Molecular Cancer Therapeutics最新文献

{"title":"The Antibody-Drug Conjugate Sacituzumab Govitecan (IMMU-132) Represents a Potential Novel Therapeutic Strategy in Cholangiocarcinoma.","authors":"Racha Hosni, Niklas Klümper, Christine Sanders, Sana Hosni, Vittorio Branchi, Alexander Semaan, Abdullah Alajati, Natalie Pelusi, Susanna S Ng, Damian J Ralser, Saif-Eldin Abedellatif, Hanno Matthaei, Jörg Kalff, Jasmitha Boovadira Poonacha, Veronika Lukacs-Kornek, Glen Kristiansen, Maria A Gonzalez-Carmona, Michael Hölzel, Marieta I Toma","doi":"10.1158/1535-7163.MCT-24-0972","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0972","url":null,"abstract":"<p><p>Cholangiocarcinoma is a rare and aggressive cancer type with limited therapeutic options. Several novel antibody-drug conjugates (ADC) have demonstrated promising antitumor activity in solid tumors. This study aimed to investigate the expression and the potential prognostic role of the protein targets of the recently developed ADCs in cholangiocarcinoma. Moreover, the study aimed to establish patient-derived tumor organoids (PDO) and to employ them for in vitro ADC testing. We evaluated the expression of TROP2, NECTIN4, folate receptor 1, HER2, and HER3 via IHC in a cholangiocarcinoma tissue microarray (n = 113) and analyzed the expression level with respect to clinicopathologic parameters. Furthermore, we generated cholangiocarcinoma PDO culture lines and used them to test the antitumor activity of ADCs in vitro. IHC analyses revealed that TROP2 was the most frequently expressed (91% of cases), followed by folate receptor 1 (51%), NECTIN4 (49%), HER3 (20%), and HER2 (7%). TROP2 showed moderate to high expression (H-score ≥100) in 74% of cases. No significant correlations with overall or disease-free survival, tumor grade, or tumor stage were observed. Six cholangiocarcinoma PDO lines were successfully established (55% success rate). All PDO lines expressed TROP2 concordantly with their parental tumors and showed growth inhibition (IC50 = 0.1-0.4 μg/mL) in response to sacituzumab govitecan (TROP2-targeting ADC). This study reveals that TROP2 is widely expressed in cholangiocarcinoma. Moreover, it provides preclinical evidence for the potential of the use of sacituzumab govitecan as a novel therapeutic strategy in treating patients with cholangiocarcinoma.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF14"},"PeriodicalIF":5.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591762","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":"KRAS codon-specific mutations differentially toggle PI3K pathway signaling and alter sensitivity to inavolisib (GDC-0077).","authors":"Kyung W Song, Christy C Ong, Eva Lin, Jeff Lau, Nicole M Sodir, Dexter X Jin, Katherine E Hutchinson, Shiqi Xie, Jenille Tan, Yuxin Liang, Zora Modrusan, Scott E Martin, Danilo Maddalo, Marc Hafner, Anwesha Dey","doi":"10.1158/1535-7163.MCT-24-0995","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0995","url":null,"abstract":"<p><p>PIK3CA and KRAS are among the most frequently mutated oncogenes and often co-mutated in colorectal cancers. Understanding how KRAS codon-specific mutations affect cross-talks between the PI3K and MAPK pathways and response to targeted therapies, such as the p110α-specific inhibitor inavolisib (GDC-0077), is critical for advancing precision oncology. Focusing on colorectal PIK3CA+KRAS co-mutated models, we found that KRAS G12D-mutated cells were more sensitive to inavolisib than models with KRAS G13D, or other MAPK pathway mutations, even though the PI3K and MAPK pathways were active in both genotypes. In most co-mutated models, regardless of the type of KRAS alteration, combination of inavolisib with MAPK pathway inhibitors showed synergy in vitro and in vivo. Our work highlights how specific codon substitutions in KRAS differentially toggle pathway activity and alter sensitivity to inavolisib, which could inform whether patients would benefit more from single-agent inavolisib or combination with MAPK pathway inhibitors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584320","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":"Integration of whole genome sequencing analysis with unique patient-derived models reveals clinically relevant drug targets in TFCP2 fusion-defined rhabdomyosarcoma.","authors":"Patrick Bergsma, Sean Porazinski, Aji Istadi, Diego Chacon-Fajardo, Yasir Mahmood, Silvia Lombardi, Diana Schuhmacher, Henry Barraclough-Franks, Dario Strbenac, Claude V Dennis, Payam Faizi-Sobbi, Emer Cahill, Vivek A Bhadri, Jeneffer De Almeida Silva, Trina Lum, James Wykes, Timothy Manzie, Carsten E Palme, Jean Y H Yang, Jonathan R Clark, Ruta Gupta, Marina Pajic","doi":"10.1158/1535-7163.MCT-24-0704","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0704","url":null,"abstract":"<p><p>Precision medicine is a likely future for all cancer treatment, but may have its greatest impact for less common, high-mortality and molecularly heterogeneous cancers. TFCP2-rearranged Rhabdomyosarcoma is a rare, aggressive cancer with poor survival due to a lack of effective therapies, as well as relevant models to facilitate research. Here, we establish the first matched patient-derived xenograft and cell line model for TFCP2-rearranged intraosseous Rhabdomyosarcoma (IORMS), coupled with comprehensive multi-omic and functional analysis, to discover and preclinically validate novel actionable molecular targets for this malignancy. Sequencing analyses of matched patient tumor and xenograft material revealed alterations in gene networks associated with the oncogenic, potentially targetable PI3K/AKT pathway. Preclinical assessments revealed that targeting the pathway with a small molecule PI3K/mTOR inhibitor dactolisib presents a promising treatment approach for this rare cancer, decreasing cancer cell viability in vitro and significantly reducing tumor growth in vivo. Parallel identification of the codeletion of adjacent genes CDKN2A and MTAP in these tumors, led us to further explore PRMT5 inhibition as a potential therapeutic approach. Strikingly, combined inhibition of PRMT5 and PI3K/mTOR signaling synergistically enhanced anti-tumor response and significantly improved survival in vivo. This study highlights the importance of new patient-derived models for the elucidation of the biology of rare cancers, and identification of new therapeutic entry points, with clear implications for the future treatment of TFCP2-rearranged IORMS.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trametinib thwarts activation of survival pathways induced by pro-ferroptotic drug conjugate ACXT-3102 resulting in enhanced pancreatic cancer cell death.","authors":"Kumar S Bishnupuri, Kenneth F Newcomer, Qingqing Gong, Rony Takchi, Li Ye, Suwanna Vangveravong, Lauren Ross, Brian A Van Tine, William G Hawkins, Dirk Spitzer","doi":"10.1158/1535-7163.MCT-24-1032","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-1032","url":null,"abstract":"<p><p>Ferroptosis has recently been described as an iron-dependent subroutine of programmed cell death (PCD). Cancers driven by oncogenic Ras mutations, such as pancreatic ductal adenocarcinoma (PDAC), are particularly vulnerable to ferroptosis and are thus promising candidates for antineoplastic drugs targeting this unique form of PCD. Our group has developed a cancer-specific drug conjugate (ACXT-3102), consisting of a pro-apoptotic sigma-2 ligand as a delivery moiety (SV119), linked to an inhibitor of the cystine antiporter xCT (dm-Erastin), an established inducer of ferroptosis. We hypothesized that ACXT-3102 would trigger apoptosis and ferroptosis via its discrete chemical components, representing a new approach to clinical therapy for PDAC. In vitro, cell viability assays corroborated our earlier findings that ACXT-3102 is a potent inducer of cancer cell death. The sigma-2 delivery component of ACXT-3102 induced canonical markers of apoptosis, including cleaved caspase-3/7 and poly (ADP-ribose) polymerase (PARP), whereas the dm-Erastin cargo component induced canonical markers of ferroptosis, including lipid peroxidation and consumption of glutathione peroxidase 4 (GPX4). These changes resulted in the accumulation of reactive oxygen species (ROS). Subsequently, we found that ACXT-3102-mediated cell death was accompanied by activation of MAPK/ERK signaling, presumably via ROS-dependent degradation of dual-specificity phosphatase 6 (DUSP6), a negative MAPK/ERK phosphorylation regulator. We suspected this was a compensatory reaction and that ACXT-3102-induced cancer cell death would be augmented by inhibition of MAPK/ERK signaling. We successfully combined ACXT-3102 with trametinib (MEK inhibitor) to enhance the overall efficacy of treatment in vitro and in vivo, presumably by targeting ACXT-3102-induced upregulation of MAPK/ERK.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553997","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":"Pretargeted Anti-CD20 Radioimmunotherapy with scFv Fusion Protein Safely Combines with BEAM and ASCT in patients with High-Risk B-cell Lymphomas.","authors":"Johnnie J Orozco, Manuela C Matesan, Sally J Lundberg, Robyn L Haaf, Robert S Miyaoka, Darrell R Fisher, Ted A Gooley, Damian J Green, Brenda M Sandmaier, Paul S Martin, Ajay K Gopal","doi":"10.1158/1535-7163.MCT-24-0550","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0550","url":null,"abstract":"<p><p>Despite new therapies, many patients with NHL relapse and need more effective salvage therapies. This study (NCT02483000) evaluated the safety of B9E9-FP, a tetrameric single-chain anti-CD20-streptavidin fusion protein used in pre-targeted radioimmunotherapy (PRIT), when combined with BEAM and autologous stem cell transplantation (ASCT) for NHL patients. High-risk NHL patients received B9E9-FP on day -17, clearing agent on day -15, and DOTA-biotin (DOTA-Bt) equally divided and labeled with dose-escalated yttrium-90 (90Y), or with indium-111 (111In for imaging) on day -14. BEAM chemotherapy started day -7 before stem cell infusion. Three NHL patients (MCL, transformed DLBCL, and de novo DLBCL), ages 52-62 years, were treated with 30, 50, or 70 mCi (1110, 1850, or 2590 MBq) 90Y/m2 before ASCT without any dose-limiting toxicity. One case of diarrhea (grade 2) and one case of rash (grade 1) were possibly associated with B9E9-FP or DOTA-Bt, respectively. Pharmacokinetic (PK) studies showed peak blood biological percent injected dose per gram blood (% ID/g) of 90Y-DOTA-Bt at 15 min after infusion (14.8 - 49.4 % ID), with only 0.82 - 2.59 % ID after 72 hours. Uptake was preferential at bone marrow (1.73 - 5.96 cGy/mCi injected) and spleen (2.4 - 4.17 cGy/mCi injected) compared to lungs (0.19 - 0.48 cGy/mCi). Unbound 90Y-DOTA-Bt was excreted renally without any renal dysfunction noted up to 2 years later. Two of the 3 enrolled patients are alive and in remission 3.5 to 4.9 years after transplant. PK, dosimetry, and outcomes data support that B9E9-FP PRIT and 90Y-augmented ASCT DOTA-Bt is feasible.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553996","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":"Advances in Antibody-Drug Conjugates for Endometrial Cancer.","authors":"Pan Tu, Gaofeng Li, Wen Zou, Chao Xu, Jingjing Wang","doi":"10.1158/1535-7163.MCT-24-0763","DOIUrl":"10.1158/1535-7163.MCT-24-0763","url":null,"abstract":"<p><p>The treatment of advanced endometrial cancer is clinically challenging, prompting the exploration of innovative therapeutic strategies such as antibody-drug conjugates (ADC). ADCs, which include mAbs, cytotoxic components, and linkers, demonstrate robust targeting, cytotoxicity, and manageable adverse effects. To provide a thorough understanding of the status of research, this review elucidates promising therapeutic targets in endometrial cancer, such as HER2, folate receptor α, and trophoblast surface antigen-2, and summarizes preclinical and clinical trial data on related ADC drugs in endometrial cancer. We also discuss the toxicity of ADC drugs. Most adverse events arise from cytotoxic components such as microtubule inhibitors and topoisomerase inhibitors. The ocular toxicity may be mainly related to off-target effects of monomethyl auristatin F/DF4 payloads. Interstitial lung disease is a serious adverse event, mainly caused by antibodies, and most of them are of grade 1 to 2 toxicity. Among them, anti-HER2 ADC-induced interstitial pneumonia is commonly dose-dependent. Moreover, we identified potential new targets for endometrial cancer treatment and explored strategies to overcome ADC resistance, such as choosing combination therapy or developing a new generation of ADC drugs. Continuous research and innovation in this field hold promise for improving the survival and overall quality of life of patients with advanced endometrial cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"993-1004"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663723","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":"M4205 (IDRX-42) Is a Highly Selective and Potent Inhibitor of Relevant Oncogenic Driver and Resistance Variants of KIT in Cancer.","authors":"Christina Esdar, Nina Linde, Andreas Blum, Hanno Schieferstein, Christine Drechsler, Eva Sherbetjian, Carl Petersson, Edith Ross, Birgitta Leuthner, Ulrich Grädler, Dieter Dorsch, Andree Blaukat","doi":"10.1158/1535-7163.MCT-24-0699","DOIUrl":"10.1158/1535-7163.MCT-24-0699","url":null,"abstract":"<p><p>Primary activating mutations in KIT (exon 9/11) are key driver alterations in about 80% of gastrointestinal stromal tumors (GIST). Imatinib, a small-molecule tyrosine kinase inhibitor, is used successfully as first-line therapy for patients with unresectable metastatic or recurrent GIST, but secondary resistance mutations in the KIT kinase domains frequently occur. Currently approved later-line therapies target these mutations incompletely with limited clinical benefit. M4205, a kinome-selective KIT inhibitor, was designed to address this high unmet medical need by inhibiting all relevant KIT driver and resistance mutations. Compared with imatinib, M4205 shows stronger antitumor activity in preclinical GIST models driven by oncogenic KIT driver mutations. M4205 demonstrates clinically relevant efficacy in a range of preclinical GIST models expressing different secondary KIT resistance mutations. The kinase selectivity profile of M4205 is superior to the registered standard of care and investigational agents. M4205, now IDRX-42, is currently being investigated in a phase I first-in-human study in participants with GIST.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1040-1053"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523869","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":"Coinhibition of Aurora Kinase B and SUV4-20H Induces Synthetic Lethality in Wild-type p53-Deficient Cancer Cells.","authors":"Lei Duan, Kelsey M O'Hara, Andrew Caldemeyer, Carl G Maki","doi":"10.1158/1535-7163.MCT-24-0928","DOIUrl":"10.1158/1535-7163.MCT-24-0928","url":null,"abstract":"<p><p>The tumor suppressor p53 is inactivated by mutation or deletion in more than half of all human cancers. Wild-type p53 induces a G1-phase arrest when activated to halt cell proliferation and division. Accordingly, p53-mutated or -deficient cancers may be especially sensitive to agents that target proliferating and/or dividing cells. Barasertib (AZD2811) targets the mitotic Aurora kinase B and is in current clinical trials for various cancers. SUV4-20H1 and H2 are histone methyltransferases that can affect mitosis by regulating chromatin compaction in and around centromeres. The drug A196 inhibits SUV4-20H1 and H2. In the current study, we found combined treatment with barasertib plus A196 induces a pronounced synthetic lethality effect in p53-deficient cancer cells. Mechanistically, we found barasertib plus A196 kills p53-deficient cells by inhibiting the spindle assembly checkpoint and inducing massive chromosome missegregations and toxic aneuploidy. Among breast cancer subtypes, triple-negative breast cancer cells were the most sensitive to this drug combination. Lastly, we found in two different p53-mutated cell line tumor models that barasertib plus A196 has greater antitumor activity than either single agent. Our results suggest cotargeting of Aurora kinase B and SUV4-20H1/2 could be effective against p53-mutated or -deficient cancers, including triple-negative breast cancers in which approximately 80% of cases are p53-mutated.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1020-1029"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657827","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":"PF-08046032: A Novel, Investigational CD25-Directed Antibody-Drug Conjugate Optimized for Selective Depletion of Regulatory T Cells in Advanced Malignant Tumors.","authors":"Sherif Abdelhamed, Xinqun Zhang, Weiping Zeng, Bryan Grogan, Luke Schilperoort, Reice James, Kelli C Burley, Samantha M Sarrett, Lauren Bou, Paromita Raha, Devra J Olson, Heather L Sigurjonsson, Melissa M C Dominguez, Tyler Nicholas, Haley D Neff-LaFord, James Fishburn, Andrea R Lim, Daniel Diolaiti, Priyanka Gupta, Cristina L Abrahams, Christopher M Carosino, Ryan A Heiser, Shyra J Gardai, Matthew R Levengood","doi":"10.1158/1535-7163.MCT-25-0101","DOIUrl":"10.1158/1535-7163.MCT-25-0101","url":null,"abstract":"<p><p>Regulatory T cells (Treg) are known to suppress antitumor immune responses, and their presence in the tumor microenvironment is associated with cancer progression; therefore, Treg depletion is a promising strategy to enhance cancer immunotherapy. PF-08046032 is a novel antibody-drug conjugate (ADC) designed to target Tregs in the tumor microenvironment via CD25, the α-chain of the IL-2 receptor frequently upregulated by intratumoral Tregs. PF-08046032 is composed of an affinity-detuned anti-CD25 antibody linked to monomethyl auristatin E, a potent cytotoxic agent. Affinity detuning increases PF-08046032 selectivity for CD25high intratumoral Tregs while minimizing peripheral blood Treg depletion, thus reducing the risk of autoimmune toxicities. In preclinical experiments, PF-08046032 selectively depleted Tregs compared with CD8+ T cells and preferentially depleted Tregs with high CD25 expression. PF-08046032 showed dose-dependent antitumor activity in CD25-expressing human lymphoma xenograft models, whereas a similarly detuned anti-mouse CD25 surrogate ADC depleted intratumoral Tregs and drove CD8+ T-cell activation in murine tumor models. This effect resulted in robust antitumor activity as a single agent and in combination with anti-PD1 checkpoint inhibitor blockade. Lastly, PF-08046032 was well-tolerated in nonhuman primates and mitigated the persistent depletion of peripheral blood Treg that was observed with a high-affinity anti-CD25 ADC comparator, demonstrating the safety benefit of a detuned-affinity ADC format. PF-08046032 represents an innovative therapeutic approach for depletion of intratumoral Tregs that may offer an improved safety profile and efficacy over traditional Treg-depleting agents.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"963-975"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013332","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":"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 Aderson, 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":"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 it 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 interacts 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":"1030-1039"},"PeriodicalIF":5.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221788/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}