Molecular Cancer Therapeutics最新文献

{"title":"Combination therapy of avutometinib and MRTX1133 synergistically suppresses cell growth by inducing apoptosis in KRASG12D-mutated pancreatic cancer.","authors":"Ema Toyokuni, Mano Horinaka, Emi Nishimoto, Akihiro Yoshimura, Michiaki Fukui, Toshiyuki Sakai","doi":"10.1158/1535-7163.MCT-24-0831","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0831","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a poor prognosis, and over 90% of PDAC cases involve activating mutations in the oncogene KRAS. Therapeutic strategies that inhibit the mitogen-activated protein kinase pathway, a critical effector pathway in KRAS-mutated cancers, have garnered significant attention. Among several molecular-targeted drugs, avutometinib (CKI27(2)/CH5126766/RO5126766/VS-6766), a novel dual RAF/MEK clamp, shows promise for patients with KRAS-mutated cancers. However, its efficacy as a single agent remains insufficient, highlighting the need for more effective treatment strategies. In this study, we found that avutometinib alone was insufficiently effective against pancreatic cancer cells with KRASG12D mutation. In these cells, combining avutometinib with the KRASG12D inhibitor MRTX1133 demonstrated synergistic inhibitory effects on cell growth. We further investigated the efficacy of this combination therapy in in vitro and in vivo experiments. In these experiments, the combination therapy upregulated BIM, downregulated survivin, and induced apoptosis in pancreatic cancer cells with the KRASG12D mutation. In in vivo experiments, the combination therapy markedly delayed tumor growth compared to either therapy alone. Therefore, the combination of avutometinib and MRTX1133 may represent a promising therapeutic approach for KRASG12D-mutated pancreatic cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174202","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":"RGN6024 is a brain-penetrant, small molecule tubulin destabilizer for the treatment of glioblastoma.","authors":"Lilian A Patrón, Helen Yeoman, Joseph Ramos, April L Risinger, Vijay Gokhale, Teri C Suzuki","doi":"10.1158/1535-7163.MCT-24-1208","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-1208","url":null,"abstract":"<p><p>Glioblastoma (GB) is the most common and aggressive malignant brain tumor in adults, with a median survival of ~15 months. Given the poor survival with the currently approved treatments, new therapies are urgently needed. Microtubule-targeting agents (MTAs) represent one of the most successful first-line therapies for cancers, however, the inability of approved MTAs to cross the blood-brain barrier (BBB) limits their use for central nervous system (CNS) cancers. The development of novel MTAs with good BBB penetrance, decreased toxicity, and an ability to overcome drug-induced resistance is an attractive prospect. Herein, we describe the characterization of RGN6024, a brain-penetrant small molecule tubulin destabilizer that binds the colchicine binding site of tubulin. RGN6024 has excellent in vitro potency against GB cell lines in viability assays with IC50 values in the low to mid nanomolar range. RGN6024 is less susceptible to common drug resistance mechanisms: its activity is unaffected by βIII-tubulin overexpression and it demonstrates good blood brain penetration in in vivo mouse and rat models. With oral dosing, RGN6024 shows excellent BBB penetration in both mice (Cmax = 3530 ng/g) and rats (Cmax = 1667 ng/g). Drug efficacy was confirmed in two xenograft models. In a TMZ-resistant LN-18 glioblastoma xenograft model, RGN6024 showed a reduction in tumor growth when dosed orally at 7.5 or 15 mg/kg. Additionally, RGN6024 suppressed the growth of BT142 glioblastoma cells in an orthotopic murine model and significantly prolonged survival. Taken together, these data provide support for the development of RGN6024 for the treatment of GB.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110903","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":"A novel conditionally replicative oncolytic adenovirus under the control of the SALL4 promoter inhibits the growth of rhabdoid tumors.","authors":"Satoru Oya, Hideki Yoshida, Akimasa Tomida, Mitsuru Miyachi, Shigeki Yagyu, Yoshiki Katsumi, Ken Kikuchi, Kunihiko Tsuchiya, Eiichi Konishi, Subbaya Subramanian, Masato Yamamoto, Tomoko Iehara","doi":"10.1158/1535-7163.MCT-24-0710","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0710","url":null,"abstract":"<p><p>Rhabdoid tumors (RTs) are highly aggressive pediatric malignancies with limited treatment options. SALL4, a gene essential for embryonic stem cell pluripotency and self-renewal, is frequently overexpressed in RTs. To exploit this, we developed a conditionally replicating oncolytic adenovirus (pSALL4-OAd) by placing the E1 region under the control of the SALL4 promoter, restricting viral replication to SALL4-positive cells. SALL4 protein expression was analyzed in 10 clinical RT specimens via immunohistochemistry, while SALL4 mRNA levels and promoter activity were assessed in eight RT cell lines using quantitative PCR and dual-luciferase assays. The replication selectivity and cytopathic effects of pSALL4-OAd were tested in vitro at doses of 0-1000 viral particles (vp)/cell. In vivo, 1.0 × 10^7 G401 cells were implanted subcutaneously into immunodeficient mice, followed by intratumoral administration of pSALL4-OAd (3 × 10^10 vp) or phosphate-buffered saline. Tumor growth was monitored over the treatment period. SALL4 protein was detected in 40% of clinical RT specimens, and RT cell lines exhibited 4- to 400-fold higher SALL4 mRNA levels compared with normal tissues. Elevated SALL4 promoter activity was confirmed in three of five RT cell lines. pSALL4-OAd selectively replicated in SALL4-positive cells and induced significant cytopathic effects proportional to promoter activity in vitro. In vivo, pSALL4-OAd administration caused tumor necrosis, reduced SALL4-positive cells, and suppressed tumor proliferation. These results demonstrate the potential of pSALL4-OAd as a targeted and effective therapeutic strategy for SALL4-expressing RTs.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094172","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":"PROTAC-Mediated Degradation of TAF1 Induces Apoptosis in AML Cells and Inhibits Tumor Growth In Vivo.","authors":"Lihong Chen, Zachary P Shultz, Marianna Sansone, Bin Fang, Xiang Liu, Mingxiang Teng, Ernst Schonbrunn, Justin M Lopchuk, Jiandong Chen","doi":"10.1158/1535-7163.MCT-24-1091","DOIUrl":"10.1158/1535-7163.MCT-24-1091","url":null,"abstract":"<p><p>The bromodomain-containing protein, transcription factor IID subunit 1 (TAF1; transcription factor II-250), is the largest component of the multiprotein assembly transcription factor IID, a dynamic complex that serves as a general factor for transcription initiation. CRISPR and RNAi screens of pan-cancer cell lines revealed that TAF1 is broadly required for optimal cell growth and survival, but a subset of cell lines showed enhanced TAF1 dependence. These observations suggest that TAF1 has the potential to serve as a therapeutic target in sensitive tumors. Current approaches employed to target TAF1 are limited to monovalent small-molecule inhibitors of the bromodomain. However, recent studies showed that such inhibitors lack cancer cell kill potential. We applied a structure-guided approach to generate cereblon recruiting Proteolysis Targeting Chimera (PROTAC) degraders of TAF1 using the chemical scaffolds of ceralasertib and GNE371. We present evidence that GNE371-based PROTACs are effective in degradation of TAF1 at concentrations as low as 1 nmol/L. TAF1 depletion activated p53 and induced apoptosis in acute myeloid leukemia (AML) cell lines and certain solid tumor cells. An in vivo active TAF1 PROTAC inhibited the growth of AML tumor xenografts. The results showed that inhibition of the bromodomain is not sufficient to inactivate TAF1 functions, whereas a PROTAC approach induces strong biological effects. Furthermore, TAF1 PROTACs have therapeutic potential against AML and other sensitive tumors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF10"},"PeriodicalIF":5.3,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079141","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":"Inhibition of MCL-1 and MEK overcomes MEK inhibitor resistance in triple-negative and inflammatory breast cancers.","authors":"Mohd Mughees, Moises J Tacam, Alex W Tan, Mary K Pitner, LaKesla R Iles, Xiaoding Hu, Emilly S Villodre, Bisrat G Debeb, Takahiro Kogawa, Bora Lim, Rachel M Layman, Wendy A Woodward, Naoto T Ueno, Debu Tripathy, Savitri Krishnamurthy, Yuan Qi, Lajos Pusztai, Jian Wang, Varsha Gandhi, Geoffrey Bartholomeusz, Chandra Bartholomeusz","doi":"10.1158/1535-7163.MCT-24-0593","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0593","url":null,"abstract":"<p><p>The MAPK pathway can drive resistance in highly aggressive breast cancers. Our previous work showed that MEK inhibitor (MEKi) AZD6244 (selumetinib) prevented lung metastasis in a breast cancer xenograft model. In clinical studies, MEKis as single agents have had only modest activity against solid tumors due to the onset of resistance. Using synthetic-lethality siRNA screening, we identified myeloid cell leukemia-1 (MCL-1) as a potential contributor to AZD6244 resistance. We hypothesized that MCL-1 promotes MEKi resistance in highly aggressive breast cancers and that MCL-1 inhibition overcomes AZD6244 resistance. We established two AZD6244-resistant cell lines: MDA-MB-231-R (triple-negative breast cancer) and SUM149-R (triple-negative inflammatory breast cancer). These resistant cells were characterized with respect to different parameters, and a combination of an MCL-1 inhibitor (MCL-1i) together with a MEKi was evaluated in vitro and in vivo to overcome the acquired resistance. Compared with their respective parental cells, MDA-MB-231-R and SUM149-R cells showed increased proliferation, colony formation, stemness, anchorage-independent growth, and MCL-1 expression levels. MCL-1 knockdown in resistant cells decreased cell proliferation and colony formation, increased apoptosis, and was associated with high expression of the pro-apoptotic proteins PUMA, NOXA, BAK, and BAX. MEKi resistance was overcome when resistant cells were treated with MCL-1i and MEKi combined. In an in vivo mouse model, inhibition of MCL-1 restored sensitivity to AZD6244. Our results suggest that MCL-1 is a driver of MEKi resistance and that combining an MCL-1i with a MEKi warrants further investigation in triple-negative and triple-negative inflammatory breast cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979126","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":"Characterization of mAb104, a Monoclonal Antibody Targeting a Conformationally Exposed, Tumor-specific epitope of HER2.","authors":"Sagun Parakh, Nhi Huynh, Diana Dong Cao, Angela Rigopoulos, Benjamin Gloria, Ingrid J G Burvenich, Carmel Murone, Christian W Wichmann, Nancy Yanan Guo, Clare Senko, Adam Parslow, Laura Allan, Laura D Osellame, Peter W Janes, Fiona E Scott, Zhanqi Liu, Hui K Gan, Andrew M Scott","doi":"10.1158/1535-7163.MCT-24-0583","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0583","url":null,"abstract":"<p><p>We generated a novel HER2 monoclonal antibody (mAb104) which binds to an epitope in domain II of HER2 that is conformationally exposed in tumors in response to HER2 amplification or activation but is not accessible to antibody binding in normal tissues. Consistent with other studies that evaluated antibodies targeting conformationally exposed epitopes, mAb104 lacked in vitro activity however showed potent anti-tumor activity in vivo. The anti-tumor effect in vivo was similar in magnitude to trastuzumab and pertuzumab, whilstand combination with trastuzumab was superior to trastuzumab alone. Immunohistochemistry screening of normal and tumor tissues with mAb104 showed mAb104 did not bind to normal tissues, confirming tumor specificity of mAb104. In vivo biodistribution and imaging data demonstrated specific tumor targeting of mAb104 in HER2 expressing tumors. Confocal microscopy clearly demonstrated internalization of mAb104 into the tumor cells, consistent with mAb104:HER2 trafficking. Mab104 is tumor specific, exhibits potent antitumor activity in HER2-positive models and internalizes into HER2-positive tumor cells. These results demonstrate the potential of mAb104 as a novel HER2 targeting therapy both as a naked antibody for signalling abrogation therapy, and for payload delivery as an antibody-drug conjugate or for beta/alpha particle therapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018164","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":"CRISPR screens identify POLB as a synthetic lethal enhancer of PARP inhibition exclusively in BRCA-mutated tumors.","authors":"Katherine Lazarides, Justin L Engel, Michele Meseonznik, Tianshu Feng, Ashley H Choi, Yi Yu, Shangtao Liu, Samuel R Meier, Hongxiang Zhang, Binzhang Shen, Robert Tjin Tham Sjin, Douglas A Whittington, Brian J McMillan, Brian Doyon, Xuewen Pan, Erik Wilker, Alan Huang, Jannik N Andersen, William D Mallender, Madhavi Bandi","doi":"10.1158/1535-7163.MCT-24-0822","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0822","url":null,"abstract":"<p><p>Poly (ADP-ribose) polymerases inhibitors (PARPi) are an approved class of anticancer therapeutics that inhibit the activities of PARP1/2 and produce synthetic lethality in BRCA1/2 mutated cancers due to the absence of a functional homologous recombination (HR)-dependent DNA repair pathway. Although PARP inhibitors have led to successful clinical outcomes, two-thirds of patients develop acquired resistance, limiting long-term utility as maintenance therapy. Motivated by this clinical need, we utilized a CRISPR target discovery screening platform to identify POLB as a gene that acts selectively and synergistically with PARPi in BRCA1/2 mutated cancers and found that POLB knockout along with PARPi treatment enhanced loss of viability in BRCA1/2 mutant and BRCA2 null cells, but not in isogenic BRCA1/2 wildtype cells. Overexpression of either POLB wildtype or catalytically inactive mutants confirmed that perturbation of both the polymerase and lyase catalytic activities of POLB are required for synergistic PARP-BRCA synthetic lethality. Mechanistically, POLB knockout was associated with an increase in single- and double-strand DNA breaks, cell cycle arrest, and apoptosis when in combination with PARP inhibition. The translational nature of this interaction was further examined using murine xenograft models of BRCA1 mutant and BRCA2 null cell lines, wherein the combination of POLB knockout and niraparib led to profound tumor regression and prevented tumor regrowth even after cessation of treatment. Together, these results suggest that POLB is a synergistic enhancer of the synthetic lethal interaction between PARP and BRCA and support POLB as a promising therapeutic target for improving antitumor responses to PARPi in HR-deficient cancers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024970","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":"Novel chimeric CTLA-4 B-cell epitope peptide vaccines demonstrate effective anti-tumor immunity with/without PD1/PDL1 blockade in multiple syngeneic murine models of breast and colorectal cancers.","authors":"Linlin Guo, Jay Overholser, Sarah Naylon, Stephane Roche, Nicholas Ede, Pravin T P Kaumaya","doi":"10.1158/1535-7163.MCT-24-0908","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0908","url":null,"abstract":"<p><p>Cancer immunotherapy with checkpoint inhibitors has resulted in impressive clinical results in several cancer indications. Despite this success, only a fraction of patients shows durable and complete response to blockade by Ipilimumab an anti-CTLA-4 monoclonal antibody. We identified four cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4) peptide sequences from which engineered chimeric B-cell epitope constructs incorporating a \"promiscuous\" T-cell epitope elicited highly immunogenic anti-CTLA-4 natural polyclonal antibodies by immunization. Combination of CTLA-4 peptide vaccine with other checkpoint inhibitor vaccines PD1-Vaxx or PDL1-Vaxx were investigated in several breast and colon carcinoma BALB/c syngeneic models (CT26, 4T1 and D2F2). CTLA-4 vaccines showed significant tumor suppression and prolonged survival rates as compared to anti-mouse CTLA-4 mAb 9H10. The resulting antipeptide antibodies suppressed tumor proliferation and migration similar to ipilimumab. We focused on one CTLA-4 epitope sequence 130-150 that embodies the \"MYPPPY\" motif that ipilimumab binds to. Combination of MVF-CTLA-4(130-150) with either PD1-Vaxx or PDL1-Vaxx showed synergistic activity. The 130-150 peptide mimic demonstrated the polyproline type II helix motif showed inhibition of tumor growth and therapeutic efficacy in the syngeneic CT26/BALB/c model. Several CTLA-4 vaccines have been identified which shows synergistic activities with other checkpoint inhibitor vaccines to PD-1 and PDL1.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001847","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":"Inhibition of DKK-1 by WAY262611 Inhibits Osteosarcoma Metastasis.","authors":"Adit Tal, Shimara Gunawardana-Zeigler, Da Peng, Yuqi Tan, Natalia Munoz Perez, Rachel Offenbacher, Laurel Kastner, Paul Ciero, Matthew E Randolph, Yun Gong, Hong-Wen Deng, Patrick Cahan, David M Loeb","doi":"10.1158/1535-7163.MCT-24-0744","DOIUrl":"10.1158/1535-7163.MCT-24-0744","url":null,"abstract":"<p><p>Osteosarcoma is the most common primary malignant bone tumor in childhood. Patients who present with metastatic disease at diagnosis or relapse have a very poor prognosis, and this has not changed over the past four decades. The Wnt signaling pathway plays a role in regulating osteogenesis and is implicated in osteosarcoma pathogenesis. DKK-1 inhibits the canonical Wnt signaling pathway, causing inhibition of osteoblast differentiation and disordered bone repair. Our lab previously demonstrated that an mAb against DKK-1 prevented metastatic disease in a mouse model. This study expands upon those findings by demonstrating similar results with a small-molecule inhibitor of DKK-1, WAY262611, both in vitro and in vivo. WAY262611 was evaluated in vitro on osteosarcoma cell lines, including proliferation, caspase activation, cell-cycle analysis, and signaling pathway activation. We utilized our orthotopic implantation/amputation model of osteosarcoma metastasis in vivo to determine the impact of WAY262611 on primary tumor progression and metastatic outgrowth of disseminated tumor cells. Differentiation status was determined using single-cell RNA sequencing. We show here that WAY262611 activates canonical Wnt signaling, enhances nuclear localization and transcriptional activity of β-catenin, and slows proliferation of osteosarcoma cell lines. We also show that WAY262611 induces osteoblastic differentiation of a patient-derived xenograft of osteosarcoma in vivo, as well as inhibiting metastasis. This work credentials DKK-1 as a therapeutic target in osteosarcoma, allowing for manipulation of the Wnt signaling pathway and providing preclinical justification for the development of new biologics for the prevention of osteosarcoma metastasis.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"728-739"},"PeriodicalIF":5.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951624","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":"Dual-Nuclide Biodistribution and Therapeutic Evaluation of a Novel Antibody-Based Radiopharmaceutical in Anaplastic Thyroid Cancer Xenografts.","authors":"Anja Charlotte Lundgren Mortensen, Hanna Berglund, Preeti Jha, Adam Stenman, Ram Kumar Selvaraju, Hans Lundqvist, Camilla Hofström, Helena Persson, C Christofer Juhlin, Jan Zedenius, Fredrik Y Frejd, Marika Nestor","doi":"10.1158/1535-7163.MCT-24-0524","DOIUrl":"10.1158/1535-7163.MCT-24-0524","url":null,"abstract":"<p><p>Anaplastic thyroid cancer (ATC) is a rare but severe form of thyroid cancer responsible for approximately 50% of thyroid cancer deaths. Consequently, the identification of innovative therapies remains crucial for the effective treatment of ATC. Molecular radiotherapy is a rapidly growing field within oncology, and the cell surface antigen CD44v6, which is overexpressed in several cancers, is a plausible target for molecular radiotherapy of ATC. IHC of 39 patient samples with ATC was evaluated for CD44v6 expression. Biodistribution and dosimetry of iodine-125 (125I)-/lutetium-177 (177Lu)-labeled UU-40, a CD44v6-specific antibody, followed by in vivo efficacy in two ATC xenograft models with varying target expression levels (ACT-1 and BHT-101), accompanied by single-photon emission computed tomography (SPECT) imaging, evaluated radiolabeled UU-40 for therapeutic efficiency in ATC xenografts. The IHC revealed CD44v6 immunoreactivity in 46% of patient samples with ATC. The biodistribution favored 177Lu-labeled UU-40 over the 125I-labeled antibody and confirmed the in vivo specificity of both radioconjugates. The in vivo efficacy and accompanied SPECT imaging of a moderate CD44v6-expressing xenograft model (BHT-101) verified the tumor specificity, as well as the target-specific effect of 177Lu-labeled UU-40 on tumor growth and survival. A 100% complete response rate was demonstrated as a result of therapy using a single dose of 16 MBq 177Lu-labeled UU-40 in a high CD44v6-expressing xenograft model (ACT-1), and SPECT imaging revealed excellent tumor uptake of the radioconjugate at 14 days after injection. This study verifies the expression of CD44v6 in ATC and strengthens the superiority and promise of 177Lu-labeled UU-40 over 131I-labeled UU-40 for antibody-based molecular radiotherapy of CD44v6-positive ATC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"753-762"},"PeriodicalIF":5.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458675","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}