Molecular Cancer Therapeutics最新文献

Ubiquitination of oncogenic mutant p53 via attenuation of ribosome biogenesis machinery effectively inhibits pancreatic tumor growth. 通过核糖体生物发生机制的衰减，致癌突变体p53的泛素化有效抑制胰腺肿瘤的生长。

IF 5.5 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-10-07 DOI: 10.1158/1535-7163.MCT-25-0097

Mudassier Ahmad, Sahir Sultan Alvi, Haider Ahsan, Carlos Perez, Andrew Massey, Vivek K Kashyap, Neeraj Chauhan, Emmanuel Anning, Manish K Tripathi, Dae J Kim, Nirakar Sahoo, Tamer Oraby, Murali M Yallapu, Mohammad Moshahid Khan, Manu M Sebastian, Subhash C Chauhan, Bilal B Hafeez

{"title":"Ubiquitination of oncogenic mutant p53 via attenuation of ribosome biogenesis machinery effectively inhibits pancreatic tumor growth.","authors":"Mudassier Ahmad, Sahir Sultan Alvi, Haider Ahsan, Carlos Perez, Andrew Massey, Vivek K Kashyap, Neeraj Chauhan, Emmanuel Anning, Manish K Tripathi, Dae J Kim, Nirakar Sahoo, Tamer Oraby, Murali M Yallapu, Mohammad Moshahid Khan, Manu M Sebastian, Subhash C Chauhan, Bilal B Hafeez","doi":"10.1158/1535-7163.MCT-25-0097","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0097","url":null,"abstract":"Dysregulated ribosome biogenesis and p53 mutations are known to play oncogenic roles in various cancers, including pancreatic cancer (PanCa). In this study, we demonstrated the therapeutic potential of BMH-21, a pharmacological inhibitor of RNA polymerase I (Pol I), against PanCa by uncovering a novel molecular mechanism involving RPA194-mediated ubiquitination of mutant p53 without affecting the ubiquitination of WT p53. Our key findings include: (i) BMH-21 selectively induces apoptosis and cell growth inhibition of PanCa cells with no effect on normal human pancreatic ductal epithelial cells, (ii) BMH-21 degrades RPA194, (iii) BMH-21 inhibits recruitment of both RPA194 and RPA135 on rDNA to suppress pre-rRNA synthesis, (iv) RPA194 physically interacts with p53 and BMH-21-induced degradation of RPA194 selectively exposes truncated and mutated p53 for ubiquitination with no effect on ubiquitination of WT p53 in PanCa cells and (v) BMH-21 treatment significantly reduces the growth of orthotopic xenograft pancreatic tumors in athymic nude mice with no observed toxicity. Altogether, these findings suggest that BMH-21 is a promising, non-toxic therapeutic agent for PanCa patients with aberrant ribosome biogenesis and mutant p53, offering a potential new avenue for targeted treatment.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239285","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 aGD2-SIRPα fusion antibodies targeting neuroblastoma and the innate immune checkpoint receptor CD47. 靶向神经母细胞瘤和先天免疫检查点受体CD47的aGD2-SIRPα融合抗体的研制

IF 5.5 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-10-07 DOI: 10.1158/1535-7163.MCT-24-1090

Fabian Schuurmans, Anja Wittner, Renske J E van den Bijgaart, Siret Tahk, Matthia G M Boros, Maaike W G Looman, Nadja C Fenn, Andreas Humpe, Karl-Peter Hopfner, Gosse J Adema

{"title":"Development of aGD2-SIRPα fusion antibodies targeting neuroblastoma and the innate immune checkpoint receptor CD47.","authors":"Fabian Schuurmans, Anja Wittner, Renske J E van den Bijgaart, Siret Tahk, Matthia G M Boros, Maaike W G Looman, Nadja C Fenn, Andreas Humpe, Karl-Peter Hopfner, Gosse J Adema","doi":"10.1158/1535-7163.MCT-24-1090","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-1090","url":null,"abstract":"Neuroblastoma (NB) is a childhood malignancy characterized by overexpression of disialoganglioside GD2. Treatment with anti-GD2 monoclonal antibodies (aGD2 mAbs) has prolonged the survival of NB patients, however, long-term efficacy needs further improvement. NB tumor cells upregulate expression of the innate immune checkpoint and don't eat me signal CD47 to evade immune recognition and phagocytosis by Signal regulatory protein alpha (SIRPα) expressing myeloid cells. Targeting of CD47 remains challenging because ubiquitous CD47 expression on healthy cells causes on-target off-tumor related toxicities and functions as an antigen sink. To locally restrict CD47 blockade to the NB tumor site, we successfully developed aGD2-SIRPα fusion mAbs for the murine and human setting. These fusion mAbs are equipped with a functional Fc-domain and the extracellular SIRPα domain 1 either fused to the N-terminus of the light chain or to the C-terminus of the heavy chain. Both aGD2-SIRPα fusion mAbs selectively bind NB tumor cells and provide GD2-dependent SIRPα domain-mediated CD47 blockade (Fig. 1a). Furthermore, they potently induce innate immune effector mechanisms through the interaction of the mAbs Fc-domain with Fcγ receptors. Functional analysis of the fusion mAbs demonstrated enhanced phagocytosis and NK cell-mediated killing of NB tumor cells compared to the conventional aGD2 mAb. In addition, these novel antibodies modulate the cytokine production by primary macrophages. The aGD2-SIRPα fusion mAbs outperformed aGD2 mAb across a broad range of CD47/GD2 co-expressing tumor cells. This research shows the successful development of aGD2-SIRPα fusion mAbs to provide targeted blockade of CD47 for the treatment of solid NB tumors.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239288","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

IKS04, a CanAg-Targeting Antibody-Drug Conjugate with Pyrrolobenzodiazepine, Shows Enhanced Efficacy with Unconjugated Antibody Coadministration in Animal Models. pyrolobenzodiazepine的canag靶向抗体-药物偶联物IKS04在动物模型中与非偶联抗体共给药显示出增强的疗效。

IF 5.5 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-10-07 DOI: 10.1158/1535-7163.MCT-25-0484

Haolong Huang, Jutta Deckert, Justyna Mysliwy, Adam Lodge, Robert J Lutz, Greg M Thurber

{"title":"IKS04, a CanAg-Targeting Antibody-Drug Conjugate with Pyrrolobenzodiazepine, Shows Enhanced Efficacy with Unconjugated Antibody Coadministration in Animal Models.","authors":"Haolong Huang, Jutta Deckert, Justyna Mysliwy, Adam Lodge, Robert J Lutz, Greg M Thurber","doi":"10.1158/1535-7163.MCT-25-0484","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0484","url":null,"abstract":"CanAg (CA242) is a carbohydrate antigen highly overexpressed in most gastrointestinal (GI) cancers with minimal expression in normal tissue, making it an attractive target for ADC therapeutics in these cancers. Previous efforts to target CanAg with ADCs have shown limited clinical efficacy, possibly due to resistance to the tubulin inhibitor payloads used. IKS04 is a novel CanAg targeting ADC comprised of an anti-CanAg humanized monoclonal antibody Isumab04 and a highly potent pyrrolobenzodiazepine (PBD) prodrug payload. However, the use of potent payloads such as PBDs can limit the maximum tolerated dose (MTD) of ADCs, which in turn limits tumor tissue penetration and efficacy, particularly for high-expression targets such as CanAg. Coadministration of unconjugated antibody can potentially improve tumor tissue penetration, resulting in increased ADC efficacy. In this study, we evaluated the impact of Isumab04 coadministration on the distribution and efficacy of IKS04 in human tumor xenograft mouse models with different CanAg expression levels. While the addition of Isumab04 antibody showed minimal impact on IKS04 cell killing activity in vitro in cells with moderate and high CanAg expression, coadministration of Isumab04 with IKS04 improved tumor tissue distribution of the ADC in both tumor spheroids and in vivo tumor models. This improved distribution correlated with increased efficacy in vivo, where increasing doses of unconjugated antibody resulted in greater efficacy until apparent tumor saturation was reached. These results support the use of antibody coadministration to improve the efficacy of ADCs targeting high-expression antigens with highly potent payloads.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239315","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 activity of the DLL3-targeted T cell engager MK-6070 in neuroendocrine prostate cancer. dll3靶向T细胞接合物MK-6070在神经内分泌前列腺癌中的临床前活性

IF 5.5 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-10-03 DOI: 10.1158/1535-7163.MCT-25-0453

Sheng-Yu Ku, Nishat Manzar, Maria Mica Garcia, Min Jin Kim, David J Einstein, Steven P Balk, Yasutaka Yamada, Himisha Beltran

{"title":"Preclinical activity of the DLL3-targeted T cell engager MK-6070 in neuroendocrine prostate cancer.","authors":"Sheng-Yu Ku, Nishat Manzar, Maria Mica Garcia, Min Jin Kim, David J Einstein, Steven P Balk, Yasutaka Yamada, Himisha Beltran","doi":"10.1158/1535-7163.MCT-25-0453","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0453","url":null,"abstract":"Neuroendocrine prostate cancer is an aggressive variant of prostate cancer with limited therapeutic options. Delta-like ligand 3 (DLL3) is a cell surface protein and therapeutic target expressed in the vast majority of NEPC tumors. The DLL3-targeted T cell activating construct MK-6070 (formerly called HPN328) binds to both DLL3 on tumor cells and CD3 on T cells, as well as serum albumin to extend half-life. A phase 1/2 trial of MK-6070 is currently underway which includes an NEPC cohort (NCT04471727). Here we report the preclinical activity of MK-6070 in prostate cancer models, showing high specificity and anti-tumor activity in DLL3-expressing NEPC models both in vitro and in vivo, with T cell activation and tumor infiltration of T cells after treatment. MK-6070 also demonstrates anti-tumor activity in mixed tumors, impacting DLL3-negative prostate cancer cells after engagement with surrounding DLL3-expressing tumor cells, supporting a potential bystander effect. Overall, these data demonstrate promising activity of MK-6070 in NEPC preclinical models including heterogeneous tumors, supporting the clinical development of MK-6070.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213249","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

Identification and non-clinical characterization of SAR444200, a novel anti-GPC3 NANOBODY® T-cell engager, for the treatment of GPC3+ solid tumors. 新型抗GPC3 NANOBODY®t细胞接合剂SAR444200的鉴定和非临床特征，用于治疗GPC3+实体瘤。

IF 5.5 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-10-03 DOI: 10.1158/1535-7163.MCT-24-1049

Paolo Meoni, Ana Paula B Vintém, Virna F Cortez-Retamozo, Jasper Jacobs, Evelyn De Tavernier, Paola Fiorentini, Diane Van Hoorick, Joseph D Batchelor, Egor Svidritskiy, Yu Qiu, Eline Dejonckheere, Aiqun Li, Lily I Pao, Marie-Ange Buyse

{"title":"Identification and non-clinical characterization of SAR444200, a novel anti-GPC3 NANOBODY® T-cell engager, for the treatment of GPC3+ solid tumors.","authors":"Paolo Meoni, Ana Paula B Vintém, Virna F Cortez-Retamozo, Jasper Jacobs, Evelyn De Tavernier, Paola Fiorentini, Diane Van Hoorick, Joseph D Batchelor, Egor Svidritskiy, Yu Qiu, Eline Dejonckheere, Aiqun Li, Lily I Pao, Marie-Ange Buyse","doi":"10.1158/1535-7163.MCT-24-1049","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-1049","url":null,"abstract":"T-cell engager (TCE) immunotherapy has demonstrated significant clinical activity in multiple cancers by inducing co-engagement of T-cells and tumor cells, resulting in T-cell activation and T-cell-dependent cellular cytotoxicity (TDCC) against tumor cells. Current-generation TCEs are predominantly composed of antibody-based binding domains targeting the CD3e molecule of the T-cell antigen receptor (TCR)/CD3 complex on T-cells and a tumor-associated antigen on tumor cells. However, limitations of this approach include cytokine release syndrome and a limited therapeutic window. Here, we report the generation and preclinical evaluation of SAR444200, the first NANOBODY®-based TCE clinical candidate binding to TCRαβ and GPC3 to co-engage T-cells and GPC3+ tumor cells, causing TDCC. SAR444200 bound with nanomolar to picomolar affinity to TCRαβ and GPC3 respectively and induced in vitro TDCC against multiple human tumor cell lines with differential GPC3 expression with picomolar potency. In vivo analysis using human cancer cell line-derived (HuH-7 and HepG2) xenografts in immunodeficient mice showed complete tumor regression at doses starting from 0.7 mg/kg. In exploratory non-human primate studies, intravenous administration of SAR444200 was well tolerated up to 8 mg/kg and exhibited greater than dose-proportional clearances and dose-proportional maximum concentrations across the tested dose range. The highly potent and efficacious activity of SAR444200 in diverse models of GPC3+ tumors and the extremely wide tolerated dose range merits further development of this compound. Furthermore, NANOBODY®-based TCEs developed using an anti-TCRαβ moiety may have specific advantages for the development of TCEs.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213228","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

Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors. 药物基因组学合成致死筛选揭示了nf1相关肿瘤的潜在脆弱性和新的治疗方法。

IF 5.5 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-10-02 DOI: 10.1158/1535-7163.MCT-24-1053

Kyle B Williams, Alex T Larsson, Bryant J Keller, Katherine E Chaney, Rory L Williams, Minu M Bhunia, Garrett M Draper, Tyler A Jubenville, Wendy A Hudson, Gunda I Georg, Christopher L Moertel, Nancy Ratner, David A Largaespada

{"title":"Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors.","authors":"Kyle B Williams, Alex T Larsson, Bryant J Keller, Katherine E Chaney, Rory L Williams, Minu M Bhunia, Garrett M Draper, Tyler A Jubenville, Wendy A Hudson, Gunda I Georg, Christopher L Moertel, Nancy Ratner, David A Largaespada","doi":"10.1158/1535-7163.MCT-24-1053","DOIUrl":"10.1158/1535-7163.MCT-24-1053","url":null,"abstract":"Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome caused by heterozygous loss of function mutations in the tumor suppressor gene NF1. Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild-type NF1 allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA-approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST. The genetic basis of NF1 syndrome makes associated tumors ideal for using synthetic drug sensitivity approaches to uncover therapeutic vulnerabilities. We developed a drug discovery pipeline to identify therapeutics for NF1-related tumors using isogeneic pairs of NF1-proficient and deficient immortalized human Schwann cells. We utilized these in a large-scale high throughput screen (HTS) for drugs that preferentially kill NF1-deficient cells, through which we identified 23 compounds capable of killing NF1-deficient Schwann cells with selectivity. Multiple hits from this screen clustered into classes defined by the method of action. Four clinically interesting drugs from these classes were tested in vivo using both a genetically engineered mouse model of high-grade peripheral nerve sheath tumors and human MPNST xenografts. All drugs tested showed single-agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor Selumetinib. This HTS platform yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206913","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

PSMA-Targeted Small Molecule-Drug Conjugates Based on a Postprolyl Peptidase-Cleavable Linker for the Treatment of Prostate Cancer. 基于后脯氨酸肽酶可切割连接体的psma靶向小分子药物偶联物治疗前列腺癌。

IF 5.5 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-10-01 DOI: 10.1158/1535-7163.MCT-24-0750

Tony Georgiev, Sara Puglioli, Lucrezia Principi, Ettore Gilardoni, Christian Pellegrino, Gabriele Bassi, Andrea Galbiati, Dario Neri, Samuele Cazzamalli

{"title":"PSMA-Targeted Small Molecule-Drug Conjugates Based on a Postprolyl Peptidase-Cleavable Linker for the Treatment of Prostate Cancer.","authors":"Tony Georgiev, Sara Puglioli, Lucrezia Principi, Ettore Gilardoni, Christian Pellegrino, Gabriele Bassi, Andrea Galbiati, Dario Neri, Samuele Cazzamalli","doi":"10.1158/1535-7163.MCT-24-0750","DOIUrl":"10.1158/1535-7163.MCT-24-0750","url":null,"abstract":"Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed on the surface of cancerous prostate cells both in primary tumors and in metastases. Small organic ligands targeting PSMA have been broadly and successfully used to deliver radionuclide payloads to prostate cancer lesions. 177Lu-PSMA-617 (Pluvicto, a Novartis product) is a PSMA-targeted product that has been recently approved for the treatment of metastatic castration-resistant prostate cancer. By contrast, no small molecule-drug conjugates (SMDC) directed against PSMA have gained marketing authorization yet. In this article, we present the development of novel SMDCs generated by conjugating the tumor-targeting moiety of Pluvicto (here named \"OncoPSMA\") to highly cytotoxic auristatin payloads through cleavable linkers, including valine-citrulline, disulfide bridges, and a recently described postprolyl peptidase-cleavable linker [glycine-proline (Gly-Pro)]. The efficiency of payload release at the cancer site and in healthy tissues was assessed via biodistribution studies using mass spectrometry quantification upon systemic administration in tumor-bearing mice. SMDCs based on the Gly-Pro linker mediated the highest payload release in solid tumors compared with widely utilized cathepsin B-cleavable and disulfide linkers. The in vivo efficacy of OncoPSMA-Gly-Pro-monomethyl auristatin E and OncoPSMA-Gly-Pro-monomethyl auristatin F was tested in therapy studies alone and in combination with an antibody-IL2 fusion protein, capable of preferential homing to solid tumors. Combination treatments resulted in complete and durable responses, highlighting the potential benefit of this therapeutic modality to patients with metastatic prostate cancer.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1561-1569"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542574","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

A Novel Squaramide Derivative, HR-19011, Induces the Integrated Stress Response via the HRI-eIF2α-ATF4 Pathway, Effectively Inhibiting Hematologic Malignancies. 一种新的方酰胺衍生物HR-19011通过HRI-eIF2α-ATF4途径诱导综合应激反应，有效抑制血液恶性肿瘤。

IF 5.5 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-10-01 DOI: 10.1158/1535-7163.MCT-24-0998

Min-Jung Kim, Jinsook Kwak, Hyung Seok Kim, Jihyung Han, Ji An Kang, Jeyun Jo, Jisu Kim, Da-Jung Kim, Ho Sup Lee, Hwayoung Yun, Jee-Yeong Jeong

{"title":"A Novel Squaramide Derivative, HR-19011, Induces the Integrated Stress Response via the HRI-eIF2α-ATF4 Pathway, Effectively Inhibiting Hematologic Malignancies.","authors":"Min-Jung Kim, Jinsook Kwak, Hyung Seok Kim, Jihyung Han, Ji An Kang, Jeyun Jo, Jisu Kim, Da-Jung Kim, Ho Sup Lee, Hwayoung Yun, Jee-Yeong Jeong","doi":"10.1158/1535-7163.MCT-24-0998","DOIUrl":"10.1158/1535-7163.MCT-24-0998","url":null,"abstract":"We investigated the therapeutic potential and mechanisms of HR-19011, a novel eukaryotic translation initiation factor 2 subunit α (eIF2α) phosphorylation inducer, with a focus on its effects on the integrated stress response (ISR) pathway and cell-cycle regulation in K562 cells. Our findings revealed that HR-19011 exerts its anticancer effects primarily through the activation of heme-regulated inhibitor (HRI), leading to the phosphorylation of eIF2α, the induction of ISR signaling, and subsequent G1/S cell-cycle arrest. RNA sequencing analysis further highlighted significant changes in gene expression associated with the ISR pathway, particularly those involving the key components, activating transcription factor 4 and CHOP, underscoring the specific targeting of HRI by HR-19011. Additionally, HR-19011 suppressed the mTORC1 pathway, a critical regulator of cell growth and metabolism, through the downregulation of components such as phosphorylated S6K and phosphorylated 4EBP1, mediated by activating transcription factor 4 and CHOP. In vivo studies demonstrated that HR-19011 effectively inhibited tumor growth in a K562 xenograft model, without significant toxicity, and its broad efficacy across various hematologic malignancies further suggests its potential as a versatile anticancer agent. Our findings position HR-19011 as a promising candidate for targeting the HRI-eIF2α axis in cancer treatment, warranting further investigation and optimization for clinical application.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1546-1560"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019788","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

Specific Genetic Mutations Impact Chemotherapy Resistance and Therapeutic Efficacy of Oncolytic Viruses in Ovarian Cancer. 特异性基因突变影响卵巢癌溶瘤病毒的化疗耐药性和治疗效果。

IF 5.5 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-10-01 DOI: 10.1158/1535-7163.MCT-24-0906

Alison O Cudmore, Galaxia M Rodriguez, Vincent Maranda, Salar Farokhi Boroujeni, Humaira Murshed, Elizabeth A Macdonald, Melanie Grondin, Kenneth Garson, Kathy Matuszewska, Jean-Simon Diallo, James J Petrik, Barbara C Vanderhyden

{"title":"Specific Genetic Mutations Impact Chemotherapy Resistance and Therapeutic Efficacy of Oncolytic Viruses in Ovarian Cancer.","authors":"Alison O Cudmore, Galaxia M Rodriguez, Vincent Maranda, Salar Farokhi Boroujeni, Humaira Murshed, Elizabeth A Macdonald, Melanie Grondin, Kenneth Garson, Kathy Matuszewska, Jean-Simon Diallo, James J Petrik, Barbara C Vanderhyden","doi":"10.1158/1535-7163.MCT-24-0906","DOIUrl":"10.1158/1535-7163.MCT-24-0906","url":null,"abstract":"Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer, and those affected are in urgent need of new therapeutic strategies. Standard treatment is surgery followed by taxane- and platinum-based chemotherapy. However, the rate of relapse is high, and the 5-year survival is only 45%. Oncolytic viruses (OV) are a promising approach to EOC therapy through remodeling the immune composition of the tumor microenvironment. Treatment response in EOC tumors can differ based on the presence of key tumorigenic mutations. This study evaluated the impact of specific tumor mutations on the response to the current standard-of-care carboplatin, two promising OV candidates VSVΔM51 and MG1, an infected cell vaccine (ICV-MG1) regimen, and the antiangiogenic drug Fc3TSR. Mice with tumors harboring constitutive K-Ras activation showed an enhanced response to carboplatin and VSVΔM51 treatment. Additionally, VSVΔM51 treatment prolonged survival of syngeneic mice bearing tumors with mutations in Pten and Kras, Pten and Trp53, or Trp53 and Brca2 with increased activation of CD4+ and CD8+ T lymphocytes in the peritoneal tumor microenvironment. To enhance OV potency, an MG1-based infected cell vaccine inducing the expression of IL21 or IL15 + IL21 was developed and found to enable strong and long-lasting antitumoral immunity in two carboplatin-refractory syngeneic models, ID8-Trp53-/- and STOSE. VSVΔM51 combined with the antiangiogenic Fc3TSR enhanced efficacy in the ID8 model. In summary, OV-based immunotherapy has shown promise in diverse murine models of EOC-bearing clinically relevant mutations, thus laying the foundation for developing new OV-based strategies to target a large spectrum of EOC genotypes.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1626-1639"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586353","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

Development of Multivalent FAP-Targeted Small Molecule-Drug Conjugates with Tailored MMAE Release Kinetics. 具有定制MMAE释放动力学的多价fap靶向小分子药物偶联物的开发。

IF 5.5 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-10-01 DOI: 10.1158/1535-7163.MCT-25-0026

Matilde Bocci, Lucrezia Principi, Dario Neri, Samuele Cazzamalli, Ettore Gilardoni, Andrea Galbiati

{"title":"Development of Multivalent FAP-Targeted Small Molecule-Drug Conjugates with Tailored MMAE Release Kinetics.","authors":"Matilde Bocci, Lucrezia Principi, Dario Neri, Samuele Cazzamalli, Ettore Gilardoni, Andrea Galbiati","doi":"10.1158/1535-7163.MCT-25-0026","DOIUrl":"10.1158/1535-7163.MCT-25-0026","url":null,"abstract":"Antibody-drug conjugates are one of the most diffused targeted therapeutic modalities for cancer treatment and consist of a tumor-targeted monoclonal antibody connected to a cytotoxic payload, which is released selectively at the tumor site. Small molecule-drug conjugates (SMDC) represent an alternative approach, in which the antibody is replaced by a tumor-homing small organic ligand. Thanks to their small molecular size, SMDCs are characterized by rapid extravasation and enhanced penetration in solid tumors compared with antibody-drug conjugates. We recently developed SMDCs targeting fibroblast activation protein (FAP), a cell surface endopeptidase abundant in the tumor microenvironment, using the highly specific FAP inhibitor OncoFAP as a targeting moiety. In this study, we compared the tumor-targeting properties and in vivo activity of SMDCs based on OncoFAP against products based on a stronger FAP inhibitor (i.e., trivalent OncoFAP), aiming to tune the release kinetic of the cytotoxic payload to the neoplastic site. We compared the kinetic profiles of the monovalent and trivalent derivatives of OncoFAP through in vivo and ex vivo biodistribution and therapy studies. The distinct in vivo monomethyl auristatin E (MMAE) release obtained for OncoFAP-GlyPro-MMAE and TriOncoFAP-GlyPro-MMAE did not lead to substantial differences in therapeutic efficacy in a preclinical FAP-positive cancer model.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1487-1496"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528882","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}

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