Molecular Cancer Therapeutics最新文献

{"title":"The discovery and characterization of HBS-101, a novel inhibitor of midkine, as a therapeutic agent for the treatment of triple negative breast cancer.","authors":"Megharani Mahajan, Alondra L Rodriguez Sanchez, Sridharan Jayamohan, Dileep K Vijayan, Jessica D Johnson, Huan Xie, Yang Wang, Dong Liang, John R Sanchez, Panneerdoss Subbarayalu, Manjeet K Rao, Ratna K Vadlamudi, Gangadhara R Sareddy, Hareesh B Nair, Suryavathi Viswanadhapalli","doi":"10.1158/1535-7163.MCT-25-0130","DOIUrl":"10.1158/1535-7163.MCT-25-0130","url":null,"abstract":"<p><p>Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor clinical outcome. There is a dire need for the development of new targeted therapies for TNBC. Midkine (MDK), a multifunctional cytokine/growth factor, functions as an oncoprotein and its expression is elevated in various cancers. The absence of small molecule inhibitors targeting MDK represents a significant knowledge gap for translation. In this study, we identified HBS-101 as a potent MDK-inhibitor with high specificity. Our modeling studies revealed that the interaction of HBS-101 with MDK is primarily driven by hydrophobic forces, and this interaction disrupted MDK's binding to its endogenous receptors. Microscale thermophoresis (MST), cellular thermal shift assay (CETSA) and biotin pulldown studies confirmed the direct interaction of HBS-101 with MDK. Therapeutically, HBS-101 treatment significantly reduced cell viability (IC50 0.3-2.8 µM), clonogenic survival, invasiveness, and increased apoptosis. The underlying mechanism of HBS-101 involves suppression of Akt/mTOR, STAT3, and NF-B pathways. Importantly, HBS-101 exhibits distinct pharmacologic advantages, including oral bioavailability, blood-brain-barrier penetration, and in vivo stability. Histologically, up to a dose of 10 mg/kg showed no observable organ toxicity and had no effect on the mice's body weight. Dose range studies identified 5 mg/kg as the minimal effective dose, achieving more than 50% tumor reduction. HBS-101 treatment led to a significant reduction in the growth of TNBC patient-derived xenograft tumors in vivo and markedly reduced TNBC brain-metastatic-tumor growth and prolonged mice survival. Collectively, our studies identified a first-in-class MDK inhibitor, HBS-101, that can be used to treat MDK-driven cancers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033800","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":"Efficacy of ATR kinase inhibitor elimusertib monotherapy or combination in tumors with DNA damage response pathway and other genomic alterations.","authors":"Kaushik Varadarajan, Christian X Cruz Pico, Kurt W Evans, Maria Gabriela Raso, Yasmeen Qamar Rizvi, Xiaofeng Zheng, Dhruv Chachad, Timothy P DiPeri, Bailiang Wang, Stephen M Scott, Ming Zhao, Argun Akcakanat, Antje M Wengner, Timothy A Yap, Funda Meric-Bernstam","doi":"10.1158/1535-7163.MCT-24-0884","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0884","url":null,"abstract":"<p><p>The ataxia telangiectasia and RAD3-related (ATR) kinase functions with ataxia telangiectasia mutated (ATM) kinase as a modulator of DNA damage response (DDR). We assessed the antitumor effects of the ATR inhibitor elimusertib (BAY 1895344) in patient-derived xenograft (PDX) models with DDR alterations. Antitumor activity was assessed by change in tumor volume (TV) from baseline. Responses were categorized as follows: partial response (PR): >30% decrease in TV; >20% increase in TV: progressive disease (PD); and non-PR/PD: stable disease (SD). Event-free survival was defined as time for tumor doubling (EFS-2). Of 21 PDX models tested, 11 had significant prolongation of EFS-2 with elimusertib monotherapy. Four models had a PR and 4 had SD. PR/SD was observed in 2 of 5 models with ATM loss on IHC and in models with a variety of alterations in DDR genes, including BRCA1/2 and ATM. Elimusertib prolonged EFS-2 in three of 5 models with known PARP inhibitor resistance. Pharmacodynamic studies conducted in 4 PDX models showed an increase in DNA damage markers. PI3K/mTOR pathway signaling increased in 2 of 4 models. The combination of the PI3K inhibitor copanlisib with elimusertib enhanced EFS-2 compared to monotherapy in 3 of 11 models tested. The combination of elimusertib with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib enhanced antitumor activity compared to single agents in PARP-resistant PDX models. Our study shows that ATR inhibition has antitumor activity, including in models with both intrinsic and acquired PARP inhibitor resistance. Further work is needed to better refine patient selection for ATR-based therapies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024911","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":"6-((1,4-naphthoquinone-2-yl)methyl)thio-glucose conjugates, a novel targeted approach for advanced prostate cancer.","authors":"Tobias Busenbender, Dmitry N Pelageev, Jessica Hauschild, Moritz Kaune, Lukas Boeckelmann, Christoph Krisp, Mohamed E Elsesy, Alexandra Zielinski, Thomas Mair, Maria Riedner, Ayham Moustafa, Simone Venz, Malte Kriegs, Konstantin Hoffer, Yuri E Sabutski, Ksenia L Borisova, Nadja Strewinsky, Svetlana M Kovach, Ekaterina A Khmelevskaya, Hartmut Schlüter, Victor Ph Anufriev, Derya Tilki, Markus Graefen, Wael Y Mansour, Carsten Bokemeyer, Sergey A Dyshlovoy, Gunhild von Amsberg","doi":"10.1158/1535-7163.MCT-24-0955","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0955","url":null,"abstract":"<p><p>The Warburg effect is a shift from oxidative phosphorylation to anaerobic glycolysis, accompanied by an enormous increase in glucose uptake into cancer cells. We have utilized this effect to design a new group of targeted 1,4-naphthoquinone-glucose derivatives conjugated with a novel thiomethylene linker, which are cytotoxic to prostate cancer cells. Compound PeS-9 revealed the highest efficacy and selectivity, which was conditioned by a GLUT-1-mediated uptake. PeS-9 induced androgen receptor degradation followed by downregulation of its signaling. In addition, it increased reactive oxygen species production and induced DNA double-strand breaks. Combinational therapy with PARP-inhibitor olaparib resulted in synergistic effects in homologous recombination deficient cells. The underlying mode of PeS-9's cytotoxic action involved mitochondrial targeting, leading to a loss of mitochondrial membrane potential, release of cytochrome C and AIF, activation of caspases-3 and -9, PARP cleavage, and apoptotic cell death. This process was stipulated by down-regulation of several antiapoptotic factors and induction of endoplasmic reticulum stress. Moreover, drug-induced activation of signaling pathway mediated by p38, JNK1/2, and ERK1/2 kinases was identified as an important factor of the cytotoxic activity. The anticancer activity of PeS-9 could be confirmed ex vivo using patients-derived tumoroids as well as in vivo in xenografts demonstrating suppression of tumor growth and decreased dissemination of prostate cancer cells to the lungs. No serious side effects were observed in animal models. This unique combination of anticancer properties makes PeS-9 an attractive candidate for targeted monotherapy against GLUT-1-overexpressing tumors and as a potential combination partner, especially with PARP inhibitors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032956","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":"PLK4 inhibition as a strategy to enhance non-small cell lung cancer radiosensitivity.","authors":"Irma G Dominguez-Vigil, Kishore Banik, Marta Baro, Joseph N Contessa, Thomas J Hayman","doi":"10.1158/1535-7163.MCT-24-0978","DOIUrl":"10.1158/1535-7163.MCT-24-0978","url":null,"abstract":"<p><p>Lung cancer is the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer and comprises 85% of cases. Despite treatment advances, local control after curative-intent chemoradiation for NSCLC remains suboptimal. Polo-like kinase 4 (PLK4) is a serine-threonine kinase that plays a critical role in the regulation of centrosome duplication and cell cycle progression and is overexpressed in NSCLC, thus, making it a potential therapeutic target. CFI-400945 is an orally available PLK4 inhibitor currently undergoing clinical trial evaluation. As radiation causes cell death primarily by mitotic catastrophe, a process enhanced by alterations in centrosome amplification, we hypothesized that disruption of the mitotic machinery by inhibition of PLK4 would enhance the effects of radiation in NSCLC. PLK4 inhibition by CFI-400945 resulted in radiosensitization of NSCLC cell lines. In contrast, CFI-400945 had no effect on the radiosensitivity of normal lung fibroblasts. PLK4 inhibition did not affect cell cycle phase distribution prior to radiation, but rather the combination of CFI-400945 and radiation resulted in increased G2/M cell cycle arrest, increased centrosome amplification, and a concomitant increase in cell death through mitotic catastrophe. Lastly, CFI-400945 treatment enhanced the radiation-induced tumor growth delay of NSCLC tumor xenografts. These data indicate that targeting PLK4 is a novel approach to enhance the radiation sensitivity of NSCLC in vitro and in vivo through potentiation of centrosome amplification and cell death through mitotic catastrophe.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel 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":"https://doi.org/10.1158/1535-7163.MCT-24-0998","url":null,"abstract":"<p><p>We investigated the therapeutic potential and mechanisms of HR-19011, a novel 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 eukaryotic translation initiation factor 2 (eIF2)α, 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 (ATF4) 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 (p)-S6K and p-4EBP1, mediated by ATF4 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.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-28","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}

{"title":"Navitoclax, a Bcl-2/xL Inhibitor, and YM155, a Survivin Inhibitor, in Combination with Carboplatin, Effectively Inhibit Ovarian Cancer Tumor Growth.","authors":"Hilary A Kenny, Carman Ka Man Ip, Lucy Kelliher, Tejas Samantaray, Kasjusz Kordylewicz, Rachael Hoffmann, Sarah Rauch, Beatrice Malacrida, Sophie L P Skingsley, Frances R Balkwill, Chiara Battistini, Ugo Cavallaro, Wolf R Wiedemeyer, Ernst Lengyel","doi":"10.1158/1535-7163.MCT-23-0863","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0863","url":null,"abstract":"<p><p>High-grade serous ovarian cancer is generally treated with upfront chemotherapy, including carboplatin. The persistence of platinum-resistant cells drives recurrent disease. A high-throughput screen using a 3D organotypic culture assembled with extracellular matrix, primary human fibroblasts, and mesothelial cells was established and validated. Using a library of FDA-approved drugs, the 3D high-throughput screen was performed with the goal of identifying a combination of drugs that synergistically target two populations of ovarian cancer: aldehyde dehydrogenase (ALDH) high (ALDHhi) and ALDH low (ALDHlo) enzyme activity cells, which are less sensitive to carboplatin treatment than the bulk ovarian cancer cells. Initial results showed that omipalisib, verteporfin, CA3, mitoxantrone, navitoclax, venetoclax, and YM155 had significant single-drug activity in either the ALDHlo or both the ALDHlo/ALDHhi cell populations. Synergistic drug activity was identified with three drug combinations: navitoclax/omipalisib, navitoclax/YM155, and YM155/omipalisib. In vitro, the combination of navitoclax/YM155 was most efficient at blocking primary human ovarian cancer sphere formation and the proliferation of four different ovarian cancer cell lines in the 3D organotypic culture. In vivo, the combination of navitoclax/YM155/carboplatin decreased ovarian cancer metastasis, decreased the percentage of ALDHhi ovarian cancer cells in tumors, and increased survival when compared with carboplatin treatment alone in xenograft models. Our results suggest that the combination of navitoclax/YM155/carboplatin has promise as a therapy for treating ovarian cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF13"},"PeriodicalIF":5.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033799","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 anti-FRα antibody-drug conjugate luveltamab tazevibulin demonstrates efficacy in non-small cell lung cancer preclinical models and induces immunogenic cell death.","authors":"Robert Yuan, Andrew McGeehan, Sihong Zhou, Christine Cheng, Mark Armanini, Jennifer Smith, Millicent Embry, Rhoneil Pena, Danielle K Lewis, Genevive Hernandez, Krishna Bajjuri, Cuong Tran, Gang Yin, Cristina L Abrahams, Xiaofan Li, Hans-Peter Gerber, Alice Yam, Helena Kiefel","doi":"10.1158/1535-7163.MCT-24-0649","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0649","url":null,"abstract":"<p><p>Luveltamab tazevibulin is a folate receptor alpha (FRα)-targeting antibody-drug conjugate currently being evaluated in Phase I and II/III clinical trials in endometrial and ovarian cancer (NCT03748186 and NCT05870748), respectively. Here, we report non-small cell lung cancer (NSCLC) as an additional cancer subtype enriched for FRα expression. In NSCLC patient derived xenograft (PDX) models, FRα-expressing tumors demonstrated robust tumor growth inhibition following luveltamab tazevibulin treatment, demonstrating its potential use for NSCLC treatment. Luveltamab tazevibulin was additionally identified as a potent inducer of immunogenic cell death (ICD). In in vitro cell-killing assays, luveltamab tazevibulin induced all three hallmarks of ICD-high mobility group box 1 (HMGB1) release, ATP release, and surface exposure of calreticulin. Furthermore, in in vivo vaccination studies, injection of luveltamab-tazevibulin treated tumor cells established protective immunity against subsequent tumor challenge. Consistent with ICD induction, luveltamab tazevibulin treatment in tumor bearing mice also altered tumor immune cell infiltrate and activation, demonstrating its ability to modulate the tumor immune microenvironment. Given the success of immune checkpoint therapy in NSCLC and luveltamab tazevibulin's ability to potentiate the immune response, we evaluated combination therapy of luveltamab tazevibulin with immune checkpoint blockade in syngeneic mouse models and demonstrated that combination treatment results in enhanced efficacy compared to either monotherapy alone. This improved activity with combination therapy was associated with increased tumoral infiltration of CD8+ T cells. In conclusion, the work presented here provides rationale for evaluating luveltamab tazevibulin in NSCLC either as monotherapy or in combination with immune checkpoint blockade.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990432","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":"HER1 (EGFR) and/or HER2 inclusion potentiates the antitumor effect elicited by a HER3-specific monovalent vaccine.","authors":"Ernesto Bermúdez-Abreut, Gretchen Bergado Báez, Talia Fundora-Barrios, Jessica Arencibia-Perezleo, Armando Lopez Medinilla, Lisset Chao, Belinda Sánchez Ramírez","doi":"10.1158/1535-7163.MCT-24-0973","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0973","url":null,"abstract":"<p><p>The development of active specific immunotherapies for cancer treatment has mainly focused on the design of CTL vaccines. However, the inactivation of signaling induced by membrane oncogenes highlights the value of vaccines that generate a polyclonal antibody response against these oncogenes. In this sense, the EGFR family oncogenes play a critical role in tumor biology and could, therefore, be targeted by antibodies generated through vaccination to block receptor-mediated signaling and induce antitumor effect in cancer cells. In this study, we focus on demonstrating the antitumor properties triggered by the specific polyclonal response of vaccine candidates based on three members of the EGFR family (HER1, HER2, and HER3). We are presenting two novel HER3-based multivalent vaccine candidates: a bivalent candidate that combines the extracellular domains of HER3 and HER2 in its formulation, and a trivalent candidate that includes the extracellular domains of HER3, HER2, and HER1. Both candidates are adjuvanted with a combination of VSSP and Montanide ISA 51. As part of our study, we compared the antitumor properties of both HER3-based multivalent candidates with the monovalent HER3-based vaccine candidate previously reported. Our results confirm that polyclonal response generated by HER3-based vaccine candidates has in vitro and in vivo antitumor effects through the induction of apoptosis, especially in resistance scenarios, and indicate that these effects can be enhanced with the inclusion of HER1 and HER2 in the formulation. Our results suggest the potential use of HER3-based multivalent vaccines as a first-line treatment or after resistance to first-generation anti-HER1-TKI therapies appears.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024336","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":"Moxidectin unravels the role of Hippo-YAP pathway in maintaining immunity of glioblastoma multiforme.","authors":"Itishree Kaushik, Robin Rajan, Shreyas Gaikwad, Mohamed A Eltokhy, Sanjay K Srivastava","doi":"10.1158/1535-7163.MCT-24-0594","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0594","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is a lethal and aggressive cancer with an extremely poor prognosis. Recent preclinical, clinical and genomic studies have highlighted the role of Hippo-Yap pathway in the progression of GBM. In addition, it has been identified that YAP plays a major role in creating immune suppressive tumor microenvironment facilitating drug resistance, recurrence, and metastasis of GBM tumors. Herein, we report that 'moxidectin' an anti-helminthic drug inhibits the proliferation of SF268, SF295, SF188 and CT-2A Luc GBM cells by inducing apoptosis. Immunoblotting and immunofluorescence data shows that moxidectin mediates its effects by inhibiting MEK-ERK pathway, a regulator of Hippo-YAP signaling. Inhibition of MEK-ERK by moxidectin ultimately led to blockade of the nuclear translocation and transcriptional activity of YAP/TAZ-TEAD complex in various GBM cells. Oral administration of 3.5mg/kg moxidectin suppressed the growth of GBM tumors by 90% in an intracranial tumor model. Ex-vivo analysis of excised tumors confirmed the observations made in in vitro studies. Interestingly, moxidectin enhanced antigen presentation in the tumor draining lymph nodes (TDLN) and reduced pro-tumorigenic macrophage population in brain, indicating that it might play a role in modulating the immune response. Chronic moxidectin treatment did not cause any toxicity in mice based on our toxicological evaluation. Moxidectin is an FDA approved drug, findings from our study will promote its clinical investigation as a potential therapeutic agent for GBM patients.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063118","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":"Azenosertib is a potent and selective WEE1 kinase inhibitor with broad antitumor activity across a range of solid tumors.","authors":"Jianhui Ma, Wen Liu, Jiali Li, Daehwan Kim, Sangyub Kim, Alexandra Levy, Zhen Cai, Kevin D Bunker, Alejandro Recio-Boiles, Jennifer M Segar, Shiraj Sen, Deborah B Doroshow, Danielle Jandial, Michael Rutgard, Olivier Harismendy, Stephan K Grant, Ahmed A Samatar, Kimberlee M Fischer, Mark R Lackner","doi":"10.1158/1535-7163.MCT-24-1194","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-1194","url":null,"abstract":"<p><p>Genome instability and accumulation of DNA damage are hallmarks of tumor development and progression. To ensure the maintenance of genomic integrity, cells rely on a coordinated DNA damage response network that regulates cell cycle progression, including activation of WEE1-dependent cell cycle checkpoints. If DNA damage occurs during replication, the WEE1 checkpoint is activated, thereby preventing the progression of the cell cycle. This allows damaged DNA to be repaired before cells enter mitosis, or if the damage is too extensive, induction of apoptosis. These observations have made WEE1 a promising anticancer therapeutic target. Azenosertib (ZN-c3) is a novel, selective, and orally bioavailable WEE1 inhibitor. The antiproliferative activity of azenosertib on cancer cell lines is consistent with a WEE1-dependent mechanism of action exemplified by reduction of pY15-CDK1 levels and increases in DNA damage markers. Azenosertib further exacerbates the effect of replicative stress and DNA damage by allowing cancer cells to prematurely enter mitosis, leading to mitotic catastrophe and apoptosis. Azenosertib has optimized pharmacokinetic and pharmacodynamic (PD) properties, yielding robust tumor growth inhibition in a broad range of tumor models and is highly effective at delaying the duration of tumor regrowth after cessation of treatment. We have explored various dosing schedules in preclinical efficacy models for azenosertib that preserve antitumor activity with minimal toxicity. Phase I studies with azenosertib as monotherapy have shown preliminary clinical activity in patients with advanced solid tumors. The data presented herein supports further studies of azenosertib monotherapy across multiple solid tumor indications.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035539","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}