Molecular Cancer Therapeutics最新文献

{"title":"Denfivontinib Activates Effector T Cells Through the NLRP3 Inflammasome, Yielding Potent Anticancer Effects by Combination with Pembrolizumab.","authors":"Dong Kwon Kim, Chun-Bong Synn, Wongeun Lee, Ha-Ni Jo, Chai Young Lee, Seul Lee, Joon Yeon Hwang, Youngtaek Kim, Seong-San Kang, Sujeong Baek, Kwangmin Na, Seung Min Yang, Mi Hyun Kim, Heekyung Han, Yu Jin Han, Jae Hwan Kim, So Young Park, Young Joon Park, Gang-Taik Lee, Su-Jin Choi, Jie-Ohn Sohn, Sang-Kyu Ye, Jii Bum Lee, Sun Min Lim, Min Hee Hong, Kyoung-Ho Pyo, Byoung Chul Cho","doi":"10.1158/1535-7163.MCT-24-0501","DOIUrl":"10.1158/1535-7163.MCT-24-0501","url":null,"abstract":"<p><p>Various combination therapies have been investigated to overcome the limitations of using immune checkpoint inhibitors. However, determining the optimal combination therapy remains challenging. To overcome the therapeutic limitation, we conducted a translational research to elucidate the mechanisms by which AXL inhibition enhances antitumor effects when combined with anti-PD-1 antibody therapy. Herein, we demonstrated improved antitumor effects through combination treatment with denfivontinib and pembrolizumab which resulted in enhanced differentiation into effector CD4+ and CD8+ memory T cells, accompanied by an increase in IFN-γ expression in the YHIM-2004 xenograft model derived from patients with non-small cell lung cancer. Concurrently, a reduction in the number of immunosuppressive M2 macrophages and myeloid-derived suppressor cells was observed. Mechanistically, denfivontinib potentiated the NOD-like receptor pathway, thereby facilitating NLRP3 inflammasome formation. This leads to macrophage activation via NF-κB signaling pathway activation. We have confirmed that the positive interaction between macrophages and T cells arises from the enhanced antigen-presenting machinery of activated macrophages. Furthermore, the observed tumor effects in AXL knockout mice confirmed that AXL inhibition by denfivontinib enhances the antitumor effects, thus opening new avenues for therapeutic interventions aimed at overcoming limitations in immunotherapy. To demonstrate the extent to which our findings reflect clinical results, we analyzed bulk RNA sequencing data from 21 patients with non-small cell lung cancer undergoing anti-PD-1 immunotherapy. The NLRP3 inflammasome score influenced enhanced immune responses in patient data undergoing anti-PD-1 immunotherapy, suggesting a role for the NLRP3 inflammasome in activating immune responses during treatment.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"354-369"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780606","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":"M4205 (IDRX-42) is a highly selective and potent inhibitor of relevant oncogenic driver and resistance variants of KIT in cancer.","authors":"Christina Esdar, Nina LInde, Andreas Blum, Hanno Schieferstein, Christine Drechsler, Eva Sherbetjian, Carl Petersson, Edith Ross, Birgitta Leuthner, Ulrich Grädler, Dieter Dorsch, Andree Blaukat","doi":"10.1158/1535-7163.MCT-24-0699","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0699","url":null,"abstract":"<p><p>Primary activating mutations in KIT (exons 9/11) are key driver alterations in about 80% of gastrointestinal stromal tumors (GIST). Imatinib, a small molecule tyrosine kinase inhibitor, is used successfully as first-line therapy for unresectable metastatic or recurrent GIST patients, but secondary resistance mutations in the KIT kinase domains frequently occur. Currently approved later-line therapies target these mutations incompletely with limited clinical benefit. M4205, a kinome-selective KIT inhibitor, was designed to address this high unmet medical need by inhibiting all relevant KIT driver and resistance mutations. Compared to imatinib, M4205 shows stronger antitumor activity in preclinical GIST models driven by oncogenic KIT driver mutations. M4205 demonstrates clinically relevant efficacy in a range of preclinical GIST models expressing different secondary KIT resistance mutations. The kinase selectivity profile of M4205 is superior to registered standard of care and investigational agents. M4205, now IDRX-42, is currently being investigated in a Phase 1 first-in-human study in participants with GIST.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523869","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":"Mechanisms Of Response And Resistance To PSMAXCD3 Bispecifics In CD34+ Humanized Mice.","authors":"Bethany K Mattson Cypert, Krista Menard, Gerald Chu, Theresa McDevitt, Raluca I Verona, Brent Rupnow, Kathryn Packman","doi":"10.1158/1535-7163.MCT-23-0779","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0779","url":null,"abstract":"<p><p>Prostate cancer is considered immunologically \"cold\", with low mutational burden, tumor-infiltrating immune cells, and PD-L1 levels, culminating in poor response to immune checkpoint therapies. Bispecific CD3 redirection antibodies can elicit T cell-mediated cytotoxicity and hold promise for immune cell recruitment into prostate tumors. CD3 redirection antibodies in solid tumors are still in early phases of clinical development, and it is not yet understood whether these potential therapies will achieve the high response rates observed in hematological malignancies or result in durable T cell responses. Here we demonstrated that treatment with a PSMA targeted CD3 redirector resulted in efficacy against LnCaP.AR human prostate xenografts in CD34+ cord blood humanized mice. Efficacy correlated with T cell infiltration into tumors with an activated phenotype, but also increased PD-L1 expression. Engineered overexpression of PD-L1 in LNCaP.AR tumors resulted in resistance to PSMAxCD3 bispecific antibody treatment, whereas sensitivity was restored in combination with anti-PD-1 antibody pembrolizumab. PSMAxCD3 and anti-PD-1 combination treatment resulted in complete tumor responses in approximately 20% of mice, and elicited immune responses that delayed growth of rechallenged tumors. In a second prostate model, patient derived LuCaP 86.2 xenografts, PSMAxCD3 monotherapy treatment resulted in complete responses in 25% of mice. When PSMAxCD3-treated responder mice were rechallenged with LuCaP 86.2 tumors, partial control of tumor regrowth was associated with expansion of effector memory T cells. These studies show that PSMAxCD3 treatment elicits antitumor memory T cell responses, and that combination with PD-1 blockade can enhance these effects in tumors with immune suppressive tumor microenvironments.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502675","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":"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":"https://doi.org/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. Immunohistochemistry (IHC) of 39 ATC patient samples were evaluated for CD44v6 expression. Biodistribution and dosimetry of 125I/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 SPECT-imaging evaluated radiolabeled UU-40 for therapeutic efficiency in ATC xenografts. The IHC revealed CD44v6 immunoreactivity in 46% of ATC patient samples. The biodistribution favored 177LuUU-40 over the 125I-labeled antibody and confirmed 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 -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 -UU-40 in a high CD44v6-expressing xenograft model (ACT-1), and SPECT-imaging revealed excellent tumor uptake of the radioconjugate at 14 days post-injection. This study verifies the expression of CD44v6 in ATC and cements the superiority and promise of 177Lu -UU-40 over 131I-UU-40 for antibody-based molecular radiotherapy of CD44v6-positive ATC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blockade of the PGE2 pathway inhibits the growth of PTEN deficient HNSCC tumors.","authors":"Jacqueline P Nguyen, Shorook Na'ara, Liam C Woerner, Nathan K VanLandingham, Marius Hoerner, Rodell T Santuray, Kelly Blum, Mi-Ok Kim, Daniel E Johnson, Jennifer R Grandis","doi":"10.1158/1535-7163.MCT-24-0604","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0604","url":null,"abstract":"<p><p>Increased PI3K signaling as a result of PIK3CA mutation or amplification or decreased expression of PTEN (phosphatase and tensin homolog deleted on chromosome 10) is one of the most common alterations in head and neck squamous cell carcinoma (HNSCC). PTEN negatively regulates PI3K signaling and its downstream effectors including COX2. COX2 mediates the synthesis of PGE2 which contributes to immunosuppression in the tumor microenvironment. PGE2 also binds to one or more EP receptors (EP1-EP4) and promotes the growth of tumor cells via activation of EP2 and EP4. However, the role of PGE2 in PTEN-deficient HNSCC is incompletely understood. Here, we assessed PGE2 signaling in PTEN-deficient HNSCC and evaluated the effect of aspirin or TPST-1495, a dual EP2/EP4 antagonist, on the growth of PTEN knockout (KO) and PIK3CA-altered HNSCC tumors in immunocompetent mice. Our results demonstrated that aspirin selectively inhibits the growth of PTEN KO HNSCC tumors. TPST-1495 inhibited tumor growth and substantially increased the anti-tumor activity of the immune checkpoint inhibitor anti-PD1. To date, there are no FDA-approved therapies for PI3K pathway-altered HNSCC. Our findings suggest that NSAIDs demonstrate anti-tumor activity in PTEN-deficient or PI3K-altered tumors whereas EP2/EP4 targeting may augment FDA-approved anti-PD1 therapy in HNSCC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458674","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":"Evaluation of VLA-4 (integrin α4β1) as a shared target for radiopharmaceutical therapy across solid tumors.","authors":"Jeyshka M Reyes-González, Harikrishnan Rajkumar, Woonghee Lee, Kwamena E Baidoo, Robert S Edinger, George Diehl, Divya Nambiar, Reona Okada, Elijah F Edmondson, Stanley Fayn, John Buckley, Ambika P Jaswal, Angel Cortez, Ian R Marsh, Anders Josefsson, Gary Kohanbash, Jessie R Nedrow, Carolyn J Anderson, Freddy E Escorcia, Rosa Nguyen, Ravi B Patel","doi":"10.1158/1535-7163.MCT-24-0370","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0370","url":null,"abstract":"<p><p>Radiopharmaceutical therapy (RPT) is a promising approach to treating solid tumors, but therapeutic advances are impeded by the lack of broadly expressed targets and shared molecular vulnerability across different tumor types. We evaluate VLA-4 (integrin α4β1) as a potential target for RPT in solid tumors using radiolabeled copper-64 ([64Cu]Cu-) and copper-67 ([67Cu]Cu-CB-TE1A1P-PEG4-LLP2A) LLP2A, a peptidomimetic ligand of VLA-4, for preclinical imaging and RPT testing. Expression analysis of ITGA4, encoding the alpha 4 subunit of VLA-4, revealed overexpression in hematological malignancies and various solid tumors compared to healthy tissue. Flow cytometry showed medium to high VLA-4 expression in 77% of tested cancer cell lines. PET/CT imaging with [64Cu]Cu-LLP2A demonstrated tracer uptake in tumors and lymphoid tissues. In toxicity studies, [67Cu]Cu-LLP2A administered at 37-74 MBq was well-tolerated, causing only thymic atrophy without long-term hematological or tissue toxicity. Tumor dose response was observed in B16-F10 melanoma models. Using orthotopic syngeneic models (B16-F10, B78, 4T1, GL261, TH-MYCN, and E2A-PBX1) and human cancer models (SK-MEL-37, 143B, and IMR-5), we conducted PET/CT imaging and biodistribution studies, with selected models used for [64Cu]Cu-LLP2A dosimetry calculations. Given VLA-4's broad expression across cancer tissues, demonstrated on-target effects, acceptable toxicity profile, and favorable dosimetry in preclinical models, further investigation of [67Cu]Cu-LLP2A as an RPT agent is warranted.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255979","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":"Kinome reprogramming of G2/M kinases and repression of MYCN contribute to superior efficacy of lorlatinib in ALK-driven neuroblastoma.","authors":"Smita Matkar, Michael P East, Timothy J Stuhlmiller, Gabriela Witek, Alvin Farrel, Steven Pastor, Denis O Okumu, Anne Kennedy, Joshua R Kalna, Esther R Berko, Colleen E Casey, Kateryna Krytska, Khushbu Patel, Jo Lynne Rokita, Mark Gerelus, John M Maris, Gary L Johnson, Yael P Mossé","doi":"10.1158/1535-7163.MCT-24-0684","DOIUrl":"10.1158/1535-7163.MCT-24-0684","url":null,"abstract":"<p><p>Mutations in the tyrosine kinase domain of the Anaplastic Lymphoma Kinase (ALK) oncogene in neuroblastoma occur most frequently at one of three hotspot amino acid residues, with the F1174* and F1245* variants conferring de novo resistance to first and second generation ALK inhibitors including crizotinib and ceritinib. Lorlatinib, a third generation ALK/ROS inhibitor, overcomes de novo resistance and induces complete and sustained tumor regressions in patient-derived xenograft (PDX) models unresponsive to crizotinib. Lorlatinib has now completed Phase 1 testing in children and adults with relapsed/refractory ALK-driven neuroblastoma and entered pivotal Phase 3 testing within the Children's Oncology Group. To define mechanisms underlying the superior activity of lorlatinib, we utilized a chemical proteomics approach to quantitatively measure functional kinome dynamics in response to lorlatinib and crizotinib in clinically relevant ALK-driven neuroblastoma PDX models. Lorlatinib was a markedly more potent inhibitor of ALK and preferentially downregulated several kinases implicated in G2/M cell cycle transition compared to crizotinib. Lorlatinib treatment also led to the repression of MYCN expression and its occupancy at promoters of the same G2/M kinases. These data providing mechanistic insight into the superior efficacy of lorlatinib over crizotinib for the treatment of ALK-driven neuroblastoma.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189849","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":"OBI-992, a Novel TROP2-Targeted Antibody-Drug Conjugate, Demonstrates Antitumor Activity in Multiple Cancer Models.","authors":"Wan-Fen Li, Ming-Feng Chiang, Hao-Cheng Weng, Jhih-Jie Yang, Hsin-Shan Wu, Szu-Yu Wu, Yu-Jung Chen, Chi-Huan Lu, Jyy-Shiuan Tu, Ren-Yu Hsu, Chi-Sheng Shia, Teng-Yi Huang, Ming-Tain Lai","doi":"10.1158/1535-7163.MCT-24-0588","DOIUrl":"10.1158/1535-7163.MCT-24-0588","url":null,"abstract":"<p><p>Trophoblast cell surface antigen 2 (TROP2) is highly expressed in multiple cancers relative to normal tissues, supporting its role as a target for cancer therapy. OBI-992 is an antibody-drug conjugate (ADC) derived from a novel TROP2-targeted antibody linked to the topoisomerase 1 (TOP1) inhibitor exatecan via an enzyme-cleavable hydrophilic linker, with a drug-antibody ratio of 4. This study evaluated and compared the antitumor activity of OBI-992 with that of benchmark TROP2-targeted ADCs datopotamab deruxtecan (Dato-DXd) and sacituzumab govitecan (SG) in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. OBI-992 treatment exhibited statistically significant antitumor activity versus controls at doses of 3 and 10 mg/kg in various CDX and PDX models, demonstrating comparable or better antitumor activity with benchmark ADCs. In a large-tumor model, longer survival times were observed in OBI-992-treated mice compared with Dato-DXd-treated mice. OBI-992 treatment induced marked bystander killing of TROP2-negative cells in the presence of nearby TROP2-positive cells in both in vitro and in vivo studies. In lung adenocarcinoma CDX models with overexpression of either P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) to mimic ATP-binding cassette transporter-mediated multidrug resistance, OBI-992 treatment maintained antitumor activity when Dato-DXd treatment became less effective. The combination of OBI-992 at suboptimal doses with either poly (ADP-ribose) polymerase (PARP) inhibitors or an immune check point inhibitor produced synergistic antitumor effects in mouse models. Taken together, these translational results support further development of OBI-992 as a cancer therapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"163-175"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951560","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":"Inflammation and Immunity in Liver Neoplasms: Implications for Future Therapeutic Strategies.","authors":"Jieun Kim, Ekihiro Seki","doi":"10.1158/1535-7163.MCT-23-0726","DOIUrl":"10.1158/1535-7163.MCT-23-0726","url":null,"abstract":"<p><p>Over the past two decades, the \"hallmarks of cancer\" have revolutionized cancer research and highlighted the crucial roles of inflammation and immunity. Protumorigenic inflammation promotes cancer development along with inhibition of antitumor immunity, shaping the tumor microenvironment (TME) toward a tumor-permissive state and further enhancing the malignant potential of cancer cells. This immunosuppressive TME allows tumors to evade immunosurveillance. Thus, understanding the complex interplay between tumors and the immune system within the TME has become pivotal, especially with the advent of immunotherapy. Although immunotherapy has achieved notable success in many malignancies, primary liver cancer, particularly hepatocellular carcinoma, presents unique challenges. The hepatic immunosuppressive environment poses obstacles to the effectiveness of immunotherapy, along with high mortality rates and limited treatment options for patients with liver cancer. In this review, we discuss current understanding of the complex immune-mediated mechanisms underlying liver neoplasms, focusing on hepatocellular carcinoma and liver metastases. We describe the molecular and cellular heterogeneity within the TME, highlighting how this presents unique challenges and opportunities for immunotherapy in liver cancers. By unraveling the immune landscape of liver neoplasms, this review aims to contribute to the development of more effective therapeutic interventions, ultimately improving clinical outcomes for patients with liver cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"188-199"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375651","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":"Harnessing the Potential of FAP-IL12mut TMEkine for Targeted and Enhanced Antitumor Responses.","authors":"Dahea Lee, Dongsu Kim, Donggeon Kim, Jisu Kang, Kiram Lee, Hyunji Lee, Yujin Yoon, Youngin Lee, Nahmju Kim, Byoung Chul Cho, Jihoon Chang, Byoung Chul Lee","doi":"10.1158/1535-7163.MCT-24-0125","DOIUrl":"10.1158/1535-7163.MCT-24-0125","url":null,"abstract":"<p><p>Although cancer immunotherapy has yielded encouraging outcomes in hematologic malignancies, it has faced challenges in achieving the same level of effectiveness in numerous solid tumors, primarily because of the presence of immunosuppressive tumor microenvironments (TME). The immunosuppressive qualities of the TME have generated considerable interest, making it a focal point for treatments aimed at enhancing immune responses and inhibiting tumor progression. Fibroblast activation protein (FAP), an attractive candidate for targeted immunotherapy, is prominently expressed in the TME of various solid tumors. IL12, recognized as a key mediator of immune responses, has been explored as a potential candidate for cancer treatment. Nevertheless, initial efforts to administer IL12 systemically demonstrated limited efficacy and notable side effects, emphasizing the necessity for innovation. To address these concerns, our molecules incorporated specific IL12 mutations, called IL12mut, which reduced toxicity. This study explored the therapeutic potential of the FAP-IL12mut TMEkine-a novel immunotherapeutic agent selectively engineered to target FAP-expressing cells in preclinical cancer models. Our preclinical results, conducted across diverse murine cancer models, demonstrated that FAP-IL12mut significantly inhibits tumor growth, enhances immune cell infiltration, and promotes a shift toward a cytotoxic immune activation profile. These findings suggest that FAP-IL12mut could offer effective cancer treatment strategies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"176-187"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988384","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}