Molecular Cancer Therapeutics最新文献

{"title":"Targeting Tumor-Infiltrating Immune Cells for Targeted Alpha Therapy in Gliomas: Optimization of [225Ac]Ac-DOTA-αCD11b Dosing through PET Imaging.","authors":"Ambika P Jaswal, Anders Josefsson, Angel G Cortez, Abhinav Bhise, Bo Li, Chaim T Sneiderman, Sarah R Vincze, Michal Nisnboym, Joseph D Latoche, Kathryn E Day, Robert S Edinger, Itay Raphael, Lora H Rigatti, Wilson B Edward, Gary Kohanbash, Jessie R Nedrow","doi":"10.1158/1535-7163.MCT-24-0996","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0996","url":null,"abstract":"<p><p>Myeloid cells are key mediators of immunosuppression and treatment resistance in primary brain tumors, including glioblastoma (GBM). This study aims to eradicate CD11b+ immunosuppressive cells at the tumor site to enhance overall survival in a model of GBM using an α-emitting radiopharmaceutical therapy targeted to tumor-associated myeloid cells as a monotherapy or in combination with immune checkpoint inhibitors. An anti-CD11b (αCD11b) antibody was modified for radiolabeling with diagnostic (zirconium-89) or therapeutic (actinium-225) radioisotopes. Initial PET imaging and biodistribution studies using 89Zr-αCD11b found that an antibody concentration of ∼5 mg/kg of αCD11b (100 μg) was effective in saturating on-target/off-site sinks, such as the spleen, but effective in increasing tumor accumulation. The estimated maximum tolerable activity of [225Ac]Ac-DOTA-αCD11b (225Ac-αCD11b) was determined by biodistribution and dosimetry studies, including the free in vivo-generated decay daughters. The dose-limiting tissue was the bone marrow, and an estimated maximum tolerable activity (∼0.55 kBq, 100 μg) was determined. The therapeutic efficacy of 225Ac-αCD11b was evaluated by survival studies, both as a monotherapy and in combination with immune checkpoint inhibitors. Combination therapy resulted in increased survival in the GBM model compared with the monotherapy and controls; in addition, long-term survival was observed in 50% of the mice receiving combination therapy as well as in a single mouse receiving 225Ac-αCD11b alone. No long-term surviving mice were observed in the control groups. Long-term surviving mice were rechallenged, and potential antitumor immunity was observed, as no tumors developed over 120 days after rechallenge. Overall, these results validate the preclinical relevance of CD11b-targeted image-guided α-emitting radiopharmaceutical therapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF11"},"PeriodicalIF":5.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trametinib Thwarts Activation of Survival Pathways Induced by Pro-ferroptotic Drug Conjugate ACXT-3102 Resulting in Enhanced Pancreatic Cancer Cell Death.","authors":"Kumar S Bishnupuri, Kenneth F Newcomer, Qingqing Gong, Rony Takchi, Li Ye, Suwanna Vangveravong, Lauren Ross, Brian A Van Tine, William G Hawkins, Dirk Spitzer","doi":"10.1158/1535-7163.MCT-24-1032","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-1032","url":null,"abstract":"<p><p>Ferroptosis has recently been described as an iron-dependent subroutine of programmed cell death. Cancers driven by oncogenic Ras mutations, such as pancreatic ductal adenocarcinoma, are particularly vulnerable to ferroptosis and are thus promising candidates for antineoplastic drugs targeting this unique form of programmed cell death. Our group has developed a cancer-specific drug conjugate (ACXT-3102), consisting of a proapoptotic sigma-2 ligand as a delivery moiety (SV119), linked to an inhibitor of the cystine antiporter xCT (dm-erastin), an established inducer of ferroptosis. We hypothesized that ACXT-3102 would trigger apoptosis and ferroptosis via its discrete chemical components, representing a new approach to clinical therapy for pancreatic ductal adenocarcinoma. In vitro cell viability assays corroborated our earlier findings that ACXT-3102 is a potent inducer of cancer cell death. The sigma-2 delivery component of ACXT-3102 induced canonical markers of apoptosis, including cleaved caspase-3/7 and PARP, whereas the dm-erastin cargo component induced canonical markers of ferroptosis, including lipid peroxidation and consumption of glutathione peroxidase 4. These changes resulted in the accumulation of reactive oxygen species. Subsequently, we found that ACXT-3102-mediated cell death was accompanied by the activation of MAPK/ERK signaling, presumably via the reactive oxygen species-dependent degradation of dual-specificity phosphatase 6, a negative regulator of MAPK/ERK phosphorylation. We suspected that this was a compensatory reaction and that ACXT-3102-induced cancer cell death would be augmented by inhibition of MAPK/ERK signaling. We successfully combined ACXT-3102 with trametinib (MEK inhibitor) to enhance the overall efficacy of treatment in vitro and in vivo, presumably by targeting ACXT-3102-induced upregulation of MAPK/ERK.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF12"},"PeriodicalIF":5.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659680","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":"TUB-040, a homogenous and hydrophilic NaPi2b-targeting ADC with stably linked exatecan, exhibits long-lasting anti-tumor activity and a well-tolerated safety profile.","authors":"Annette M Vogl, Saskia Schmitt, Isabelle Mai, Paul Machui, Sarah Herterich, Natascia Leonardi, Philipp Cyprys, Danila Hauswald, Philipp Ochtrop, Izabela Kozlowska, Annabel Kitowski, Marcus Gerlach, Florian Waldmann, Olivier Marcq, Pamela A Trail, Dominik Schumacher, Günter R Fingerle-Rowson, Björn Hock, Marc-André Kasper, Jonas Helma","doi":"10.1158/1535-7163.MCT-25-0254","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0254","url":null,"abstract":"<p><p>TUB-040 is a highly homogenous and hydrophilic antibody-drug conjugate (ADC) targeting NaPi2b, a surface receptor overexpressed in ovarian cancer and non-small cell lung adenocarcinoma. Previous NaPi2b-directed therapies have shown target-mediated and expression-dependent clinical activity. However, none of the previous tubulin inhibitor-based ADCs has been able to leverage the full therapeutic potential of the target. TUB-040 was constructed with a drug-to-antibody ratio (DAR) of 8 using the Tubutecan linker-payload technology based on ethynylphosphonamidates (P5 conjugation chemistry), a protease cleavage site and exatecan, a potent topoisomerase 1 (TOP1) inhibitor. TUB-040 induces potent antigen-specific cytotoxicity against NaPi2b-expressing cancer cells and demonstrates strong bystander activity. It displays a favorable pharmacokinetic behavior, showing dose-proportionality and superimposable total antibody and intact ADC curves and low free payload levels, reflecting the high stability of TUB-040 enabled by the P5 conjugation platform. This specific feature also ensures sustained delivery of exatecan to tumor sites which translates into excellent in vivo efficacy and tolerability. In cell line- and patient-derived xenograft models, including those with low target expression, single-dose TUB-040 administration leads to prolonged tumor growth inhibition and significant rates of complete remission, with a minimally effective dose (MED) level of 1 mg/kg in the OVCAR-3 model. Repeated-dose toxicological assessment in rats indicates that TUB-040 is well-tolerated, with no evidence of lung toxicity or thrombocytopenia. Taken together, TUB-040 is designed to enable long-lasting, durable tumor responses and to optimize both efficacy and tolerability, supporting the advancement of TUB-040 into clinical trials.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Transcriptional Cyclin-Dependent Kinases in Cancer.","authors":"Aleksandra Kolodziejczyk, Piotr Sicinski","doi":"10.1158/1535-7163.MCT-23-0677","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0677","url":null,"abstract":"<p><p>Cyclin-dependent kinases (CDKs) are critical regulators of cell-cycle progression and transcription, and their dysregulation is a hallmark of many cancers. While cell-cycle inhibitors have transformed the treatment of certain cancer types, transcriptional CDKs (tCDKs) are now gaining attention as potential therapeutic targets. tCDKs regulate essential processes, including RNA polymerase activation, transcriptional elongation, and RNA processing, making them crucial for tumor growth and survival. Targeting tCDKs offers a promising strategy, particularly in tumors reliant on enhanced transcriptional activity. Inhibitors of tCDKs have demonstrated efficacy in preclinical models by selectively targeting cancer cells while sparing normal cells. This selectivity arises from how normal and cancer cells utilize transcriptional machinery, with cancer cells often exhibiting heightened dependence on transcription for survival, known as oncogene addiction. Despite promising results, several challenges remain, such as the lack of specificity of tCDKs inhibitors or limited understanding of their broader impact on the tumor microenvironment and immune response. Emerging therapeutic strategies, including targeted degradation of tCDKs and their associated cyclins, offer additional means to selectively target individual cyclin-CDK complexes. Future research is essential to address those issues and bring inhibitors of tCDKs into routine cancer care.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The recycling collagen receptor uPARAP is a unique mediator of stromal drug delivery to carcinoma cells.","authors":"Kirstine S Nørregaard, Ida M E Larsen, Henrik J Jürgensen, Michaela Hansen Blomquist, Pınar Çakılkaya, Virginia Metrangolo, Alba Martinez Perlado, Oliver Krigslund, Henrik Gårdsvoll, Thomas T Poulsen, Dominik Mumberg, Eric Santoni-Rugiu, Lars H Engelholm, Niels Behrendt","doi":"10.1158/1535-7163.MCT-25-0051","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0051","url":null,"abstract":"<p><p>The genetic instability of cancer cells leads to cellular resistance against most targeted cancer drugs. Cancer-associated fibroblasts (CAFs) infiltrate all carcinomas and are genetically stable. Using antibody-drug conjugates (ADCs), we exploit the unique properties of a rapidly recycling endocytic receptor, uPARAP, to achieve a highly efficient CAF-mediated drug delivery and kill of carcinomas. This receptor is generally not present on carcinoma cells and is only expressed in a restricted group of mesenchymal cancer cell types which are sensitive to uPARAP-directed ADCs. However, we show that uPARAP is highly expressed in CAFs in all carcinoma types examined. This property is recapitulated in mouse xenograft carcinoma models. In these models, despite the absence of uPARAP on the carcinoma cells, uPARAP-targeting ADCs with clinically validated payloads MMAE and Dxd eradicated tumors with remarkable efficiency. Systemic treatment with anti-uPARAP ADC led to permanent eradication of tumors in mice carrying subcutaneous xenografts with human EBC-1 lung carcinoma cells. A pronounced repression of tumor growth and strongly increased mouse survival was also obtained with human HT29 colon adenocarcinoma cells, both when these tumors were growing subcutaneously and after homing of tumor cells to bone from the circulation. CAFs were largely refractory to ADC treatment and retained a high expression of uPARAP. uPARAP-expressing fibroblasts could also process an anti-uPARAP ADC in vitro and deliver the cytotoxic component to carcinoma cells. The current bystander mechanism may be exploited in the majority of the most prevalent solid cancers, thus making uPARAP an extraordinarily versatile target for ADC-based cancer treatment.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting SUMOylation triggers interferon-ß-dependent activation of patient and allogenic Natural Killer cells in preclinical models of Acute Myeloid Leukemia.","authors":"Rawan Hallal, Marion de Toledo, Denis Tempé, Rayane Berrahouane, Sara Zemiti, Loïs Coënon, Delphine Gitenay, Simon George, Moritz Schüssler, Nadine Laguette, Sarah Bonnet, Ludovic Gabellier, Guillaume Cartron, Mireia Pelegrin, Martin Villalba, Guillaume Bossis","doi":"10.1158/1535-7163.MCT-25-0504","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0504","url":null,"abstract":"<p><p>Natural Killer (NK) cells can play a significant role in the anti-tumoral immune response. In patients with Acute Myeloid Leukemia (AML), NK cells are however often found in low numbers and exhibit poor activity, contributing to leukemic progression. Allogenic NK cells are emerging as promising cellular therapies for hematological cancer treatment. New strategies are however required to both reactivate NK cells in AML patients and enhance the anti-tumor activity of transplanted NK cells. Here, we demonstrate that targeting SUMOylation, a protein post-translational modification, activates NK cells from both healthy donors and AML patients. Subasumstat (TAK-981), a first-in-class inhibitor of SUMOylation used in phase I/II clinical trials, enhances NK cells degranulation, secretion of inflammatory cytokines (IFN-γ, TNF-α, FasL) and cytotoxicity against AML cells. In vivo, TAK-981 improves the anti-leukemic efficacy of ex-vivo expanded cord-blood NK cells in leukemia-bearing mice. One early effect of TAK-981 is to specifically increase the accessibility and activation of cis-regulatory regions of type I interferon (IFN-I) pathway genes and induce their transcription. TAK-981-induced secretion of interferon-ß, mostly by NK cells and myeloid cells, is required for NK cells activation. Surprisingly, IFNB1 induction does not require its best-characterized activators MDA5, cGas, IRF-1, -3 and -7. Altogether, this suggests that targeting SUMOylation activates a non-canonical IFN-I pathway, which enhances the anti-leukemic potential of NK cells.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BCL-2 family inhibition enhances MTORC1/2 inhibition in PIK3CA mutant colorectal cancer.","authors":"Rebecca A DeStefanis, Alexa E Schmitz, Alyssa K Steimle, Susan N Payne, Gioia C Sha, Autumn M Olson, Alec Cornelio, Anna E L Lippert, Sean G Kraus, Katherine A Johnson, Peter F Favreau, Amani Gillette, Christopher Babiarz, Devon Miller, Carley M Sprackling, Cheri A Pasch, Stephanie Pritzl, Dana R Van De Hey, Demetra P Korkos, Tyler M Foley, Alexander E Yueh, Aurora L J X Greane, Linda Clipson, Melissa C Skala, Dustin A Deming","doi":"10.1158/1535-7163.MCT-24-1096","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-1096","url":null,"abstract":"<p><p>Targeting PIK3CA mutant colorectal cancers (CRCs) with precision medicine strategies is of great clinical interest. However, resistance to single agent PI3K pathway inhibitors has been observed across multiple clinical trials, necessitating identification of combination therapies that overcome or prevent resistance to precision medicine strategies. Previously, our group identified that inhibition of MTORC1/2 is necessary to induce a response in PIK3CA mutant CRCs. The PI3K/MTORC1/2 inhibitor copanlisib has demonstrated some clinical activity in PIK3CA mutant solid tumors as part of the NCI MATCH trial. Here we evaluate potential combination therapies that could enhance the efficacy of copanlisib and other similar inhibitors in PIK3CA mutant CRCs. Using a novel high-throughput drug screen method in Apc and Pik3ca mutant mouse-derived cancer organoids, we identify navitoclax, a BCL-2 family inhibitor, as a drug that could potentially enhance the response to copanlisib. Across multiple in vitro and in vivo CRC models, navitoclax enhanced PI3K/MTOR inhibition (copanlisib, sapanisertib, and dactolisib) and induced apoptosis. Furthermore, we examine these combination therapies across a panel of patient-derived cancer organoids with a range of mutation profiles. These studies indicate that KRAS mutations could confer resistance. Furthermore, we identify BCL-xL as the major BCL-2 family target important for the response to this combination in this setting. This provides a strong rationale for MTORC1/2 and BCL-2 family inhibition as a potential treatment strategy for PIK3CA mutant CRCs.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

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

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