Molecular Cancer Therapeutics最新文献_第9页

Humanized antibody-drug conjugates for Somatostatin receptor 2 (SSTR2)-positive tumor treatment. 促生长抑素受体2 （SSTR2）阳性肿瘤的人源化抗体-药物偶联物治疗。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-07-15 DOI: 10.1158/1535-7163.MCT-25-1440

Zhuoxin Zhou, Zhantao Du, Jiashuai Zhang, Anusua Sarkar, Davis Ballard, Natsorn Watcharadulyarat, Selena Khanal, Phoebe Hu, Lufang Zhou, Xiaoguang Liu

{"title":"Humanized antibody-drug conjugates for Somatostatin receptor 2 (SSTR2)-positive tumor treatment.","authors":"Zhuoxin Zhou, Zhantao Du, Jiashuai Zhang, Anusua Sarkar, Davis Ballard, Natsorn Watcharadulyarat, Selena Khanal, Phoebe Hu, Lufang Zhou, Xiaoguang Liu","doi":"10.1158/1535-7163.MCT-25-1440","DOIUrl":"10.1158/1535-7163.MCT-25-1440","url":null,"abstract":"Somatostatin receptor 2 (SSTR2) is overexpressed in neuroendocrine tumors (NETs) and meningiomas. The objective of this study was to develop an SSTR2-targeted therapy to treat both tumors. We developed a humanized anti-SSTR2 monoclonal antibody demonstrating strong cancer cell binding, internalization in cancer cells, and tumor specificity, as evidenced by flow cytometry, confocal microscopy, and live-animal imaging. Antibody-drug conjugates were generated by conjugating the SSTR2 mAb with potent payloads, including monomethyl auristatin F or mertansine. In vitro assessments revealed high cytotoxicity across NET subtypes and meningioma cell lines. In vivo efficacy was confirmed in two mouse models, i.e. subcutaneous NET xenografts and intracranial meningioma xenografts, where treatment inhibited proliferation, induced apoptosis and cell death, exhibited minimal toxicity, and extended survival. The mechanism of action was further elucidated through bulk RNA sequencing after treatment. These findings highlight the therapeutic potential of our humanized SSTR2 mAb for targeted payload delivery in NETs and meningiomas.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13477831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456372","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}

引用次数: 0

Tinengotinib (TT-00420) inhibits tumor growth and overcomes multidrug resistance in gastrointestinal cancers. Tinengotinib （TT-00420）抑制肿瘤生长并克服胃肠道癌症的多药耐药。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-07-15 DOI: 10.1158/1535-7163.MCT-25-0633

Mingyang Ma, Congcong Ji, Bingqing Zhao, Panpan Zhang, Xiaoyan Qiang, Peng Peng, Lin Shen, Cheng Zhang

{"title":"Tinengotinib (TT-00420) inhibits tumor growth and overcomes multidrug resistance in gastrointestinal cancers.","authors":"Mingyang Ma, Congcong Ji, Bingqing Zhao, Panpan Zhang, Xiaoyan Qiang, Peng Peng, Lin Shen, Cheng Zhang","doi":"10.1158/1535-7163.MCT-25-0633","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0633","url":null,"abstract":"Gastrointestinal malignancies have a high incidence and mortality rates worldwide; however, treatment challenges persist, including the lack of effective targets, limited therapeutic options, and primary and acquired resistance. Tinengotinib (TT-00420), an innovative multi-target kinase inhibitor developed by TransThera Sciences (Nanjing), Inc., has demonstrated strong antitumor activity in breast cancer, cholangiocarcinoma, and small cell lung cancer, but its therapeutic potential in gastrointestinal cancers has not been fully explored. In this study, human gastric cancer and colorectal cancer cell lines, together with patient-derived xenograft, cell line-derived xenograft, and patient-derived organoid models, were used to comprehensively evaluate the antitumor efficacy of TT-00420 in regulating tumor growth. In addition, trastuzumab-resistant and immunotherapy-resistant models were established to assess the antitumor activity of TT-00420 in treatment-refractory settings. TT-00420 effectively suppressed tumor growth in both gastric and colorectal cancer PDX models while maintaining a favorable safety profile and demonstrated robust efficacy in trastuzumab-resistant and immunotherapy-resistant models. Mechanistically, Western blot analysis revealed that Aurora A expression was downregulated following TT-00420 treatment, and the IC50 of TT-00420 increased in AURKA-knockdown cell lines, suggesting that Aurora A contributes to the antitumor activity of TT-00420. Collectively, these findings indicate that TT-00420 is a highly promising antitumor agent with potent efficacy against gastric and colorectal cancers, providing a potential therapeutic strategy for gastrointestinal malignancies and offering valuable insights for future clinical research.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456444","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}

引用次数: 0

Therapeutic targeting of β-catenin in cancer. β-连环蛋白在癌症中的靶向治疗。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-07-15 DOI: 10.1158/1535-7163.MCT-26-0062

Paola Martinelli, Peter Repiscak, Norbert Kraut

{"title":"Therapeutic targeting of β-catenin in cancer.","authors":"Paola Martinelli, Peter Repiscak, Norbert Kraut","doi":"10.1158/1535-7163.MCT-26-0062","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0062","url":null,"abstract":"Mutations in β-catenin, together with recurrent genetic alterations affecting the WNT signaling pathway, define one of the most prevalent oncogenic axes, collectively occurring in approximately 10% of human cancers. Thus, β-catenin is a prime target for precision oncology. Over the three decades following the pathway's discovery, substantial progress has been made in elucidating how aberrant WNT/β-catenin signaling can drive cancer initiation, progression and maintenance. Attempts to therapeutically address this pathway have until recently been unsuccessful. Approaches to block the pathway upstream of relevant mutations were ineffective while progress in directly targeting β-catenin, either by blocking its interaction with key complex partners, most notably T cell factor (TCF) proteins, or by inducing β-catenin degradation has long remained an unreachable goal for conventional drug discovery approaches. In this review, we describe opportunities and challenges in the development of therapies that directly aim to target β-catenin. We highlight recent progress based on novel approaches, suggesting that cracking this previously considered \"undruggable\" central oncogenic driver is becoming a reality. Effective targeting of β-catenin has the potential to address extensive unmet patient needs in hard-to-treat cancer types such as colorectal cancer, hepatocellular carcinoma as well as other cancers driven by WNT/β-catenin pathway alterations.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456419","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}

引用次数: 0

Preclinical Evaluation of Liposomal Eribulin (E7389-LF) in a Panel of Sarcoma Patient-Derived Xenograft Models. 埃利布林脂质体（E7389-LF）在一组肉瘤患者来源的异种移植模型中的临床前评估。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-07-15 DOI: 10.1158/1535-7163.MCT-26-0096

Misato Jinno, Shigehiro Yagishita, Shoraku Ryu, Akira Yokoi, Taro Semba, Ayumu Arakawa, Shun-Ichi Watanabe, Kan Yonemori, Mitsuya Ishikawa, Akinobu Hamada

{"title":"Preclinical Evaluation of Liposomal Eribulin (E7389-LF) in a Panel of Sarcoma Patient-Derived Xenograft Models.","authors":"Misato Jinno, Shigehiro Yagishita, Shoraku Ryu, Akira Yokoi, Taro Semba, Ayumu Arakawa, Shun-Ichi Watanabe, Kan Yonemori, Mitsuya Ishikawa, Akinobu Hamada","doi":"10.1158/1535-7163.MCT-26-0096","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0096","url":null,"abstract":"Sarcomas are rare, heterogeneous tumors with poor prognoses, underscoring the urgent need for novel therapies. Liposomal eribulin (E7389-LF) was developed to improve the efficacy and safety profile of eribulin; however, its preclinical evaluation in sarcomas remains limited. This study aimed to evaluate the clinical applicability of E7389-LF. E7389-LF was comprehensively evaluated and compared with eribulin using 12 patient-derived xenograft (PDX) models representing six sarcoma subtypes. Antitumor activity was assessed across five treatment groups, including independently scaled, clinically relevant regimens of eribulin (0.47 mg/kg) and E7389-LF (0.77 mg/kg). Pharmacokinetic analyses were performed using liquid chromatography-tandem mass spectrometry and fluorescence immunostaining. In addition, correlations between antitumor activity and clinical efficacy were descriptively investigated. Treatment with E7389-LF (0.77 mg/kg) induced tumor regression in 7 of 12 models (58%), compared with 4 of 12 models (33%) treated with eribulin (0.47 mg/kg). Notable responses were observed in rhabdomyosarcoma, Ewing sarcoma, and leiomyosarcoma models. No apparent weight loss was observed in either treatment group. Pharmacokinetic analyses indicated increased systemic and intratumoral drug exposure with E7389-LF. In three PDX models derived from patients treated with eribulin, tumor responses reflected the corresponding clinical outcomes, providing preliminary evidence for the translational relevance of these models. This study demonstrates that E7389-LF exerts antitumor activity broadly comparable to eribulin and exerts antitumor activity in several models across sarcoma PDX models, with favorable tolerability and improved intratumoral drug retention. These findings support the clinical development of E7389-LF for patients with sarcoma who have limited treatment options.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456450","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}

引用次数: 0

Fedratinib induces non-classical G2/M arrest via mitotic-kinase inhibition and synergizes with mitomycin C to suppress pancreatic ductal adenocarcinoma. Fedratinib通过有丝分裂激酶抑制诱导非经典G2/M阻滞，并与丝裂霉素C协同抑制胰腺导管腺癌。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-07-14 DOI: 10.1158/1535-7163.MCT-26-0137

Hui-Ying Li, Pei-Ming Yang

{"title":"Fedratinib induces non-classical G2/M arrest via mitotic-kinase inhibition and synergizes with mitomycin C to suppress pancreatic ductal adenocarcinoma.","authors":"Hui-Ying Li, Pei-Ming Yang","doi":"10.1158/1535-7163.MCT-26-0137","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0137","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive form of pancreatic cancer, with a 5-year survival rate below 10%, largely due to late diagnosis, high metastatic capacity, and resistance to standard therapies. Drug repurposing guided by polypharmacology offers a time- and cost-effective strategy to identify new treatments with reduced clinical risk. Fedratinib, a JAK2 inhibitor approved for myelofibrosis, was previously identified through our bioinformatics analysis as a compound capable of reversing KRAS-driven transcriptional programs in PDAC cells. This study investigates the therapeutic potential and underlying mechanisms of fedratinib in PDAC. Two KRAS-mutant PDAC cell lines were used for in vitro analyses. Cell viability, protein expression, and cell-cycle distribution or apoptosis were assessed using MTT assays, Western blot analysis, and flow cytometry, respectively. Cellular thermal shift assays (CETSA) were performed to evaluate drug-target engagement. In vivo efficacy was examined using a PANC-1 xenograft mouse model treated with fedratinib alone or in combination with mitomycin C. Fedratinib significantly reduced PDAC cell viability, which was associated with caspase-independent cell death, and induced a non-canonical G2/M phenotype characterized by G2/M accumulation, reduced expression of mitotic markers, and accelerated mitotic exit after release from prometaphase arrest. Kinome profiling revealed off-target inhibition of multiple mitotic kinases, which was confirmed by CETSA. Combination screening identified strong synergy between fedratinib and mitomycin C, which was validated in vitro and in vivo. Overall, these findings highlight fedratinib as a promising repurposed therapeutic agent for PDAC and support its combination with mitomycin C as a potential new treatment strategy.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148436938","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}

引用次数: 0

Targeting mitochondrial protease in diffuse gliomas. 弥漫性胶质瘤的线粒体蛋白酶靶向。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-07-14 DOI: 10.1158/1535-7163.MCT-26-0156

Olga Kim, Jinkyu Jung, Shaunak Sathe, Guangyang Yu, Zach Sergi, Qi Li, Peng Lu, Meili Zhang, Ru-Ching Hsia, Michael J Kruhlak, Raj Chari, Herui Wang, Bao Tran, Ronald J Holewinski, Marina Chan, Thorkell Andresson, Zheng-Gang Liu, Lee M Graves, Taranjit S Gujral, Edwin J Iwanowicz, Jing Wu

{"title":"Targeting mitochondrial protease in diffuse gliomas.","authors":"Olga Kim, Jinkyu Jung, Shaunak Sathe, Guangyang Yu, Zach Sergi, Qi Li, Peng Lu, Meili Zhang, Ru-Ching Hsia, Michael J Kruhlak, Raj Chari, Herui Wang, Bao Tran, Ronald J Holewinski, Marina Chan, Thorkell Andresson, Zheng-Gang Liu, Lee M Graves, Taranjit S Gujral, Edwin J Iwanowicz, Jing Wu","doi":"10.1158/1535-7163.MCT-26-0156","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0156","url":null,"abstract":"Caseinolytic protease proteolytic subunit (ClpP) is part of the mitochondrial ClpXP protease responsible for degrading damaged proteins in the matrix, thus maintaining metabolic homeostasis. Small molecule activators of ClpP (ClpP agonists) have recently shown great promise against metabolically active cancers. TR107, a novel ClpP activator, demonstrates potent and selective cytotoxicity against glioma cells at nanomolar concentrations. Compared to the FDA-approved ClpP agonist ONC201 (Dordaviprone), TR107 shows greater efficacy across patient-derived and isogenic glioma models. TR107 effects are ClpP-dependent and result in widespread mitochondrial dysfunction evident by extensive protein degradation, impaired OxPhos, reduced mtDNA copy number, and ATP depletion. These disruptions are more severe in IDH-mutant than IDH-wildtype glioma cells, leading to enhanced cell cycle arrest, apoptosis, and inhibition of mTOR/AKT/4EBP1 signaling pathway. In this study, we show that ClpP agonism demonstrates preferential anti-tumor activity against IDH-mutant glioma in in vitro, ex vivo, and in vivo models. These findings support TR107 as a promising new targeted therapeutic for IDH-mutant gliomas.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148437120","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}

引用次数: 0

H3K27M enhances basal ATM signaling but is not required for radiosensitization of diffuse midline glioma via ATM inhibition with AZD1390. H3K27M增强了基础ATM信号，但不需要通过AZD1390抑制ATM来实现弥漫性中线胶质瘤的放射增敏。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-07-14 DOI: 10.1158/1535-7163.MCT-24-1019

Erik R Peterson, Leslie A Parsels, Zian Li, Xinyi Zhao, Luke D Hess, Yupei Guo, Dana Messinger, Joshua D Parsels, Zhuwen Wang, Tingting Qin, Victoria M Valvo, Andrea T Franson, Maria G Castro, Vivekanand N Yadav, Theodore S Lawrence, Carl Koschmann, Qiang Zhang, Daniel R Wahl, Meredith A Morgan

{"title":"H3K27M enhances basal ATM signaling but is not required for radiosensitization of diffuse midline glioma via ATM inhibition with AZD1390.","authors":"Erik R Peterson, Leslie A Parsels, Zian Li, Xinyi Zhao, Luke D Hess, Yupei Guo, Dana Messinger, Joshua D Parsels, Zhuwen Wang, Tingting Qin, Victoria M Valvo, Andrea T Franson, Maria G Castro, Vivekanand N Yadav, Theodore S Lawrence, Carl Koschmann, Qiang Zhang, Daniel R Wahl, Meredith A Morgan","doi":"10.1158/1535-7163.MCT-24-1019","DOIUrl":"10.1158/1535-7163.MCT-24-1019","url":null,"abstract":"H3K27-altered diffuse midline glioma (DMG) is an aggressive and treatment-resistant form of pediatric high-grade glioma (pHGG). The disease is defined by point mutations in histone H3 that convert lysine 27 to methionine (termed H3K27M), resulting in genome-wide epigenetic changes that drive tumorigenesis. While radiation therapy is the standard of care, subsequent recurrence, often within the high dose radiation field, is universal. We found that the apical DNA damage response kinase Ataxia Telangiectasia-Mutated (ATM) was uniquely upregulated in H3K27Mexpressing patient tumor samples compared to pHGG expressing only wild type histone H3. Using a panel of H3K27 isogenic cell lines, we further found that H3K27M was associated with reduced H3K27me3 within the ATM promoter, increased ATM mRNA levels, and elevated DNA damage response (DDR) signaling, even in the absence of radiation-induced DNA damage. In assessing the effect of these changes on the ability of AZD1390, a clinical-grade, CNS-penetrant ATM inhibitor, to sensitize cells to radiation, we found that while exogenous expression of H3K27M conferred preferential radiosensitization by AZD1390, CRISPR/Cas9 deletion of H3K27M did not attenuate the efficacy of AZD1390 in patient derived DMG cell lines. Finally, AZD1390 sensitized orthotopic H3K27M mutant tumors to radiotherapy in both immune deficient and syngeneic immune competent hosts with minimal adverse effects. Taken together, these data provide a direct mechanistic link between the H3K27M mutation and ATM expression and support the recently initiated clinical investigation of AZD1390 with radiotherapy in newly diagnosed pHGG.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148436979","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}

引用次数: 0

Decitabine reverses innate immune gene suppression in rare melanomas. 地西他滨逆转罕见黑色素瘤的先天免疫基因抑制。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-07-14 DOI: 10.1158/1535-7163.MCT-25-1325

Morgan L MacBeth, Stacey M Bagby, Jessica S W Borgers, Jacqueline A Turner, Kelsey Anderson, Phaedra A Whitty, Sarah J Hartman, Betelehem Yacob, Vito W Rebecca, Eduardo Davila, Todd M Pitts, Theresa M Medina, Sapna P Patel, Martin D McCarter, William A Robinson, Richard P Tobin, Kasey L Couts

{"title":"Decitabine reverses innate immune gene suppression in rare melanomas.","authors":"Morgan L MacBeth, Stacey M Bagby, Jessica S W Borgers, Jacqueline A Turner, Kelsey Anderson, Phaedra A Whitty, Sarah J Hartman, Betelehem Yacob, Vito W Rebecca, Eduardo Davila, Todd M Pitts, Theresa M Medina, Sapna P Patel, Martin D McCarter, William A Robinson, Richard P Tobin, Kasey L Couts","doi":"10.1158/1535-7163.MCT-25-1325","DOIUrl":"10.1158/1535-7163.MCT-25-1325","url":null,"abstract":"Rare melanoma subtypes, including acral, mucosal, and uveal melanomas, exhibit limited responses to immune checkpoint inhibitors (ICIs), yet the molecular mechanisms of immune resistance remain poorly defined. This study aimed to characterize transcriptional programs associated with immune evasion across melanoma subtypes and identify strategies to restore immune gene expression in rare melanomas. We performed transcriptomic profiling of melanoma patient-derived xenografts (PDXs) and publicly available tumor datasets to compare intratumoral gene expression across cutaneous and rare melanoma subtypes. Cross-subtype analysis revealed convergent downregulation of innate immune pathogen sensing (IIPS) and type I interferon signaling pathways in rare melanomas compared to cutaneous tumors. Lower IIPS expression correlated with non-response to PD-1 blockade, associated with reduced CD8⁺ and memory CD4⁺ T cell infiltration and enrichment of M2 macrophages inferred by CIBERSORT. Immunomodulatory compounds were screened in vitro to identify IIPS inducing drugs, and decitabine was further evaluated in mucosal and uveal melanoma xenograft models. Decitabine treatment robustly induced IIPS and antigen presentation genes in rare melanoma cell lines and xenografts, with RNA-seq confirming IIPS re-expression as the dominant transcriptional consequence. Silencing of IIPS genes represents a recurrent immune evasion mechanism in rare melanomas. Decitabine reverses this silencing, restoring innate and adaptive immune gene expression, and may serve as a therapeutic priming strategy to enhance ICI responsiveness in patients with rare melanoma subtypes.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148436961","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}

引用次数: 0

Endosialin (CD248) Cancer Role and Therapeutics: 33 Years on. 内皮素（CD248）在癌症中的作用和治疗：33年来。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-07-02 DOI: 10.1158/1535-7163.MCT-25-0759

Beverly A Teicher, Li Chen, Dianne L Newton, Melinda G Hollingshead, Nathan P Coussens, Thomas S Dexheimer, James H Doroshow

{"title":"Endosialin (CD248) Cancer Role and Therapeutics: 33 Years on.","authors":"Beverly A Teicher, Li Chen, Dianne L Newton, Melinda G Hollingshead, Nathan P Coussens, Thomas S Dexheimer, James H Doroshow","doi":"10.1158/1535-7163.MCT-25-0759","DOIUrl":"10.1158/1535-7163.MCT-25-0759","url":null,"abstract":"Since its discovery more than 30 years ago, our understanding of the function of CD248 [also known as endosialin or tumor endothelial marker 1 (TEM1)] as a therapeutic target has evolved, and CD248 is now recognized as a potentially valuable target for therapeutics directed toward sarcomas and fibrotic diseases. The current study reviews the literature related to CD248 and examines CD248 expression across various models including patient-derived xenografts, patient-derived cell lines (pdmr.cancer.gov/), and large cell line collections, including the Cancer Cell Line Encyclopedia and the GDSC-MGH-Sanger. CD248 is highly and selectively expressed by sarcomas and by pericytes in tumor vasculature and wound-healing vasculature. It is a component of a multi-protein complex which connects various cell types into tissue structure. Multiple therapeutic approaches are being investigated to take advantage of CD248 in the treatment of sarcomas and fibrotic diseases. Endosialin/CD248/TEM1 is a promising biological target that remains poorly explored in cancer therapy. Importantly, CD248 is overexpressed in several human solid tumors and absent in most normal adult tissues, making it a suitable and potentially safe target for radioimmunotherapy, particularly in Ewing sarcoma xenograft models.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1064-1076"},"PeriodicalIF":6.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227354","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}

引用次数: 0

Development of a SIN1 Targeting Inhibitor as a Novel Therapeutic Approach for the Treatment of Malignancies. 开发一种靶向SIN1的抑制剂作为治疗恶性肿瘤的新方法。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-07-02 DOI: 10.1158/1535-7163.MCT-25-0298

Elspeth M Beauchamp, Atul Jain, Matt Clutter, Dominik Nahotko, Emely Lopez Fajardo, Purav P Vagadia, Sara F Dunne, Alain Mina, Mariafausta Fischietti, Chidera V Oku, Gavin T Blyth, Rama K Mishra, Elena Karras, Sara G Radecki, Connor Lantz, Sidharth Addepalli, Mirage Modi, Lihua Zou, Byoung-Kyu Cho, Young Ah Goo, Jenna Rossoff, Eleanor N Fish, Diana Saleiro, Gary E Schiltz, Leonidas C Platanias

{"title":"Development of a SIN1 Targeting Inhibitor as a Novel Therapeutic Approach for the Treatment of Malignancies.","authors":"Elspeth M Beauchamp, Atul Jain, Matt Clutter, Dominik Nahotko, Emely Lopez Fajardo, Purav P Vagadia, Sara F Dunne, Alain Mina, Mariafausta Fischietti, Chidera V Oku, Gavin T Blyth, Rama K Mishra, Elena Karras, Sara G Radecki, Connor Lantz, Sidharth Addepalli, Mirage Modi, Lihua Zou, Byoung-Kyu Cho, Young Ah Goo, Jenna Rossoff, Eleanor N Fish, Diana Saleiro, Gary E Schiltz, Leonidas C Platanias","doi":"10.1158/1535-7163.MCT-25-0298","DOIUrl":"10.1158/1535-7163.MCT-25-0298","url":null,"abstract":"The essential role of mTOR in promoting tumorigenesis of many cancers makes it an attractive therapeutic target. However, catalytic mTOR inhibitors, which block both mTORC1 and mTORC2, result in activation of negative feedback loops as a resistance mechanism. Selective mTORC2 inhibitors are expected to have the desired antitumor effects without engaging resistance mechanisms; however, to date, no such mTORC2 inhibitors have been developed. Using in silico screening and medicinal chemistry optimization, we identified several small molecules that bind to the unique mTORC2 component, stress-activated protein kinase-interacting protein 1 (SIN1). We demonstrate that this SIN1 inhibitor alters posttranslational modification, protein-protein interactions, and blocks mTORC2- and rapamycin-sensitive mTORC1-mediated signaling. The SIN1 inhibitor also inhibits wild-type RAS activation and downstream MAPK signaling, as well as cell proliferation of multiple cancer cell line types. SIN1 inhibition can enhance the efficacy of FDA-approved antineoplastic agents in vitro and may provide a novel approach for the treatment of different types of malignancies.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1111-1129"},"PeriodicalIF":6.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12904549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145804814","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}

引用次数: 0