Molecular Cancer Therapeutics最新文献_第8页

Characterization of TNG348: a selective, allosteric USP1 inhibitor that synergizes with PARP inhibitors in tumors with homologous recombination deficiency.

IF 5.3 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-01-31 DOI: 10.1158/1535-7163.MCT-24-0515

Antoine Simoneau, Charlotte B Pratt, Hsin-Jung Wu, Shreya S Rajeswaran, Charlotte Grace Comer, Sirimas Sudsakorn, Wenhai Zhang, Shangtao Liu, Samuel R Meier, Ashley H Choi, Tenzing Khendu, Hannah Stowe, Binzhang Shen, Douglas A Whittington, Yingnan Chen, Yi Yu, William D Mallender, Tianshu Feng, Jannik N Andersen, John P Maxwell, Scott Throner

{"title":"Characterization of TNG348: a selective, allosteric USP1 inhibitor that synergizes with PARP inhibitors in tumors with homologous recombination deficiency.","authors":"Antoine Simoneau, Charlotte B Pratt, Hsin-Jung Wu, Shreya S Rajeswaran, Charlotte Grace Comer, Sirimas Sudsakorn, Wenhai Zhang, Shangtao Liu, Samuel R Meier, Ashley H Choi, Tenzing Khendu, Hannah Stowe, Binzhang Shen, Douglas A Whittington, Yingnan Chen, Yi Yu, William D Mallender, Tianshu Feng, Jannik N Andersen, John P Maxwell, Scott Throner","doi":"10.1158/1535-7163.MCT-24-0515","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0515","url":null,"abstract":"Inhibition of the deubiquitinating enzyme USP1 can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD) and represents a novel therapeutic strategy for the treatment of BRCA1/2 mutant cancers, potentially including patients whose tumors have primary or acquired resistance to PARP inhibitors (PARPi). Here, we present a comprehensive characterization of TNG348, an allosteric, selective, and reversible inhibitor of USP1 (USP1i). TNG348 induces dose-dependent accumulation of ubiquitinated protein substrates both in vitro and in vivo. CRISPR screens show that TNG348 exerts its anti-tumor effect by disrupting the translesion synthesis pathway of DNA damage tolerance through RAD18-dependent ub-PCNA induction. Though TNG348 and PARPi share the ability to selectively kill HRD tumor cells, CRISPR screens reveal that TNG348 and PARPi do so through discrete mechanisms. Particularly, knocking out PARP1 causes resistance to PARPi but sensitizes cells to TNG348 treatment. Consistent with these findings, combination of TNG348 with PARPi leads to synergistic anti-tumor effects in HRD tumors, resulting in tumor growth inhibition and regression in multiple mouse xenograft tumor models. Importantly, our data in human cancer models further show that the addition of TNG348 to PARPi treatment can overcome acquired PARPi resistance in vivo. While the clinical development of TNG348 has been discontinued due to unexpected liver toxicity in patients (NCT06065059), the present data provides preclinical and mechanistic support for the continued exploration of USP1 as a drug target for the treatment of patients with BRCA1/2 mutant or HRD cancers.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Co-blocking TIGIT and PVRIG using a novel bispecific antibody enhances anti-tumor immunity.

IF 5.3 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-01-24 DOI: 10.1158/1535-7163.MCT-23-0614

Yuan Lin, Kan Lin, Qiang Fu, Xing Sun, Huan Wang, Lu Su, Yinghui Xu, Cheng Liao

{"title":"Co-blocking TIGIT and PVRIG using a novel bispecific antibody enhances anti-tumor immunity.","authors":"Yuan Lin, Kan Lin, Qiang Fu, Xing Sun, Huan Wang, Lu Su, Yinghui Xu, Cheng Liao","doi":"10.1158/1535-7163.MCT-23-0614","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0614","url":null,"abstract":"TIGIT and PVRIG are immune checkpoints co-expressed on activated T and NK cells, contributing to tumor immune evasion. Simultaneous blockade of these pathways may enhance therapeutic efficacy, positioning them as promising dual targets for cancer immunotherapy. This study aimed to develop a bispecific antibody (BsAb) to co-target TIGIT and PVRIG. Expression of TIGIT and PVRIG was assessed on tumor-infiltrating lymphocytes (TILs) from patients with various cancers, including non-small cell lung cancer (n=63) and colorectal cancer (n=26). The BsAb was engineered by fusing anti-PVRIG nanobodies to the N terminus of anti-TIGIT antibodies. Functional characterization of the BsAb was performed in vitro and in vivo, including assessments of T and NK cell activation and cytotoxicity. Pharmacokinetics and safety profiles were evaluated in cynomolgus monkeys. Statistical analyses were conducted using the Student's t-test. The results showed that the BsAb effectively blocked TIGIT and PVRIG from binding their respective ligands, CD155 and CD112, leading to significant increases in T cell activation (2.8-fold, p<0.05) and NK cell cytotoxicity (1.8-fold, p<0.05). In vivo, the BsAb demonstrated potent anti-tumor activity, both as a monotherapy and in combination with anti-PD-1 or anti-PD-L1, in humanized PBMC and transgenic mouse models. Pharmacokinetic studies in cynomolgus monkeys revealed a favorable profile, with no dose-limiting toxicities observed after four repeated doses of 200 mg/kg. These findings provide compelling preclinical evidence for the therapeutic potential of targeting the TIGIT-PVRIG axis with a bispecific antibody. This approach shows promise for enhancing anti-tumor immunity and warrants further investigation in clinical trials.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting Monounsaturated Fatty Acid Metabolism for Radiosensitization of KRAS Mutant 3D Lung Cancer Models. 靶向单不饱和脂肪酸代谢对KRAS突变体三维肺癌模型的放射增敏作用

IF 5.3 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-01-21 DOI: 10.1158/1535-7163.MCT-24-0213

Shan Lu, Xiao Pan, Eva Volckova, Anjali Shinde, Schuyler R Fuller, Regina Egan, Jianli Ma, Jong Kung, Christopher J Ott, Aaron N Hata, Cyril H Benes, Jing X Kang, Henning Willers

{"title":"Targeting Monounsaturated Fatty Acid Metabolism for Radiosensitization of KRAS Mutant 3D Lung Cancer Models.","authors":"Shan Lu, Xiao Pan, Eva Volckova, Anjali Shinde, Schuyler R Fuller, Regina Egan, Jianli Ma, Jong Kung, Christopher J Ott, Aaron N Hata, Cyril H Benes, Jing X Kang, Henning Willers","doi":"10.1158/1535-7163.MCT-24-0213","DOIUrl":"10.1158/1535-7163.MCT-24-0213","url":null,"abstract":"Mutations in the KRAS oncogene can mediate resistance to radiation. KRAS mutation (mut) driven tumors have been reported to express cancer stem cell (CSC)-like features and may harbor metabolic liabilities through which CSC-associated radioresistance can be overcome. We established a radiation/drug screening approach that relies on the growth of 3D spheres under anchorage-independent and lipid-limiting culture conditions, which promote stemness and lipogenesis. In this format, we screened 32 KRASmut-enriched lung cancer models. As predicted from published data, CB-839, a glutaminase inhibitor, displayed the highest degree of radiosensitization in KRASmut models with LKB1 co-mutations. Radiosensitization by inhibition of stearoyl-CoA desaturase-1, SCD1, displayed a similar genotype preference though the data also implicated KEAP1 co-mutation and SCD1 expression as potential predictors of radiosensitization. In an isogenic model, KRASmut cells were characterized by increased SCD1 expression and a higher ratio of monounsaturated fatty acids (MUFA) to saturated fatty acids. Accordingly, pharmacological inhibition or depletion of SCD1 radiosensitized isogenic KRASmut but not wild-type cells. The radiosensitizing effect was notably small, especially compared to several DNA repair inhibitors. As an alternative strategy to targeting MUFA metabolism, adding polyunsaturated FAs (PUFA) phenocopied some aspects of SCD1 inhibition, suppressed tumor growth in vivo, and opposed the CSC-like phenotype of KRASmut cells. In conclusion, we report a 3D screening approach that recapitulates clinically relevant features of KRASmut tumors and can be leveraged for therapeutic targeting of metabolic vulnerabilities. Our data highlight pronounced inter-tumoral heterogeneity in radiation/drug responses and the complexity of underlying genomic dependencies.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of DKK-1 by WAY262611 Inhibits Osteosarcoma Metastasis. WAY262611抑制DKK-1抑制骨肉瘤转移

IF 5.3 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-01-09 DOI: 10.1158/1535-7163.MCT-24-0744

Adit Tal, Shimara Gunawardana-Zeigler, Da Peng, Yuqi Tan, Natalia Munoz Perez, Rachel Offenbacher, Laurel Kastner, Paul Ciero, Matthew E Randolph, Yun Gong, Hong-Wen Deng, Patrick Cahan, David M Loeb

{"title":"Inhibition of DKK-1 by WAY262611 Inhibits Osteosarcoma Metastasis.","authors":"Adit Tal, Shimara Gunawardana-Zeigler, Da Peng, Yuqi Tan, Natalia Munoz Perez, Rachel Offenbacher, Laurel Kastner, Paul Ciero, Matthew E Randolph, Yun Gong, Hong-Wen Deng, Patrick Cahan, David M Loeb","doi":"10.1158/1535-7163.MCT-24-0744","DOIUrl":"10.1158/1535-7163.MCT-24-0744","url":null,"abstract":"Osteosarcoma (OS) is the most common primary malignant bone tumor in childhood. Patients who present with metastatic disease at diagnosis or relapse have a very poor prognosis, and this has not changed over the past four decades. The Wnt signaling pathway plays a role in regulating osteogenesis and is implicated in OS pathogenesis. DKK-1 inhibits the canonical Wnt signaling pathway, causing inhibition of osteoblast differentiation and disordered bone repair. Our lab previously demonstrated that a monoclonal antibody against DKK-1 prevented metastatic disease in a mouse model. This study expands upon those findings by demonstrating similar results with a small molecule inhibitor of DKK-1, WAY262611, both in vitro and in vivo. WAY262611 was evaluated in vitro on osteosarcoma cell lines, including proliferation, caspase activation, cell cycle analysis, and signaling pathway activation. We utilized our orthotopic implantation-amputation model of osteosarcoma metastasis in vivo to determine the impact of WAY262611 on primary tumor progression and metastatic outgrowth of disseminated tumor cells. Differentiation status was determined using single cell RNA sequencing. We show here that WAY262611 activates canonical Wnt signaling, enhances nuclear localization and transcriptional activity of beta-catenin, and slows proliferation of OS cell lines. We also show that WAY262611 induces osteoblastic differentiation of an OS patient-derived xenograft in vivo, as well as inhibiting metastasis. This work credentials DKK-1 as a therapeutic target in OS, allowing for manipulation of the Wnt signaling pathway and providing preclinical justification for the development of new biologics for prevention of osteosarcoma metastasis.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tumor Integrin-Targeted Glucose Oxidase Enzyme Promotes ROS-Mediated Cell Death that Combines with Interferon Alpha Therapy for Tumor Control. 肿瘤整合素靶向葡萄糖氧化酶可促进 ROS 介导的细胞死亡，与干扰素 alpha疗法相结合可控制肿瘤。

IF 5.3 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-01-02 DOI: 10.1158/1535-7163.MCT-24-0163

Jordan A Stinson, Allison Sheen, Brianna M Lax, Grace N Yang, Lauren Duhamel, Luciano Santollani, Elizabeth Fink, Joseph R Palmeri, Karl Dane Wittrup

{"title":"Tumor Integrin-Targeted Glucose Oxidase Enzyme Promotes ROS-Mediated Cell Death that Combines with Interferon Alpha Therapy for Tumor Control.","authors":"Jordan A Stinson, Allison Sheen, Brianna M Lax, Grace N Yang, Lauren Duhamel, Luciano Santollani, Elizabeth Fink, Joseph R Palmeri, Karl Dane Wittrup","doi":"10.1158/1535-7163.MCT-24-0163","DOIUrl":"10.1158/1535-7163.MCT-24-0163","url":null,"abstract":"Although heightened intratumoral levels of reactive oxygen species (ROS) are typically associated with a suppressive tumor microenvironment, under certain conditions ROS contribute to tumor elimination. Treatment approaches, including some chemotherapy and radiation protocols, increase cancer cell ROS levels that influence their mechanism of cell death and subsequent recognition by the immune system. Furthermore, activated myeloid cells rapidly generate ROS upon encounter with pathogens or infected cells to eliminate disease, and recently, this effector function has been noted in cancer contexts as well. Collectively, ROS-induced cancer cell death may help initiate adaptive antitumor immune responses that could synergize with current approved immunotherapies, for improved control of solid tumors. In this work, we explore the use of glucose oxidase, an enzyme which produces hydrogen peroxide, a type of ROS, to therapeutically mimic the endogenous oxidative burst from myeloid cells to promote antigen generation within the tumor microenvironment. We engineer the enzyme to target pan-tumor-expressed integrins both as a tumor-agnostic therapeutic approach and as a strategy to prolong local enzyme activity following intratumoral administration. We found the targeted enzyme potently induced cancer cell death and enhanced cross-presentation by dendritic cells in vitro and further combined with interferon alpha for long-term tumor control in murine MC38 tumors in vivo. Optimizing the single-dose administration of this enzyme overcomes limitations with immunogenicity noted for other prooxidant enzyme approaches. Overall, our results suggest ROS-induced cell death can be harnessed for tumor control and highlight the potential use of designed enzyme therapies alongside immunotherapy against cancer.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"118-130"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting Tumor Antigen 5T4 Using CAR T Cells for the Treatment of Acute Myeloid Leukemia. 利用 CAR-T 细胞靶向肿瘤抗原 5T4 治疗急性髓性白血病。

IF 5.3 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-01-02 DOI: 10.1158/1535-7163.MCT-24-0052

Richard Harrop, Daniel G Blount, Naeem Khan, Mayowa Soyombo, Laura Moyce, Mark T Drayson, Jenny Down, Michelle A Lawson, Deirdre O'Connor, Rachael Nimmo, Yatish Lad, Bernard Souberbielle, Kyriacos Mitrophanous, Anna Ettorre

{"title":"Targeting Tumor Antigen 5T4 Using CAR T Cells for the Treatment of Acute Myeloid Leukemia.","authors":"Richard Harrop, Daniel G Blount, Naeem Khan, Mayowa Soyombo, Laura Moyce, Mark T Drayson, Jenny Down, Michelle A Lawson, Deirdre O'Connor, Rachael Nimmo, Yatish Lad, Bernard Souberbielle, Kyriacos Mitrophanous, Anna Ettorre","doi":"10.1158/1535-7163.MCT-24-0052","DOIUrl":"10.1158/1535-7163.MCT-24-0052","url":null,"abstract":"Chimeric antigen receptor (CAR) T cells represent a novel targeted approach to overcome deficits in the ability of the host immune system to detect and subsequently eradicate tumors. The identification of antigens expressed specifically on the surface of tumor cells is a critical first step for a targeted therapy that selectively targets cancer cells without affecting normal tissues. 5T4 is a tumor-associated antigen expressed on the cell surface of most solid tumors. However, very little is known about its expression in hematologic malignancies. In this study, we assess the expression of 5T4 in different types of leukemias, specifically acute myeloid leukemia (AML), and normal hematopoietic stem cells (HSC). We also provide an in vitro assessment of safety and efficacy of 5T4-targeting CAR T cells against HSCs and AML tumor cell lines. 5T4 expression was seen in about 50% of AML cases; AML with mutated nucleophosmin 1, AML-myelodysplasia-related, and AML not otherwise specified showed the highest percentage of 5T4+ cases. 5T4 CAR T cells efficiently and specifically killed AML tumor cell lines, including leukemic stem cells. Coculture of 5T4 CAR T cells with HSCs from healthy donors showed no impact on subsequent colony formation, thus confirming the safety profile of 5T4. A proof-of-concept study using a murine model for AML demonstrated that CAR T cells recognize 5T4 expressed on cells and can kill tumor cells both in vitro and in vivo. These results highlight 5T4 as a promising target for immune intervention in AML and that CAR T cells can be considered a powerful personalized therapeutic approach to treat AML.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"93-104"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Zelenirstat Inhibits N-Myristoyltransferases to Disrupt Src Family Kinase Signaling and Oxidative Phosphorylation, Killing Acute Myeloid Leukemia Cells. Zelenirstat 可抑制 N-肉豆蔻酰转移酶，从而破坏 Src 家族激酶信号和氧化磷酸化，杀死急性髓性白血病细胞。

IF 5.3 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-01-02 DOI: 10.1158/1535-7163.MCT-24-0307

Jay M Gamma, Qiang Liu, Erwan Beauchamp, Aishwarya Iyer, Megan C Yap, Zoulika Zak, Cassidy Ekstrom, Rony Pain, Morris A Kostiuk, John R Mackey, Joseph Brandwein, Jean C Y Wang, Luc G Berthiaume

{"title":"Zelenirstat Inhibits N-Myristoyltransferases to Disrupt Src Family Kinase Signaling and Oxidative Phosphorylation, Killing Acute Myeloid Leukemia Cells.","authors":"Jay M Gamma, Qiang Liu, Erwan Beauchamp, Aishwarya Iyer, Megan C Yap, Zoulika Zak, Cassidy Ekstrom, Rony Pain, Morris A Kostiuk, John R Mackey, Joseph Brandwein, Jean C Y Wang, Luc G Berthiaume","doi":"10.1158/1535-7163.MCT-24-0307","DOIUrl":"10.1158/1535-7163.MCT-24-0307","url":null,"abstract":"Acute myeloid leukemia (AML) is a hematologic malignancy with limited treatment options and a high likelihood of recurrence after chemotherapy. We studied N-myristoylation, the myristate modification of proteins linked to survival signaling and metabolism, as a potential therapeutic target for AML. N-myristoylation is catalyzed by two N-myristoyltransferases (NMT), NMT1 and NMT2, with varying expressions in AML cell lines and patient samples. We identified NMT2 expression as a marker for survival of patients with AML, and low NMT2 expression was associated with poor outcomes. We used the first-in-class pan-NMT inhibitor, zelenirstat, to investigate the role of N-myristoylation in AML. Zelenirstat effectively inhibits myristoylation in AML cell lines and patient samples, leading to degradation of Src family kinases, induction of endoplasmic reticulum stress, apoptosis, and cell death. Zelenirstat was well tolerated in vivo and reduced the leukemic burden in an ectopic AML cell line and in multiple orthotopic AML patient-derived xenograft models. The leukemia stem cell-enriched fractions of the hierarchical OCI-AML22 model were highly sensitive to myristoylation inhibition. Zelenirstat also impairs mitochondrial complex I and oxidative phosphorylation, which are critical for leukemia stem cell survival. These findings suggest that targeting N-myristoylation with zelenirstat represents a novel therapeutic approach for AML, with promise in patients with currently poor outcomes.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"69-80"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Discovery of a Potent PARP1 Inhibitor Senaparib. 发现强效 PARP1 抑制剂 Senaparib。

IF 5.3 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-01-02 DOI: 10.1158/1535-7163.MCT-23-0625

Sui X Cai, Ning Ma, Xiaozhu Wang, Mingchuan Guo, Yangzhen Jiang, Ye E Tian

{"title":"The Discovery of a Potent PARP1 Inhibitor Senaparib.","authors":"Sui X Cai, Ning Ma, Xiaozhu Wang, Mingchuan Guo, Yangzhen Jiang, Ye E Tian","doi":"10.1158/1535-7163.MCT-23-0625","DOIUrl":"10.1158/1535-7163.MCT-23-0625","url":null,"abstract":"PARP1 is a critical enzyme involved in DNA damage repair. It belongs to a superfamily of proteins and catalyzes poly(ADP-ribosyl)ation (PARylation). PARP1 inhibitors are effective to treat tumors that have homologous recombination deficiency such as those with BRCA1/2 mutations. The PARP1 inhibitors that have been approved by FDA inhibit both PARP1 and PARP2. PARP2 has also been suggested to play a similar function in DNA repair as PARP1. In addition to inhibiting PARP1 enzymatic activities, PARP1 inhibitors cause the PARP1 enzyme to be \"trapped\" on DNA, stalling the DNA replication fork and eventually causing double-strand DNA breaks and cell death. Here, we report a PARP1 inhibitor, Senaparib, which has a novel chemical structure and high potency inhibiting PARP1/2 enzymes. Senaparib was highly potent in cell viability tests against tumor cells with BRCA1/2 mutations. It was efficacious in cell line-derived and patient-derived xenograft models in tumors harboring BRCA1/2 mutations. In combination studies, Senaparib used with temozolomide had shown strong synergistic cytotoxicity in both in vitro and in vivo experiments. Senaparib represents a novel class of PARP1 inhibitors that can be used for the treatment of cancer. A phase III clinical study of Senaparib for maintenance treatment following first-line chemotherapy in patients with advanced ovarian cancer has met its primary endpoint, and a new drug application of Senaparib has been accepted by the National Medical Products Administration of China for review.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"47-55"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: Inhibition of the Met Receptor Tyrosine Kinase Signaling Enhances the Chemosensitivity of Glioma Cell Lines to CDDP Through Activation of p38 MAPK Pathway. 更正：Met受体酪氨酸激酶信号的抑制通过激活p38 MAPK通路增强胶质瘤细胞系对CDDP的化学敏感性。

IF 5.3 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-01-02 DOI: 10.1158/1535-7163.MCT-24-0974

Xiuqin Lou, Qibing Zhou, Ying Yin, Cheng Zhou, Yan Shen

引用次数: 0

Looking Beyond Checkpoint Inhibitor Monotherapy: Uncovering New Frontiers for Pancreatic Cancer Immunotherapy. 超越检查点抑制剂单药治疗：探索胰腺癌免疫疗法的新前沿。

IF 5.3 2区医学

Molecular Cancer Therapeutics Pub Date : 2025-01-02 DOI: 10.1158/1535-7163.MCT-24-0311

Eileena F Giurini, Oliver Ralph, Sam G Pappas, Kajal H Gupta

{"title":"Looking Beyond Checkpoint Inhibitor Monotherapy: Uncovering New Frontiers for Pancreatic Cancer Immunotherapy.","authors":"Eileena F Giurini, Oliver Ralph, Sam G Pappas, Kajal H Gupta","doi":"10.1158/1535-7163.MCT-24-0311","DOIUrl":"10.1158/1535-7163.MCT-24-0311","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) stands out as one of the most aggressive and challenging tumors, characterized by a bleak prognosis with a mere 11% survival rate over 5 years in the United States. Its formidable nature is primarily attributed to its highly aggressive behavior and poor response to existing therapies. PDAC, being notably resistant to immune interventions, presents a significant obstacle in treatment strategies. While immune checkpoint inhibitor therapies have revolutionized outcomes for various cancers, their efficacy in PDAC remains exceedingly low, benefiting less than 1% of patients. The consistent failure of these therapies in PDAC has prompted intensive investigation, particularly at the preclinical level, to unravel the intricate mechanisms of resistance inherent in this cancer type. This pursuit aims to pave the way for the development of novel immunotherapeutic strategies tailored to the distinct characteristics of PDAC. This review endeavors to provide a comprehensive exploration of these emerging immunotherapy approaches in PDAC, with a specific emphasis on elucidating their underlying immunological mechanisms. Additionally, it sheds light on the recently identified factors driving resistance to immunotherapy and evasion of the immune system in PDAC, offering insights beyond the conventional drivers that have been extensively studied.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"18-32"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0