Molecular Cancer Therapeutics最新文献

{"title":"Histotripsy-Focused Ultrasound Treatment Abrogates Tumor Hypoxia Responses and Stimulates Antitumor Immune Responses in Melanoma.","authors":"Brian Song, Heineken Queen, Sarah F Ferris, Reliza McGinnis, Chaitanya Karanam, Natalie Gatteno, Katherine Buglak, Hanna Kim, Jintao Xu, Kristie D Goughenour, Zhen Xu, Michal A Olszewski, Clifford S Cho, Anutosh Ganguly","doi":"10.1158/1535-7163.MCT-24-0715","DOIUrl":"10.1158/1535-7163.MCT-24-0715","url":null,"abstract":"<p><p>Histotripsy-focused ultrasound treatment gives rise to systemic antitumor immune responses. We investigated whether histotripsy effects on immunosuppressive tumor hypoxia were a potential mechanism for these immunostimulatory effects. Immunocompetent or CD8-deficient C57BL/6 mice with flank B16F10 or YUMM1.7 melanoma tumors underwent sham or subtotal histotripsy. Tumor growth, immune cell infiltration, and intratumoral hypoxia responses were examined using flow cytometry and fluorescence microscopy. Chemokine receptor CXCR3 and hypoxia-inducible factor-1α (HIF1α) were intercepted with antibodies and inhibitors to assess their roles in immune responses after histotripsy. Histotripsy-treated tumors exhibited rapid loss of intratumoral hypoxia and suppression of HIF1α and downstream prosurvival proteins. Histotripsy was followed by intratumoral upregulation of the CXCR3 ligand CXCL10 and CXCR3+/CD8+ T-cell infiltration. Tumor growth inhibition by histotripsy was significantly diminished in CD8-deficient mice and mice receiving anti-CXCR3 mAb. Post-histotripsy inhibition of hypoxia and tumor growth eventually receded in parallel with cessation of CD8+ T-cell influx, and pharmacologic HIF1α suppression with the MEK inhibitor trametinib substantially augmented the therapeutic effects of histotripsy. Transient abrogation of intratumoral hypoxia and HIF1α-associated hypoxia responses is mechanistically linked with intratumoral infiltration of activated CXCR3+/CD8+ T cells via CXCL10-CXCR3 engagement. These findings suggest that the immune effects of histotripsy may be regulated by hypoxia abrogation and that pharmacologic hypoxia abrogation could potentiate the immunotherapeutic effects of histotripsy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1088-1098"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657829","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 senolytics and PARP inhibition to expand the antitumor activity of CDK4/6 inhibitors in prostate cancer.","authors":"Julian Brandariz, Lara I de Llobet, Victor Esquefa, Daniel Aguilar, Andrei Salca, Sara Arce-Gallego, Pablo Cresta Morgado, Arnau Sole Casaramona, Laura Agundez Muriel, Gisela Mir Arnau, Natalia Castro, Teresa Casals Galobart, Anna Oliveira Tercero, Irene Casanova-Salas, Marcos Malumbres, Joan Carles, Ángela Morellá-Aucejo, Andrea Bernardos, Ramón Martínez-Mañez, Joaquin Mateo, Nicolas Herranz","doi":"10.1158/1535-7163.MCT-24-0903","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0903","url":null,"abstract":"<p><p>Metastatic prostate cancer (mPC) is a lethal disease; most therapeutic options focus on androgen receptor (AR) signalling inhibition, but resistance eventually arises. Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have shown antitumor efficacy in mPC preclinical models, but their efficacy in mPC clinical trials has been limited. We hypothesize that novel combination therapies designed leveraging mPC adaptation to CDK4/6i could lead to increased and sustained antitumor effect. Herein, we demonstrate in a range of in vitro and in vivo prostate cancer models, including patient-derived xenografts, that prostate cancer cells adopt a senescent phenotype upon CDK4/6 inhibition that can be selectively targeted using senolytic compounds. Notably, interrupting CDK4/6 inhibition in intermittent drug schedules prompts a rapid bypass of the senescent phenotype that associates with a temporal downregulation of replisome proteins in RB1 proficient, but not in RB1 KO models, leading to DNA damage accumulation and replication stress following treatment withdrawal. This effect opens a window of opportunity for treatment with PARP inhibitors (PARPi): while upfront combined inhibition of CDK4/6 and PARP1 has no antitumor effect, their sequential use adding PARPi upon CDK4/6i withdrawal and cell cycle re-entry results in major antitumor activity. Our findings underscore the potential of CDK4/6i in prostate cancer therapy, particularly when administered under biology-driven sequential use of senolytic therapy or PARPi. Such strategic interventions hold promise in overcoming resistance and enhancing treatment outcomes for advanced prostate cancer patients and open avenues for repurposing CDK4/6i therapy in mPC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553995","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 B7-H4xCD3 Bispecific T-cell Engager (PF-07260437) Synergizes with Breast Cancer Standard of Care and Immune Checkpoint Therapies.","authors":"Keith Abayasiriwardana, Lei Wu, Hanane Laklai, Malgorzata Nocula-Lugowska, Lioudmila Tchistiakova, Jatin Narula, Amy Jackson-Fisher, Jonathon Golas, My-Hanh Lam, Veronika Grinstein, Jung Wook Kang, Jessica C Kearney, Christine Hosselet, Erik Upeslacis, LuAnna Lemon, Yun Zhang, Changhua Ji, Bernard S Buetow, Martin B Finkelstein, Netonia Marshall, Stephanie Bisulco, Edward Rosfjord, Divya Mathur, Jennifer Athanacio, Ashley Thomas, Alexander Trageser, Diane Fernandez, Ziyue Karen Jiang, Sripad Ram, Edward Cabral, Lisa Manzuk, Kevin Maresca, Anand Giddabasappa, Clare Lees, Andrea T Hooper, Puja Sapra, Sudhakar Chintharlapalli","doi":"10.1158/1535-7163.MCT-24-0379","DOIUrl":"10.1158/1535-7163.MCT-24-0379","url":null,"abstract":"<p><p>Immune checkpoint inhibitors have shown limited success in breast cancer, the most common and deadly cancer in women worldwide. Novel immune therapies, such as CD3-engaging bispecific antibodies, have shown clinical promise in hematologic malignancies. However, developing CD3 bispecifics for solid tumors has been challenging due to the difficulty in identifying tumor-specific antigens. B7-H4 is proposed as an attractive tumor-associated antigen for breast cancer therapeutics with comprehensive coverage regardless of breast cancer molecular subtype. We designed a B7-H4-targeting CD3 bispecific molecule, PF-07260437, and demonstrated B7-H4-dependent pharmacology in vitro by directing cytotoxic T-cell killing to breast cancer cell lines. Treatment of cell line- and patient-derived xenograft in vivo models of human breast cancer with PF-07260437 induced substantial tumoricidal activity, often resulting in complete responses. Mechanistically, PF-07260437 increased T-cell number and activation, leading to efficient tumor killing. Additionally, combining PF-07260437 with standard of care (palbociclib plus fulvestrant) and a checkpoint inhibitor (anti-PD-1) showed combinatorial benefits in an immune-competent in vivo model. Clinically relevant noninvasive PET/CT imaging with a CD8-targeting tracer demonstrated PF-07260437-mediated increases in intratumoral CD8 T cells, highlighting the utility of CD8-PET technology to potentially assess biomarker changes in the clinic. Finally, the manageable toxicity profile of PF-07260437 was highlighted in an exploratory toxicology study in cynomolgus monkeys. These data support the clinical testing of PF-07260437 for treating B7-H4-expressing solid tumors, including breast cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"976-992"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144003210","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":"Differential Efficacy of Bevacizumab and Erlotinib in Preclinical Models of Renal Medullary Carcinoma and Fumarate Hydratase-Deficient Renal Cell Carcinoma.","authors":"Niki M Zacharias, Manuel Ozambela, Menuka Karki, Rong He, Pankaj K Chauhan, Pedro I Pesquera, Andres E Hernandez Gonzalez, Oscar Ochoa, Alberto Pieretti, Huiqin Chen, Carolyn De La Cerda, Zhiyuan Yu, Abha Grover, Samantha Hicks-Peña, Natalie W Fowlkes, Lei Wang, Tapati Maity, Priya Rao, Giannicola Genovese, Nizar M Tannir, Jose A Karam, Pavlos Msaouel","doi":"10.1158/1535-7163.MCT-24-0703","DOIUrl":"10.1158/1535-7163.MCT-24-0703","url":null,"abstract":"<p><p>Renal medullary carcinoma (RMC) and fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) are rare and highly aggressive cancers. Although the combination of vascular endothelial growth factor (VEGF) inhibition by bevacizumab and epidermal growth factor receptor (EGFR) inhibition by erlotinib is clinically used for both diseases, the differential effect of each component has not been investigated. Transcriptomic profiling revealed that RMC and FH-deficient tumor tissues demonstrate increased EGFR but not VEGF expression compared with adjacent normal kidney. Subsequent in vitro studies revealed that RMC and FH-deficient cell lines are sensitive to erlotinib treatment, whereas clear cell RCC cell lines are resistant. We developed patient-derived xenograft (PDX) models of tumors exposed to first-line therapies to represent treatment-experienced RMC and FH-deficient RCC models. These models were then used to determine tumor growth response to angiogenesis inhibition by bevacizumab alone or in combination with erlotinib. The FH-deficient RCC PDX model responded to either bevacizumab or erlotinib alone or in combination while the RMC PDX responded only to erlotinib consistent with clinical and preclinical data suggesting that RMC is refractory to angiogenesis inhibition. Statistically higher expression of EGFR was observed in the RMC PDX model compared to the FH-deficient model; while higher phosphorylated tyrosine-416 SRC expression was observed in FH-deficient PDX model compared to the RMC model. Our preclinical data suggest that EGFR signaling differentially modulates tumor growth in RMC and FH-deficient RCC and that angiogenesis inhibition is a valid target in FH-deficient RCC but not RMC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553994","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":"Development of a Tumor-Specific Multivalent CD40 Agonist Antibody FAPxCD40 for Cancer Therapy: Balancing Efficacy and Toxicity.","authors":"Simeng Chen, Yuan Lin, Dan Li, Xiaoru Zhou, Xing Sun, Changyong Yang, Cheng Liao","doi":"10.1158/1535-7163.MCT-24-0717","DOIUrl":"10.1158/1535-7163.MCT-24-0717","url":null,"abstract":"<p><p>CD40 agonist antibodies are reported to augment tumor antigen presentation and have shown potential antitumor efficacy in clinical trials. Nevertheless, the limited efficacy and on-target, off-tumor toxicity restrict the further development of these antibodies. We hypothesize that the toxicity could be overcome by activating CD40 specifically through tumor-specific antigens. Additionally, limited efficacy can be improved through the strategic construction of CD40 bispecific antibodies (bsAb) to refine the degree of CD40 clustering. Therefore, we developed anti-FAPxCD40 bsAbs with varying valences of anti-CD40 moieties, including bivalent FAPxCD40-2, tetravalent FAPxCD40-4, and hexavalent FAPxCD40-6. The tetravalent design of FAPxCD40-4 led to efficient activation of antigen-presenting cells and T-cell priming in the presence of FAP. The antitumor activity and toxicity of FAPxCD40-4 were tested in the CD40-humanized mFAP-MC38 xenograft model. Compared with non-tumor-targeting CD40 agonist or bivalent bsAbs, FAPxCD40-4 displayed potent antitumor activity and negligible toxicity at low doses, indicating an ideal therapeutic window. Our results demonstrated that the valences of the anti-CD40 moieties in bsAbs can be modulated to optimize CD40 activation and enlarge the therapeutic window of this type of molecules.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1063-1074"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663843","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":"CD24-Targeted CAR-T Cells Mediated Long-term Antitumor Efficacy through Activation of Endogenous Tumor Immune Responses.","authors":"Yong Huang, Xiao Yang, Jing Li, Weilin Zhou, Fengling Wang, Jiaqian Li, Yalan Zhang, Feiyang Yan, Haozhan Gao, Xinyu Gu, Sha Luo, Yuening Yang, Mei Liu, Xiao Liang, Lin Jiang, Maorong Fu, Jinhua Su, Yuquan Wei, Wei Wang","doi":"10.1158/1535-7163.MCT-24-0597","DOIUrl":"10.1158/1535-7163.MCT-24-0597","url":null,"abstract":"<p><p>Chimeric antigen receptor-modified T (CAR-T) cell therapy has achieved remarkable progress in the treatment of B-cell malignancies, whereas suboptimal therapeutic outcomes have been observed in solid tumors. Immunosuppression from microenvironment of tumors causing decreased killing ability, poor expansion, and persistence of CAR-T cells results in reduced efficacy. Endeavors aimed at eliciting endogenous immune responses have been found to enhance and sustain the antitumor effects of CAR-T cell therapy. In this study, we reported that CAR-T cells targeting cluster of differentiation 24 (CD24), a potential tumor biomarker and an innate immune checkpoint molecule, evoked robust antitumor efficacy and elicited long-term tumor regression. CD24-targeted CAR-T (CD24 CAR-T) cells showed strong cytotoxicity to CD24-positive cancer cells in vitro and mediated inhibition of tumor growth in immunodeficient mice. Moreover, in immunocompetent mice, CD24 CAR-T cells exhibited robust antitumor ability without side effects. Of note, mice that received CD24 CAR-T cells withstood both CD24-positive and CD24-negative tumors rechallenge. We detected a high level of IFN-γ release in splenic lymphocytes of the rechallenged mice, as well as tumor-reactive antibody in serum, indicating the endogenous tumor immune responses was activated. In summary, our findings showed that CD24 CAR-T cells targeting immune checkpoint have superior antitumor efficacy in preclinical models and may provide a strategy for the treatment of solid tumors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1075-1087"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657825","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":"Zidesamtinib Selective Targeting of Diverse ROS1 Drug-Resistant Mutations.","authors":"Anupong Tangpeerachaikul, Scot Mente, Joe Magrino, Franklin Gu, Joshua C Horan, Henry E Pelish","doi":"10.1158/1535-7163.MCT-25-0025","DOIUrl":"10.1158/1535-7163.MCT-25-0025","url":null,"abstract":"<p><p>Zidesamtinib (NVL-520) is a ROS1-selective macrocyclic tyrosine kinase inhibitor designed with the aim to address clinical challenges for patients with non-small cell lung or other cancers that are ROS1 fusion-positive. These challenges include emergent ROS1 resistance mutations and brain metastases that can lead to disease progression and central nervous system adverse events attributed to off-target tropomyosin-related kinase inhibition that can be treatment-limiting. We evaluated zidesamtinib in accelerated mutagenesis screens and a brain tumor model, comparing it with other approved or investigational ROS1 inhibitors. At clinically relevant concentrations, zidesamtinib robustly inhibited >1,500 pooled ROS1 mutants with virtually no resistance emerging (≤1%), outperforming comparators crizotinib, entrectinib, and repotrectinib. Zidesamtinib also induced more durable responses than repotrectinib and taletrectinib in an aggressive intracranial ROS1 G2032R xenograft model. A 2.2 Å cocrystal structure with ROS1 G2032R, the most frequently identified ROS1 resistance mutation, reveals that zidesamtinib uniquely accommodates the mutated residue while potentially clashing with tropomyosin-related kinases, consistent with its selective ROS1-targeting design and supported by computational modeling. Taken together, these data support zidesamtinib's potential as a novel best-in-class ROS1 inhibitor.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1005-1019"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971637","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":"18F-FLT PET, a Noninvasive Pharmacodynamic Biomarker of Tumor Cell Proliferation, Detected Differential Response to Various Cyclin-Dependent Kinase (CDK) Inhibitors.","authors":"Anand Giddabasappa, Ziyue Karen Jiang, Bing Yang, Laigao Chen, Feng Liu, Edward Cabral, Sripad Ram, Britton Boras, Nanni Huser, Cathy C Zhang, Kavon Noorbehesht, Lisa K Manzuk, Ravi Visswanathan, Sepideh Mojtahedzadeh, Timothy Affolter, Jason Carmody, Aubrey Nayeon Kang, Matthew D Petroski, Penny Lai Khamphavong, Todd VanArsdale, Quang-Dé Nguyen, Kevin P Maresca, Stephen G Dann","doi":"10.1158/1535-7163.MCT-24-0856","DOIUrl":"10.1158/1535-7163.MCT-24-0856","url":null,"abstract":"<p><p>A dysregulated cell cycle is a hallmark of cancer and inhibition of cyclin-dependent kinases (CDK) is a proven therapeutic strategy in treating hormone receptor-positive/HER2- breast cancer and a variety of other cancers. 18F-3'-deoxy-3'-fluorothymidine (18F-FLT) is a validated PET biomarker to measure cell proliferation. In this study, we show the utility of 18F-FLT PET imaging as a pharmcodynamic biomarker in differentiating the efficacy of PF-07104091 (CDK2-selective inhibitor) in palbociclib (CDK4/6 inhibitor)-sensitive and -resistant tumor models. 18F-FLT PET imaging was performed after 4 days of treatment with CDK inhibitors and IHC biomarkers of tumor cell proliferation (Ki67 and pRb) were evaluated for correlation. Tumor growth inhibition studies demonstrated that palbociclib was efficacious in an MCF7 model but not in an OVCAR-3 model, whereas PF-07104091 showed dose-dependent tumor growth inhibition in both MCF7 and OVCAR-3 models. Consistent with this observation, 18F-FLT PET was able to differentiate the resistance to palbociclib from sensitivity to PF-06873600 (CDK2/4/6 inhibitor) and PF-07104091 in the OVCAR-3 model. In contrast, the 18F-FLT PET biomarker showed reduced uptake in the MCF7 model after treatment with both palbociclib and PF-07104091. Similarly, PF-07104091 demonstrated reduced 18F-FLT uptake in NIBR-5493, an ovarian cancer patient-derived xenograft model. IHC biomarkers Ki67 and pRb correlated with the 18F-FLT uptake trends in all three tumor models. This work highlights the utility of 18F-FLT PET as a quantitative, noninvasive biomarker which provides whole-body information. 18F-FLT PET has potential to be a biomarker in novel CDK inhibitor clinical trials to evaluate palbociclib resistance and to identify responding and nonresponding patients.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1111-1122"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673366","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":"A Pharmacokinetic and Pharmacodynamic Model of an IL-12 Anchored-Drug Conjugate for the Treatment of Solid Tumors.","authors":"Hitesh B Mistry, David Hodson, Sailaja Battula, Michael M Schmidt, Robert Tighe, Howard L Kaufman, Christophe Chassagnole","doi":"10.1158/1535-7163.MCT-24-1051","DOIUrl":"10.1158/1535-7163.MCT-24-1051","url":null,"abstract":"<p><p>IL-12 mediates innate and adaptive immune responses and has demonstrated therapeutic antitumor activity, but clinical development has been hindered by a narrow therapeutic window. We generated a novel IL-12-anchored drug conjugate by physiochemical linking of murine IL-12 to aluminum hydroxide (alum). The complex was designed to utilize alum as a scaffolding for durable retention of IL-12 within the tumor microenvironment as a strategy to increase the therapeutic window. To better define the systemic pharmacokinetic (PK) profile of the anchored IL-12 (mANK-101), a model-based assessment tool was developed to describe the systemic PK profile and downstream signaling factors following intratumoral injection of mANK-101. When compared with nonanchored IL-12, mANK-101 exhibited a distinct PK profile. Specifically, mANK-101 treatment was associated with a significant ninefold increase in the systemic terminal volume of distribution (Vd). Furthermore, linear mixed-effects models provided evidence that CD8+ T-cell infiltration and increased serum IFN-γ levels were correlated with tumor regression after a single dose of mANK-101. In addition, PK/pharmacodynamic modeling confirmed a link between systemic IL-12 and serum IFN-γ. The model also suggests that the anchored IL-12 drug conjugate is expected to prolong the absorption half-life (115 hours vs. 8 hours for the unanchored drug) with durable local retention and limited systemic absorption. In addition, serum IFN-γ may be a surrogate marker for drug activity. The PK modeling predictions may also contribute to determining the optimal clinical dose and schedule of mANK-101 and other anchored drug conjugates in patients with solid tumors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1054-1062"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625333","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":"Reducing Dietary Protein Enhances the Antitumor Effects of Chemotherapy through Immune-Mediated Mechanisms.","authors":"Samantha C Mulkeen, Suchandrima Saha, Carmen R Ferrara, Vladimira Bibeva, Michael C Wood, Ji Dong K Bai, Tanara V Peres, Daniel Martinez-Martinez, Alex Montoya, Pavel Shliaha, Filipe Cabreiro, David C Montrose","doi":"10.1158/1535-7163.MCT-24-0545","DOIUrl":"10.1158/1535-7163.MCT-24-0545","url":null,"abstract":"<p><p>Diet is believed to be an important mediator of oncogenesis and response to anticancer therapies although no evidence-based dietary guidelines exist for patients with cancer. Limiting protein intake can suppress tumor growth by both inducing nutrient stress and enhancing antitumor immunity. However, little is known about the impact of reducing dietary protein on the efficacy of chemotherapy, the most widely used anticancer treatment. In this study, we present evidence that reducing protein intake in mice by 50% stops the growth of established tumors, in parallel with inducing a stress response and DNA damage. Further, a reduced protein (RP) diet enhances tumor regression upon treatment with 5-fluorouracil (5-FU). This effect is accompanied by elevated apoptosis and suppressed mitosis of tumor cells. Proteomic analysis of tumors revealed marked differences between 5-FU-treated mice fed a control diet and those fed an RP diet, including decreased abundance of proteins that mediate DNA repair and replication in mice consuming RP. In vitro studies mimicking amino acid changes found in tumors from RP-fed mice showed that cGAS/STING1 signaling, including transcription of Ifnb1, was maximally increased in 5-FU-treated cells cultured in modified amino acid medium. These findings correlated with enhanced immune cell influx into tumors from mice treated with 5-FU while consuming an RP diet, an effect that was causally linked to improved response to chemotherapy. Collectively, these findings suggest that reducing dietary protein in patients with cancer may enhance the efficacy of chemotherapy by promoting antitumor immunity.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1099-1110"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657831","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}