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
{"title":"CD24-targeted CAR-T cells mediated long-term anti-tumor 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":"https://doi.org/10.1158/1535-7163.MCT-24-0597","url":null,"abstract":"<p><p>Chimeric antigen receptor T cell (CAR-T) therapy has achieved remarkable progress in the treatment of B-cell malignancies, while 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 anti-tumor effects of CAR-T therapy. Here we reported that CAR-T cells targeting CD24, a potential tumor biomarker and an innate immune checkpoint molecular, evoked robust anti-tumor 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 anti-tumor ability without side effects. Of note, mice received CD24 CAR-T cells withstand both CD24-positive and negative tumors rechallenge. It is detected that 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":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-19","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}
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
{"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":"https://doi.org/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 anti-cancer 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 anti-tumor immunity. However, little is known about the impact of reducing dietary protein on the efficacy of chemotherapy, the most widely used anti-cancer treatment. Here, 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 control or 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 Interferon beta 1, 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 a RP diet, an effect that was causally linked to improved response to chemotherapy. Collectively, these findings suggest that reducing dietary protein in cancer patients may enhance the efficacy of chemotherapy by promoting anti-tumor immunity.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sittana Matar, Seham Skah, Liza E Diomande, Tim Buss, Hanne R Hagland, Ajay Yadav, Rune J Forstrøm, Bjørn Dalhus, Kjetil Hestdal, Rolf D Pettersen, Nina Richartz
{"title":"Development of a novel bifunctional anti-CD47 fusion protein with improved efficacy and a favorable safety profile.","authors":"Sittana Matar, Seham Skah, Liza E Diomande, Tim Buss, Hanne R Hagland, Ajay Yadav, Rune J Forstrøm, Bjørn Dalhus, Kjetil Hestdal, Rolf D Pettersen, Nina Richartz","doi":"10.1158/1535-7163.MCT-24-0917","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0917","url":null,"abstract":"<p><p>Therapeutic anti-CD47 monoclonal antibodies (mAbs) are designed to block the CD47-SIRPα checkpoint and promote immune-mediated recognition and elimination of cancer cells. However, current anti-CD47 mAbs have limitations, including off-tumor toxicity and reduced effectiveness in advanced cancers. Additionally, CD47 serves as a death receptor that mediates programmed cancer cell death (PCCD), a mechanism that has not been fully explored in current therapies. In this study, we introduce CO-001, a chimeric bifunctional IgG4 mAb, and its optimized variant CO-005, a bivalent humanized single-chain fragment variable-fragment crystallizable (scFv-Fc) fusion protein. Both CO-001 and CO-005 promoted phagocytosis and PCCD. CO-005, specifically engineered to overcome the safety limitations associated with anti-CD47 antibodies, demonstrates a superior hematologic safety profile in vitro and ex vivo compared to benchmark anti-CD47 antibodies. Notably, CO-005 exhibited no binding to red blood cells (RBCs), limited binding to white blood cells (WBCs), and showed no hemagglutination activity. In pre-clinical models, CO-005 demonstrated potent antitumor activity in BCP-ALL and Raji lymphoma xenograft models through the dual action of PCCD induction and enhancement of phagocytosis. The ability of CO-005 to trigger strong PCCD while preserving conventional immune responses provides a novel and promising approach for CD47-targeted cancer therapy. Its favorable safety profile, observed in both in vitro and ex vivo studies, positions CO-005 as a promising candidate with potential therapeutic advantages over existing anti-CD47 treatments.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625336","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}
Hitesh B Mistry, David Hodson, Sailaja Battula, Michael M Schmidt, Robert Tighe, Howard L Kaufman, Christophe Chassagnole
{"title":"A pharmacokinetic and pharmacodynamic model of an interleukin-12 (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":"https://doi.org/10.1158/1535-7163.MCT-24-1051","url":null,"abstract":"<p><p>Interleukin-12 (IL-12) mediates innate and adaptive immune responses and has demonstrated therapeutic anti-tumor 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 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 (IT) injection of mANK-101. When compared to non-anchored IL-12, mANK-101 exhibited a distinct PK profile. Specifically, mANK-101 treatment was associated with a significant 9-fold increase in the systemic terminal volume of distribution (Vd). Furthermore, linear mixed-effects models provided evidence that CD8+ T cell infiltration and increased serum interferon gamma (IFNG) levels were correlated with tumor regression after a single dose of mANK-101. In addition, PK/PD modeling confirmed a link between systemic IL-12 and serum IFNG. The model also suggests that anchored IL-12 drug conjugate is expected to prolong the absorption half-life (115 h vs 8 h for the unanchored drug) with durable local retention and limited systemic absorption. In addition, serum IFNG may be a surrogate marker for drug activity. The PK modeling predictions may also contribute to determining the optimal clinical dose and schedule of ANK-101 and other anchored drug conjugates in patients with solid tumors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"hmLIGHT Enhances Vaccine Antitumor Effects by Facilitating T-cell Infiltration and Activation in the 4T1 Breast Cancer Model.","authors":"Ling Dong, Shiqi Zhang, Qimuge Wuri, Xueli Qu, Ke Zhang, Zongyu Cai, Yaru Qiao, Mengfan Feng, Chu Wang, Hui Wu, Jiaxin Wu, Wei Kong, Xianghui Yu, Haihong Zhang","doi":"10.1158/1535-7163.MCT-24-0333","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0333","url":null,"abstract":"<p><p>Mounting evidence suggests that immunotherapies are promising strategies for fighting against cancers. However, the immunosuppressive tumor microenvironment (TME), insufficient lymphocytic infiltration, and poor immunogenicity hamper the broader implementation of immunotherapies. LIGHT, a member of the TNF superfamily, has been shown to recruit T cells into the TME, turning \"cold\" tumors into \"hot\" ones. Here, a human mutant LIGHT (hmLIGHT) protein has been obtained which successfully promoted the activation and proliferation of mouse CD8+ T cells via CD28-independent co-stimulatory activity. Moreover, direct intratumoral injection of VR-hmLIGHT remodeled the TME, enhanced CD8+ T-cell infiltration into tumors, and showed antitumor efficacy in 4T1 and CT26 tumor models. In addition, our previous studies of a DNA vaccine (OsFS) have shown promising antitumor activity. In this study, we evaluated a new combination of VR-hmLIGHT and OsFS to enhance efficacy in the 4T1 tumor model. The combined treatment has a remarkable antitumor effect, with a tumor inhibition rate of 70%, whereas OsFS and VR-hmLIGHT groups displayed 32% and 42% inhibition, respectively. These findings indicate the clinical potential of LIGHT as monotherapy or combination therapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF11"},"PeriodicalIF":5.3,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605387","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}
Si Zhang, Hui Xue, Nelson K Y Wong, Thomas Doerksen, Fuqiang Ban, Shawn Anderson, Stanislav Volik, Yen-Yi Lin, Zhongye Dai, Ivica Bratanovic, Hongwei Cheng, Colin Collins, Artem Cherkasov, Jeremy E Wulff, Yuzhuo Wang
{"title":"5'-S-(3-aminophenyl)-5'-thioadenosine, a novel chemoprotective agent for reducing toxic side effects of fluorouracil in treatment of MTAP-deficient cancers.","authors":"Si Zhang, Hui Xue, Nelson K Y Wong, Thomas Doerksen, Fuqiang Ban, Shawn Anderson, Stanislav Volik, Yen-Yi Lin, Zhongye Dai, Ivica Bratanovic, Hongwei Cheng, Colin Collins, Artem Cherkasov, Jeremy E Wulff, Yuzhuo Wang","doi":"10.1158/1535-7163.MCT-24-0656","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0656","url":null,"abstract":"<p><p>Nucleobase analogue (NBA) drugs, such as 5-fluorouracil (5-FU), are effective chemotherapeutics, but their clinical use is limited by severe side effects. Compelling evidence suggests that the use of S-methyl-5'-thioadenosine (MTA) can selectively reduce NBA toxicity on normal tissues while maintaining the efficacy of NBAs on methylthioadenosine phosphorylase (MTAP)-deficient cancers. However, we found that MTA induced hypothermia at its effective dose, limiting its translational potential. We hypothesized that an MTA analogue can retain the protective function of MTA without undesired side effects. We screened a library of MTA analogues and identified 5'-S-(3-aminophenyl)-5'-thioadenosine (m-APTA) as a substrate of MTAP that could be converted to adenine, a necessary step for protection of normal cells from NBA toxicity. It selectively protected MTAP-expressing cells from 5-FU toxicity while did not interfere with the cytotoxicity of 5-FU on isogenic MTAP-deficient cell lines. At effective dose, m-APTA protected the mouse hosts from 5-FU-induced toxicity (i.e. anemia) without the induction of hypothermia. Importantly, m-APTA provided host protection without compromising the efficacy of 5-FU on MTAP-deficient bladder cancer xenografts. In silico docking studies revealed that, unlike MTA, m-APTA interact inefficiently with adenosine A1 receptor, providing a plausible explanation of the superior safety profile of m-APTA. Therefore, m-APTA can significantly improve the translational potential of the combination treatment strategy that selectively reduces NBA toxicity in normal cells while targeting MTAP-deficient cancers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586352","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}
Alison O Cudmore, Galaxia M Rodriguez, Vincent Maranda, Salar Farokhi Boroujeni, Humaira Murshed, Elizabeth A Macdonald, Melanie Grondin, Kenneth Garson, Kathy Matuszewska, Jean-Simon Diallo, James J Petrik, Barbara C Vanderhyden
{"title":"Specific Genetic Mutations Impact Chemotherapy Resistance and Therapeutic Efficacy of Oncolytic Viruses in Ovarian Cancer.","authors":"Alison O Cudmore, Galaxia M Rodriguez, Vincent Maranda, Salar Farokhi Boroujeni, Humaira Murshed, Elizabeth A Macdonald, Melanie Grondin, Kenneth Garson, Kathy Matuszewska, Jean-Simon Diallo, James J Petrik, Barbara C Vanderhyden","doi":"10.1158/1535-7163.MCT-24-0906","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0906","url":null,"abstract":"<p><p>Epithelial Ovarian Cancer (EOC) is the most lethal gynecologic cancer and those affected are in urgent need of new therapeutic strategies. Standard treatment is surgery followed by taxane- and platinum-based chemotherapy, but the rate of relapse is high and the 5-year survival is only 45%. Oncolytic viruses (OV) are a promising approach to EOC therapy through remodeling the immune composition of the tumor microenvironment (TME). Treatment response in EOC tumors can differ based on the presence of key tumorigenic mutations. This study evaluated the impact of specific tumor mutations on the response to the current standard of care carboplatin, two promising OV candidates VSV∆M51 and MG1, an infected cell vaccine (ICV-MG1) regimen, and the anti-angiogenic drug Fc3TSR. Mice with tumors harboring constitutive K-Ras activation showed an enhanced response to carboplatin and VSV∆M51 treatment. Additionally, VSV∆M51 treatment prolonged survival of syngeneic mice bearing tumors with mutations in Pten and Kras, Pten and Trp53, or Trp53 and Brca2 with increased activation of CD4+ and CD8+ T lymphocytes in the peritoneal TME. To enhance OV potency, an MG1-based infected cell vaccine inducing expression of IL-21 or IL15+21 was developed and found to enable strong and long-lasting antitumoral immunity in two carboplatin refractory syngeneic models, ID8 Trp53-/- and STOSE. VSV∆M51 combined with the anti-angiogenic Fc3TSR enhanced efficacy in the ID8 model. In summary, OV-based immunotherapy has shown promise in diverse murine models of EOC-bearing clinically relevant mutations, thus laying the foundation for developing new OV-based strategies to target a large spectrum of EOC genotypes.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586353","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}
Aiko Yamaguchi, Chisato M Yamazaki, Yasuaki Anami, Summer Y Y Ha, Wei Xiong, Robert T Ta, Ningyan Zhang, H Charles Manning, Zhiqiang An, Kyoji Tsuchikama
{"title":"177Lu-labeled antibody-drug conjugate: a dual mechanistic treatment modality in solid tumors.","authors":"Aiko Yamaguchi, Chisato M Yamazaki, Yasuaki Anami, Summer Y Y Ha, Wei Xiong, Robert T Ta, Ningyan Zhang, H Charles Manning, Zhiqiang An, Kyoji Tsuchikama","doi":"10.1158/1535-7163.MCT-24-0254","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0254","url":null,"abstract":"<p><p>To explore the potential of site-selectively radiolabeled antibody-drug conjugates (ADCs) against solid tumors, we constructed and evaluated radiolabeled ADCs equipped with lutetium-177 (177Lu) and a membrane permeable antimitotic agent. Site-selective 177Lu-labeled ADCs (anti-TROP2 177Lu-DTPA ADCs or anti-HER2 177Lu-DO3A ADCs), a 177Lu-labeled homogenous radioimmunoconjugate (homogeneous RIC), and 177Lu-labeled conventional RIC (heterogeneous RIC) were constructed. We confirmed that 177Lu-labeled ADCs and the homogeneous RIC were obtained with high homogeneity and defined chelator/payload-to-antibody ratios. Next, we performed biodistribution studies and treatment efficacy studies in xenograft mouse models bearing orthotopic breast tumor. Compared with the heterogeneous RIC, the 177Lu-DTPA TROP2-ADC and anti-TROP2 homogeneous RIC showed significantly improved radioactivity accumulation in the TROP2-expressing JIMT-1 tumor (p<0.01 at 72 h). In the therapeutic study, 177Lu-DTPA TROP2-ADC (5 MBq; 1.5 mg/kg) suppressed tumor growth significantly more than did the anti-TROP2 homo-RIC (5 MBq, p=0.0068). Anti-HER2 177Lu-DO3A ADC (5 MBq; 3.0 mg/kg) demonstrated greater in vivo treatment efficacy over MMAE DAR 2 HER2-ADC (3.0 mg/kg) monotherapy, anti-HER2 homo-RIC (5 MBq) monotherapy, and combination of MMAE DAR 2 HER2-ADC and anti-HER2 homo-RIC at matched payload and radioactivity doses in a refractory breast tumor model displaying heterogeneous HER2 expression. These results suggest that site-selectively 177Lu-labeled ADCs are effective in treating refractory tumors, including those with heterogeneous antigen expression, and warrant further exploration as a promising single-agent, dual-mechanistic treatment modality for solid tumors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573391","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}
Tony Georgiev, Sara Puglioli, Lucrezia Principi, Ettore Gilardoni, Christian Pellegrino, Gabriele Bassi, Andrea Galbiati, Dario Neri, Samuele Cazzamalli
{"title":"PSMA-targeted Small Molecule-Drug Conjugates based on a Post-Prolyl Peptidase Cleavable Linker for the Treatment of Prostate Cancer.","authors":"Tony Georgiev, Sara Puglioli, Lucrezia Principi, Ettore Gilardoni, Christian Pellegrino, Gabriele Bassi, Andrea Galbiati, Dario Neri, Samuele Cazzamalli","doi":"10.1158/1535-7163.MCT-24-0750","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0750","url":null,"abstract":"<p><p>Prostate Specific Membrane Antigen (PSMA) is a transmembrane glycoprotein that is over-expressed on the surface of cancerous prostate cells both in primary tumors and in metastases. Small organic ligands targeting PSMA have been broadly and successfully used to deliver radionuclide payloads to prostate cancer lesions. 177Lu-PSMA-617 (Pluvicto®, a Novartis product) is a PSMA-targeted product that has been recently approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). By contrast, no Small Molecule-Drug Conjugates (SMDCs) directed against PSMA have gained marketing authorization yet. In this article, we present the development of novel SMDCs generated by conjugating the tumor-targeting moiety of Pluvicto® (here named \"OncoPSMA\") to highly cytotoxic Auristatin payloads through cleavable linkers, including Valine-Citrulline, disulfide bridges, and a recently described post-prolyl peptidase-cleavable linker (Glycine-Proline or GlyPro). The efficiency of payload release at the cancer site and in healthy tissues was assessed via biodistribution studies using mass spectrometry quantification upon systemic administration in tumor-bearing mice. SMDCs based on the GlyPro linker mediated the highest payload release in solid tumors compared to widely utilized Cathepsin B-cleavable and disulfide linkers. The in vivo efficacy of OncoPSMA-GlyPro-MMAE and OncoPSMA-GlyPro-MMAF was tested in therapy studies alone and in combination with an antibody-interleukin-2 fusion protein, capable of preferential homing to solid tumors. Combination treatments resulted in complete and durable responses, highlighting the potential benefit of this therapeutic modality to metastatic prostate cancer patients.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542574","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":"All-trans Retinoic Acid Sensitizes Epithelial Ovarian Cancer to PARP Inhibition after Exposure to Cisplatin.","authors":"Bingjie Mei, Junyang Li, Dengfeng Wang, Lu Feng, Jianming Huang, Guonan Zhang","doi":"10.1158/1535-7163.MCT-24-0140","DOIUrl":"10.1158/1535-7163.MCT-24-0140","url":null,"abstract":"<p><p>Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin (CDDP). Notably, platinum-based chemotherapy induces resistance of EOC to PARP inhibition. However, therapeutic approaches targeting PARP inhibitor (PARPi) resistance remain to be explored. In this study, we show that all-trans retinoic acid (ATRA) reduces PARPi resistance-associated EOC cells induced by CDDP treatment. Clinically applicable ATRA suppressed the outgrowth of CDDP-treated EOC cells both in vitro and in vivo. Moreover, a CDDP treatment followed by niraparib maintenance therapy in combination with ATRA improved the survival of EOC-bearing mice. These phenotypes correlated with the PARPi-resistant EOC signature, which consists of elevated expression of aldehyde dehydrogenase 1 family member A1, nicotinamide phosphoribosyltransferase, PARP1, and checkpoint kinase 1, as well as elevated NAD+ level-mediated high activity of aldehyde dehydrogenase 1 family member A1 and PARP1. Mechanistically, ATRA downregulates the expression of these genes and level of intracellular NAD+. Our results suggest that ATRA in conjunction with PARPi represents a promising maintenance therapeutic strategy for EOC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"453-463"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829431","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}
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