotherapy and controls; in addition, long-term survival was observed in 50% of the mice receiving combinational therapy as well as a single mouse receiving 225Ac-αCD11b alone. No long-term surviving mice were observed in the control groups. Long-term surviving mice were rechallenged, and potential antitumor immunity was observed, as no tumors developed over 120-days post-rechallenge. Overall, these results validate the preclinical relevance of CD11b-targeted image-guided αRPT.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BCL-2 family inhibition enhances MTORC1/2 inhibition in PIK3CA mutant colorectal cancer.","authors":"Rebecca A DeStefanis, Alexa E Schmitz, Alyssa K Steimle, Susan N Payne, Gioia C Sha, Autumn M Olson, Alec Cornelio, Anna E L Lippert, Sean G Kraus, Katherine A Johnson, Peter F Favreau, Amani Gillette, Christopher Babiarz, Devon Miller, Carley M Sprackling, Cheri A Pasch, Stephanie Pritzl, Dana R Van De Hey, Demetra P Korkos, Tyler M Foley, Alexander E Yueh, Aurora L J X Greane, Linda Clipson, Melissa C Skala, Dustin A Deming","doi":"10.1158/1535-7163.MCT-24-1096","DOIUrl":"10.1158/1535-7163.MCT-24-1096","url":null,"abstract":"<p><p>Targeting PIK3CA mutant colorectal cancers (CRCs) with precision medicine strategies is of great clinical interest. However, resistance to single agent PI3K pathway inhibitors has been observed across multiple clinical trials, necessitating identification of combination therapies that overcome or prevent resistance to precision medicine strategies. Previously, our group identified that inhibition of MTORC1/2 is necessary to induce a response in PIK3CA mutant CRCs. The PI3K/MTORC1/2 inhibitor copanlisib has demonstrated some clinical activity in PIK3CA mutant solid tumors as part of the NCI MATCH trial. Here we evaluate potential combination therapies that could enhance the efficacy of copanlisib and other similar inhibitors in PIK3CA mutant CRCs. Using a novel high-throughput drug screen method in Apc and Pik3ca mutant mouse-derived cancer organoids, we identify navitoclax, a BCL-2 family inhibitor, as a drug that could potentially enhance the response to copanlisib. Across multiple in vitro and in vivo CRC models, navitoclax enhanced PI3K/MTOR inhibition (copanlisib, sapanisertib, and dactolisib) and induced apoptosis. Furthermore, we examine these combination therapies across a panel of patient-derived cancer organoids with a range of mutation profiles. These studies indicate that KRAS mutations could confer resistance. Furthermore, we identify BCL-xL as the major BCL-2 family target important for the response to this combination in this setting. This provides a strong rationale for MTORC1/2 and BCL-2 family inhibition as a potential treatment strategy for PIK3CA mutant CRCs.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing Patient Risk, Benefit, and Outcomes in Drug Development: A Decade of Dabrafenib and Trametinib Clinical Trials.","authors":"Varun Jhanji, Jacob Duncan, Taylor Gardner, Griffin K Hughes, Ryan McIntire, Andriana M Peña, Chase Ladd, Brooke Gardner, Ty Moore, Elizabeth Garrett, Courtney Cook, Alyson Haslam, Vinayak K Prasad, Matt Vassar","doi":"10.1158/1535-7163.MCT-23-0805","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0805","url":null,"abstract":"<p><p>Dabrafenib and trametinib (D&T) received accelerated approval by the FDA in 2022 for the treatment of metastatic solid tumors harboring BRAF mutations. Our aim was to evaluate the risk/benefit profile of D&T in clinical trials. A comprehensive literature search was conducted to identify relevant clinical trial publications involving D&T in adult malignancies. Trials utilizing D&T measuring responses with RECIST or other criteria were included. Data screening and extraction were performed in a masked, duplicate fashion, focusing on adverse events and primary end-points. Dabrafenib and trametinib were evaluated in many BRAF V600-mutated cancers. The median PFS across all trials was 4.5 months and the median OS was 11.5 months. However, 34% of trials did not report or reach their PFS end-point, and 54% did not report or obtain an OS value. Cumulative ORR remained consistent at around 30% throughout drug development, but the cumulative incidence of grade 3-5 AEs increased from 25% to 50% as off-label indications were studied. We found the studies that led to the accelerated approval of D&T's use in indications outside its original label to be deficient in reporting AE and outcomes. The accelerated approval filled a space needed for the treatment of other BRAF V600 malignancies that did not have a standard method of treatment. However, it is still imperative that clinical trial data be empirically driven and transparent. This encourages quality research which lays the foundation for clinical decision making that impacts patient quality of life and outcome.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Antibody-Drug Conjugate Sacituzumab Govitecan (IMMU-132) Represents a Potential Novel Therapeutic Strategy in Cholangiocarcinoma.","authors":"Racha Hosni, Niklas Klümper, Christine Sanders, Sana Hosni, Vittorio Branchi, Alexander Semaan, Abdullah Alajati, Natalie Pelusi, Susanna S Ng, Damian J Ralser, Saif-Eldin Abedellatif, Hanno Matthaei, Jörg Kalff, Jasmitha Boovadira Poonacha, Veronika Lukacs-Kornek, Glen Kristiansen, Maria A Gonzalez-Carmona, Michael Hölzel, Marieta I Toma","doi":"10.1158/1535-7163.MCT-24-0972","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0972","url":null,"abstract":"<p><p>Cholangiocarcinoma is a rare and aggressive cancer type with limited therapeutic options. Several novel antibody-drug conjugates (ADC) have demonstrated promising antitumor activity in solid tumors. This study aimed to investigate the expression and the potential prognostic role of the protein targets of the recently developed ADCs in cholangiocarcinoma. Moreover, the study aimed to establish patient-derived tumor organoids (PDO) and to employ them for in vitro ADC testing. We evaluated the expression of TROP2, NECTIN4, folate receptor 1, HER2, and HER3 via IHC in a cholangiocarcinoma tissue microarray (n = 113) and analyzed the expression level with respect to clinicopathologic parameters. Furthermore, we generated cholangiocarcinoma PDO culture lines and used them to test the antitumor activity of ADCs in vitro. IHC analyses revealed that TROP2 was the most frequently expressed (91% of cases), followed by folate receptor 1 (51%), NECTIN4 (49%), HER3 (20%), and HER2 (7%). TROP2 showed moderate to high expression (H-score ≥100) in 74% of cases. No significant correlations with overall or disease-free survival, tumor grade, or tumor stage were observed. Six cholangiocarcinoma PDO lines were successfully established (55% success rate). All PDO lines expressed TROP2 concordantly with their parental tumors and showed growth inhibition (IC50 = 0.1-0.4 μg/mL) in response to sacituzumab govitecan (TROP2-targeting ADC). This study reveals that TROP2 is widely expressed in cholangiocarcinoma. Moreover, it provides preclinical evidence for the potential of the use of sacituzumab govitecan as a novel therapeutic strategy in treating patients with cholangiocarcinoma.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF14"},"PeriodicalIF":5.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KRAS codon-specific mutations differentially toggle PI3K pathway signaling and alter sensitivity to inavolisib (GDC-0077).","authors":"Kyung W Song, Christy C Ong, Eva Lin, Jeff Lau, Nicole M Sodir, Dexter X Jin, Katherine E Hutchinson, Shiqi Xie, Jenille Tan, Yuxin Liang, Zora Modrusan, Scott E Martin, Danilo Maddalo, Marc Hafner, Anwesha Dey","doi":"10.1158/1535-7163.MCT-24-0995","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0995","url":null,"abstract":"<p><p>PIK3CA and KRAS are among the most frequently mutated oncogenes and often co-mutated in colorectal cancers. Understanding how KRAS codon-specific mutations affect cross-talks between the PI3K and MAPK pathways and response to targeted therapies, such as the p110α-specific inhibitor inavolisib (GDC-0077), is critical for advancing precision oncology. Focusing on colorectal PIK3CA+KRAS co-mutated models, we found that KRAS G12D-mutated cells were more sensitive to inavolisib than models with KRAS G13D, or other MAPK pathway mutations, even though the PI3K and MAPK pathways were active in both genotypes. In most co-mutated models, regardless of the type of KRAS alteration, combination of inavolisib with MAPK pathway inhibitors showed synergy in vitro and in vivo. Our work highlights how specific codon substitutions in KRAS differentially toggle pathway activity and alter sensitivity to inavolisib, which could inform whether patients would benefit more from single-agent inavolisib or combination with MAPK pathway inhibitors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integration of whole genome sequencing analysis with unique patient-derived models reveals clinically relevant drug targets in TFCP2 fusion-defined rhabdomyosarcoma.","authors":"Patrick Bergsma, Sean Porazinski, Aji Istadi, Diego Chacon-Fajardo, Yasir Mahmood, Silvia Lombardi, Diana Schuhmacher, Henry Barraclough-Franks, Dario Strbenac, Claude V Dennis, Payam Faizi-Sobbi, Emer Cahill, Vivek A Bhadri, Jeneffer De Almeida Silva, Trina Lum, James Wykes, Timothy Manzie, Carsten E Palme, Jean Y H Yang, Jonathan R Clark, Ruta Gupta, Marina Pajic","doi":"10.1158/1535-7163.MCT-24-0704","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0704","url":null,"abstract":"<p><p>Precision medicine is a likely future for all cancer treatment, but may have its greatest impact for less common, high-mortality and molecularly heterogeneous cancers. TFCP2-rearranged Rhabdomyosarcoma is a rare, aggressive cancer with poor survival due to a lack of effective therapies, as well as relevant models to facilitate research. Here, we establish the first matched patient-derived xenograft and cell line model for TFCP2-rearranged intraosseous Rhabdomyosarcoma (IORMS), coupled with comprehensive multi-omic and functional analysis, to discover and preclinically validate novel actionable molecular targets for this malignancy. Sequencing analyses of matched patient tumor and xenograft material revealed alterations in gene networks associated with the oncogenic, potentially targetable PI3K/AKT pathway. Preclinical assessments revealed that targeting the pathway with a small molecule PI3K/mTOR inhibitor dactolisib presents a promising treatment approach for this rare cancer, decreasing cancer cell viability in vitro and significantly reducing tumor growth in vivo. Parallel identification of the codeletion of adjacent genes CDKN2A and MTAP in these tumors, led us to further explore PRMT5 inhibition as a potential therapeutic approach. Strikingly, combined inhibition of PRMT5 and PI3K/mTOR signaling synergistically enhanced anti-tumor response and significantly improved survival in vivo. This study highlights the importance of new patient-derived models for the elucidation of the biology of rare cancers, and identification of new therapeutic entry points, with clear implications for the future treatment of TFCP2-rearranged IORMS.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trametinib thwarts activation of survival pathways induced by pro-ferroptotic drug conjugate ACXT-3102 resulting in enhanced pancreatic cancer cell death.","authors":"Kumar S Bishnupuri, Kenneth F Newcomer, Qingqing Gong, Rony Takchi, Li Ye, Suwanna Vangveravong, Lauren Ross, Brian A Van Tine, William G Hawkins, Dirk Spitzer","doi":"10.1158/1535-7163.MCT-24-1032","DOIUrl":"10.1158/1535-7163.MCT-24-1032","url":null,"abstract":"<p><p>Ferroptosis has recently been described as an iron-dependent subroutine of programmed cell death (PCD). Cancers driven by oncogenic Ras mutations, such as pancreatic ductal adenocarcinoma (PDAC), are particularly vulnerable to ferroptosis and are thus promising candidates for antineoplastic drugs targeting this unique form of PCD. Our group has developed a cancer-specific drug conjugate (ACXT-3102), consisting of a pro-apoptotic sigma-2 ligand as a delivery moiety (SV119), linked to an inhibitor of the cystine antiporter xCT (dm-Erastin), an established inducer of ferroptosis. We hypothesized that ACXT-3102 would trigger apoptosis and ferroptosis via its discrete chemical components, representing a new approach to clinical therapy for PDAC. In vitro, cell viability assays corroborated our earlier findings that ACXT-3102 is a potent inducer of cancer cell death. The sigma-2 delivery component of ACXT-3102 induced canonical markers of apoptosis, including cleaved caspase-3/7 and poly (ADP-ribose) polymerase (PARP), whereas the dm-Erastin cargo component induced canonical markers of ferroptosis, including lipid peroxidation and consumption of glutathione peroxidase 4 (GPX4). These changes resulted in the accumulation of reactive oxygen species (ROS). Subsequently, we found that ACXT-3102-mediated cell death was accompanied by activation of MAPK/ERK signaling, presumably via ROS-dependent degradation of dual-specificity phosphatase 6 (DUSP6), a negative MAPK/ERK phosphorylation regulator. We suspected this was a compensatory reaction and that ACXT-3102-induced cancer cell death would be augmented by inhibition of MAPK/ERK signaling. We successfully combined ACXT-3102 with trametinib (MEK inhibitor) to enhance the overall efficacy of treatment in vitro and in vivo, presumably by targeting ACXT-3102-induced upregulation of MAPK/ERK.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12307273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pretargeted Anti-CD20 Radioimmunotherapy with scFv Fusion Protein Safely Combines with BEAM and ASCT in patients with High-Risk B-cell Lymphomas.","authors":"Johnnie J Orozco, Manuela C Matesan, Sally J Lundberg, Robyn L Haaf, Robert S Miyaoka, Darrell R Fisher, Ted A Gooley, Damian J Green, Brenda M Sandmaier, Paul S Martin, Ajay K Gopal","doi":"10.1158/1535-7163.MCT-24-0550","DOIUrl":"10.1158/1535-7163.MCT-24-0550","url":null,"abstract":"<p><p>Despite new therapies, many patients with NHL relapse and need more effective salvage therapies. This study (NCT02483000) evaluated the safety of B9E9-FP, a tetrameric single-chain anti-CD20-streptavidin fusion protein used in pre-targeted radioimmunotherapy (PRIT), when combined with BEAM and autologous stem cell transplantation (ASCT) for NHL patients. High-risk NHL patients received B9E9-FP on day -17, clearing agent on day -15, and DOTA-biotin (DOTA-Bt) equally divided and labeled with dose-escalated yttrium-90 (90Y), or with indium-111 (111In for imaging) on day -14. BEAM chemotherapy started day -7 before stem cell infusion. Three NHL patients (MCL, transformed DLBCL, and de novo DLBCL), ages 52-62 years, were treated with 30, 50, or 70 mCi (1110, 1850, or 2590 MBq) 90Y/m2 before ASCT without any dose-limiting toxicity. One case of diarrhea (grade 2) and one case of rash (grade 1) were possibly associated with B9E9-FP or DOTA-Bt, respectively. Pharmacokinetic (PK) studies showed peak blood biological percent injected dose per gram blood (% ID/g) of 90Y-DOTA-Bt at 15 min after infusion (14.8 - 49.4 % ID), with only 0.82 - 2.59 % ID after 72 hours. Uptake was preferential at bone marrow (1.73 - 5.96 cGy/mCi injected) and spleen (2.4 - 4.17 cGy/mCi injected) compared to lungs (0.19 - 0.48 cGy/mCi). Unbound 90Y-DOTA-Bt was excreted renally without any renal dysfunction noted up to 2 years later. Two of the 3 enrolled patients are alive and in remission 3.5 to 4.9 years after transplant. PK, dosimetry, and outcomes data support that B9E9-FP PRIT and 90Y-augmented ASCT DOTA-Bt is feasible.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in Antibody-Drug Conjugates for Endometrial Cancer.","authors":"Pan Tu, Gaofeng Li, Wen Zou, Chao Xu, Jingjing Wang","doi":"10.1158/1535-7163.MCT-24-0763","DOIUrl":"10.1158/1535-7163.MCT-24-0763","url":null,"abstract":"<p><p>The treatment of advanced endometrial cancer is clinically challenging, prompting the exploration of innovative therapeutic strategies such as antibody-drug conjugates (ADC). ADCs, which include mAbs, cytotoxic components, and linkers, demonstrate robust targeting, cytotoxicity, and manageable adverse effects. To provide a thorough understanding of the status of research, this review elucidates promising therapeutic targets in endometrial cancer, such as HER2, folate receptor α, and trophoblast surface antigen-2, and summarizes preclinical and clinical trial data on related ADC drugs in endometrial cancer. We also discuss the toxicity of ADC drugs. Most adverse events arise from cytotoxic components such as microtubule inhibitors and topoisomerase inhibitors. The ocular toxicity may be mainly related to off-target effects of monomethyl auristatin F/DF4 payloads. Interstitial lung disease is a serious adverse event, mainly caused by antibodies, and most of them are of grade 1 to 2 toxicity. Among them, anti-HER2 ADC-induced interstitial pneumonia is commonly dose-dependent. Moreover, we identified potential new targets for endometrial cancer treatment and explored strategies to overcome ADC resistance, such as choosing combination therapy or developing a new generation of ADC drugs. Continuous research and innovation in this field hold promise for improving the survival and overall quality of life of patients with advanced endometrial cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"993-1004"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}