Pub Date : 2024-08-02DOI: 10.1158/2159-8290.CD-24-0775
Hamed Alborzinia, José Pedro Friedmann Angeli
PARP inhibitors (PARPi) are used as a first-line treatment option for cancers with BRCA1/2 mutations, yet a significant number of patients show a limited response to these agents. In the present study, Lei and colleagues demonstrate that PARPi promote increased ferroptosis sensitivity and this can be exploited therapeutically to improve the response to PARPi, marking an important therapeutic concept to exploit ferroptosis-based strategies in clinical settings. See related article by Lei et al., p. 1476 (2).
PARP抑制剂(PARPi)被用作BRCA1/2基因突变癌症的一线治疗方案,但相当多的患者对这些药物的反应有限。在本研究中,Lei及其同事证明了PARPi能促进铁蛋白沉积敏感性的增加,而这可以被治疗性地利用来改善对PARPi的反应,这标志着在临床环境中利用基于铁蛋白沉积的策略是一个重要的治疗概念。见 Lei 等人的相关文章,第 1476 页(2)。
{"title":"Iron: The Secret Ingredient Breaking PARPi Resistance.","authors":"Hamed Alborzinia, José Pedro Friedmann Angeli","doi":"10.1158/2159-8290.CD-24-0775","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0775","url":null,"abstract":"<p><p>PARP inhibitors (PARPi) are used as a first-line treatment option for cancers with BRCA1/2 mutations, yet a significant number of patients show a limited response to these agents. In the present study, Lei and colleagues demonstrate that PARPi promote increased ferroptosis sensitivity and this can be exploited therapeutically to improve the response to PARPi, marking an important therapeutic concept to exploit ferroptosis-based strategies in clinical settings. See related article by Lei et al., p. 1476 (2).</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-02DOI: 10.1158/2159-8290.CD-24-0002
Jai Prakash, Yuval Shaked
The extracellular matrix (ECM) is an abundant noncellular component of most solid tumors known to support tumor progression and metastasis. The interplay between the ECM and cancer therapeutics opens up new avenues in understanding cancer biology. While the ECM is known to protect the tumor from anticancer agents by serving as a biomechanical barrier, emerging studies show that various cancer therapies induce ECM remodeling, resulting in therapy resistance and tumor progression. This review discusses critical issues in this field including how the ECM influences treatment outcome, how cancer therapies affect ECM remodeling, and the challenges associated with targeting the ECM. Significance: The intricate relationship between the extracellular matrix (ECM) and cancer therapeutics reveals novel insights into tumor biology and its effective treatment. While the ECM may protect tumors from anti-cancer agents, recent research highlights the paradoxical role of therapy-induced ECM remodeling in promoting treatment resistance and tumor progression. This review explores the key aspects of the interplay between ECM and cancer therapeutics.
{"title":"The Interplay between Extracellular Matrix Remodeling and Cancer Therapeutics.","authors":"Jai Prakash, Yuval Shaked","doi":"10.1158/2159-8290.CD-24-0002","DOIUrl":"10.1158/2159-8290.CD-24-0002","url":null,"abstract":"<p><p>The extracellular matrix (ECM) is an abundant noncellular component of most solid tumors known to support tumor progression and metastasis. The interplay between the ECM and cancer therapeutics opens up new avenues in understanding cancer biology. While the ECM is known to protect the tumor from anticancer agents by serving as a biomechanical barrier, emerging studies show that various cancer therapies induce ECM remodeling, resulting in therapy resistance and tumor progression. This review discusses critical issues in this field including how the ECM influences treatment outcome, how cancer therapies affect ECM remodeling, and the challenges associated with targeting the ECM. Significance: The intricate relationship between the extracellular matrix (ECM) and cancer therapeutics reveals novel insights into tumor biology and its effective treatment. While the ECM may protect tumors from anti-cancer agents, recent research highlights the paradoxical role of therapy-induced ECM remodeling in promoting treatment resistance and tumor progression. This review explores the key aspects of the interplay between ECM and cancer therapeutics.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31DOI: 10.1158/2159-8290.CD-24-0190
Dhan Chand, David A Savitsky, Shanmugarajan Krishnan, Gabriel Mednick, Chloe Delepine, Pilar Garcia-Broncano, Kah Teong Soh, Wei Wu, Margaret K Wilkens, Olga Udartseva, Sylvia Vincent, Bishnu Joshi, Justin G Keith, Mariana Manrique, Marilyn Marques, Antoine Tanne, Daniel L Levey, Haiyong Han, Serina Ng, Jackson Ridpath, Olivia Huber, Benjamin Morin, Claire Galand, Sean Bourdelais, Randi B Gombos, Rebecca Ward, Yu Qin, Jeremy D Waight, Matthew R Costa, Alvaro Sebastian-Yague, Nils-Petter Rudqvist, Malgorzata Pupecka-Swider, Vignesh Venkatraman, Andrew Slee, Jaymin M Patel, Joseph E Grossman, Nicholas S Wilson, Daniel D Von Hoff, Justin Stebbing, Tyler J Curiel, Jennifer S Buell, Steven J O'Day, Robert B Stein
Conventional immune checkpoint inhibitors (ICI) targeting CTLA-4 elicit durable survival, but primarily in patients with immune-inflamed tumors. Although the mechanisms underlying response to anti-CTLA-4 remain poorly understood, Fc-gamma receptor (FcγR) IIIA co-engagement appears critical for activity, potentially explaining the modest clinical benefits of approved anti-CTLA-4 antibodies. We demonstrate that anti-CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T cell responsiveness, reduce intratumoral Tregs, and enhance antigen presenting cell activation. Fc-enhanced anti-CTLA-4 promoted superior efficacy in mouse models and remodeled innate and adaptive immunity versus conventional anti-CTLA-4. These findings extend to patients treated with botensilimab, an Fc-enhanced anti-CTLA-4 antibody, with clinical activity across multiple poorly immunogenic and ICI treatment-refractory cancers. Efficacy was independent of tumor neoantigen burden or FcγRIIIA genotype. However, FcγRIIA and FcγRIIIA expression emerged as potential response biomarkers. These data highlight the therapeutic potential of Fc-enhanced anti-CTLA-4 antibodies in cancers unresponsive to conventional ICI therapy.
{"title":"Botensilimab, an Fc-enhanced anti-CTLA-4 antibody, is effective against tumors poorly responsive to conventional immunotherapy.","authors":"Dhan Chand, David A Savitsky, Shanmugarajan Krishnan, Gabriel Mednick, Chloe Delepine, Pilar Garcia-Broncano, Kah Teong Soh, Wei Wu, Margaret K Wilkens, Olga Udartseva, Sylvia Vincent, Bishnu Joshi, Justin G Keith, Mariana Manrique, Marilyn Marques, Antoine Tanne, Daniel L Levey, Haiyong Han, Serina Ng, Jackson Ridpath, Olivia Huber, Benjamin Morin, Claire Galand, Sean Bourdelais, Randi B Gombos, Rebecca Ward, Yu Qin, Jeremy D Waight, Matthew R Costa, Alvaro Sebastian-Yague, Nils-Petter Rudqvist, Malgorzata Pupecka-Swider, Vignesh Venkatraman, Andrew Slee, Jaymin M Patel, Joseph E Grossman, Nicholas S Wilson, Daniel D Von Hoff, Justin Stebbing, Tyler J Curiel, Jennifer S Buell, Steven J O'Day, Robert B Stein","doi":"10.1158/2159-8290.CD-24-0190","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0190","url":null,"abstract":"<p><p>Conventional immune checkpoint inhibitors (ICI) targeting CTLA-4 elicit durable survival, but primarily in patients with immune-inflamed tumors. Although the mechanisms underlying response to anti-CTLA-4 remain poorly understood, Fc-gamma receptor (FcγR) IIIA co-engagement appears critical for activity, potentially explaining the modest clinical benefits of approved anti-CTLA-4 antibodies. We demonstrate that anti-CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T cell responsiveness, reduce intratumoral Tregs, and enhance antigen presenting cell activation. Fc-enhanced anti-CTLA-4 promoted superior efficacy in mouse models and remodeled innate and adaptive immunity versus conventional anti-CTLA-4. These findings extend to patients treated with botensilimab, an Fc-enhanced anti-CTLA-4 antibody, with clinical activity across multiple poorly immunogenic and ICI treatment-refractory cancers. Efficacy was independent of tumor neoantigen burden or FcγRIIIA genotype. However, FcγRIIA and FcγRIIIA expression emerged as potential response biomarkers. These data highlight the therapeutic potential of Fc-enhanced anti-CTLA-4 antibodies in cancers unresponsive to conventional ICI therapy.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31DOI: 10.1158/2159-8290.CD-24-0046
Liron D Grossmann, Chia-Hui Chen, Yasin Uzun, Anusha Thadi, Adam J Wolpaw, Kevin Louault, Yael Goldstein, Lea F Surrey, Daniel Martinez, Matteo Calafatti, Mark Gerelus, Peng Gao, Lobin Lee, Khushbu Patel, Rebecca S Kaufman, Guy Shani, Alvin Farrel, Sharon Moshitch-Moshkovitz, Paris Grimaldi, Matthew Shapiro, Nathan M Kendsersky, Jarrett M Lindsay, Colleen E Casey, Kateryna Krytska, Laura Scolaro, Matthew Tsang, David Groff, Smita Matkar, Josh R Kalna, Emily Mycek, Jayne McDevitt, Erin Runbeck, Tasleema Patel, Kathrin M Bernt, Shahab Asgharzadeh, Yves A DeClerck, Yael P Mosse, Kai Tan, John M Maris
Relapse rates in high-risk neuroblastoma remain exceedingly high. The malignant cells that are responsible for relapse have not been identified, and mechanisms of therapy resistance remain poorly understood. Here, we used single nucleus RNA sequencing and bulk whole genome sequencing to identify and characterize the residual malignant persister cells that survive chemotherapy from a cohort of 20 matched diagnosis and definitive surgery tumor samples from patients treated with high-risk neuroblastoma induction chemotherapy. We show that persister cells share common mechanisms of chemotherapy escape including suppression of MYCN activity and activation of NF-κB signaling, the latter is further enhanced by cell-cell communication between the malignant cells and the tumor microenvironment. Overall, our work dissects the transcriptional landscape of cellular persistence in high-risk neuroblastoma and paves the way to the development of new therapeutic strategies to prevent disease relapse.
{"title":"Identification and characterization of chemotherapy resistant high-risk neuroblastoma persister cells.","authors":"Liron D Grossmann, Chia-Hui Chen, Yasin Uzun, Anusha Thadi, Adam J Wolpaw, Kevin Louault, Yael Goldstein, Lea F Surrey, Daniel Martinez, Matteo Calafatti, Mark Gerelus, Peng Gao, Lobin Lee, Khushbu Patel, Rebecca S Kaufman, Guy Shani, Alvin Farrel, Sharon Moshitch-Moshkovitz, Paris Grimaldi, Matthew Shapiro, Nathan M Kendsersky, Jarrett M Lindsay, Colleen E Casey, Kateryna Krytska, Laura Scolaro, Matthew Tsang, David Groff, Smita Matkar, Josh R Kalna, Emily Mycek, Jayne McDevitt, Erin Runbeck, Tasleema Patel, Kathrin M Bernt, Shahab Asgharzadeh, Yves A DeClerck, Yael P Mosse, Kai Tan, John M Maris","doi":"10.1158/2159-8290.CD-24-0046","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0046","url":null,"abstract":"<p><p>Relapse rates in high-risk neuroblastoma remain exceedingly high. The malignant cells that are responsible for relapse have not been identified, and mechanisms of therapy resistance remain poorly understood. Here, we used single nucleus RNA sequencing and bulk whole genome sequencing to identify and characterize the residual malignant persister cells that survive chemotherapy from a cohort of 20 matched diagnosis and definitive surgery tumor samples from patients treated with high-risk neuroblastoma induction chemotherapy. We show that persister cells share common mechanisms of chemotherapy escape including suppression of MYCN activity and activation of NF-κB signaling, the latter is further enhanced by cell-cell communication between the malignant cells and the tumor microenvironment. Overall, our work dissects the transcriptional landscape of cellular persistence in high-risk neuroblastoma and paves the way to the development of new therapeutic strategies to prevent disease relapse.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1158/2159-8290.CD-23-1451
Tito A Sandoval, Camilla Salvagno, Chang-Suk Chae, Deepika Awasthi, Paolo Giovanelli, Matias Marin Falco, Sung-Min Hwang, Eli Teran-Cabanillas, Lasse Suominen, Takahiro Yamazaki, Hui-Hsuan Kuo, Jenna E Moyer, M Laura Martin, Jyothi Manohar, Kihwan Kim, Maria A Sierra, Yusibeska Ramos, Chen Tan, Alexander Emmanuelli, Minkyung Song, Diana K Morales, Dmitriy Zamarin, Melissa K Frey, Evelyn Cantillo, Eloise Chapman-Davis, Kevin Holcomb, Christopher E Mason, Lorenzo Galluzzi, Zhen Ni Zhou, Anna Vaharautio, Suzanne M Cloonan, Juan R Cubillos-Ruiz
Iron accumulation in tumors contributes to disease progression and chemoresistance. While targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer. Deferiprone reprogrammed ovarian cancer cells towards an immunostimulatory state characterized by production of type I interferon (IFN) and overexpression of molecules that activate natural killer (NK) cells. Mechanistically, these effects were driven by innate sensing of mitochondrial DNA in the cytosol and concomitant activation of nuclear DNA damage responses triggered upon iron chelation. Deferiprone synergized with chemotherapy and prolonged the survival of mice with ovarian cancer by bolstering type I IFN responses that drove NK cell-dependent control of metastatic disease. Hence, iron chelation may represent an alternative immunotherapeutic strategy for malignancies that are refractory to current T cell-centric modalities.
肿瘤中的铁积累会导致疾病进展和化疗耐药性。虽然针对这一过程可以影响癌症的各种特征,但铁螯合在肿瘤微环境中的免疫调节作用尚不清楚。在这里,我们报告了使用美国食品及药物管理局批准的铁螯合剂去铁酮治疗可释放抑制卵巢癌的先天性免疫反应。去铁酮能使卵巢癌细胞重新编程,进入以产生 I 型干扰素(IFN)和过表达激活自然杀伤(NK)细胞的分子为特征的免疫刺激状态。从机理上讲,这些效应是由细胞质中线粒体 DNA 的先天感应和铁螯合引发的核 DNA 损伤反应同时激活所驱动的。去铁酮能与化疗产生协同作用,并通过增强 I 型 IFN 反应延长卵巢癌小鼠的生存期,而 I 型 IFN 反应又能促进 NK 细胞对转移性疾病的依赖性控制。因此,对于目前以 T 细胞为中心的治疗方式难以奏效的恶性肿瘤,螯合铁可能是另一种免疫治疗策略。
{"title":"Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.","authors":"Tito A Sandoval, Camilla Salvagno, Chang-Suk Chae, Deepika Awasthi, Paolo Giovanelli, Matias Marin Falco, Sung-Min Hwang, Eli Teran-Cabanillas, Lasse Suominen, Takahiro Yamazaki, Hui-Hsuan Kuo, Jenna E Moyer, M Laura Martin, Jyothi Manohar, Kihwan Kim, Maria A Sierra, Yusibeska Ramos, Chen Tan, Alexander Emmanuelli, Minkyung Song, Diana K Morales, Dmitriy Zamarin, Melissa K Frey, Evelyn Cantillo, Eloise Chapman-Davis, Kevin Holcomb, Christopher E Mason, Lorenzo Galluzzi, Zhen Ni Zhou, Anna Vaharautio, Suzanne M Cloonan, Juan R Cubillos-Ruiz","doi":"10.1158/2159-8290.CD-23-1451","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-23-1451","url":null,"abstract":"<p><p>Iron accumulation in tumors contributes to disease progression and chemoresistance. While targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer. Deferiprone reprogrammed ovarian cancer cells towards an immunostimulatory state characterized by production of type I interferon (IFN) and overexpression of molecules that activate natural killer (NK) cells. Mechanistically, these effects were driven by innate sensing of mitochondrial DNA in the cytosol and concomitant activation of nuclear DNA damage responses triggered upon iron chelation. Deferiprone synergized with chemotherapy and prolonged the survival of mice with ovarian cancer by bolstering type I IFN responses that drove NK cell-dependent control of metastatic disease. Hence, iron chelation may represent an alternative immunotherapeutic strategy for malignancies that are refractory to current T cell-centric modalities.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-26DOI: 10.1158/2159-8290.CD-23-1529
Olaf Klingbeil, Damianos Skopelitis, Claudia Tonelli, Toyoki Yoshimoto, Aktan Alpsoy, Maria C Panepinto, Francesca Minicozzi, Joseph R Merrill, Amanda M Cafiero, Disha Aggarwal, Suzanne Russo, Taehoon Ha, Osama E Demerdash, Tse-Luen Wee, David L Spector, Scott K Lyons, David A Tuveson, Paolo Cifani, Christopher R Vakoc
The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. Here, we used paralog co-targeting CRISPR screens to identify the kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show can regress established tumors in vivo. Together, these findings reveal MARK2/3 as powerful co-dependencies of YAP/TAZ in human cancer; targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression.
{"title":"MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer.","authors":"Olaf Klingbeil, Damianos Skopelitis, Claudia Tonelli, Toyoki Yoshimoto, Aktan Alpsoy, Maria C Panepinto, Francesca Minicozzi, Joseph R Merrill, Amanda M Cafiero, Disha Aggarwal, Suzanne Russo, Taehoon Ha, Osama E Demerdash, Tse-Luen Wee, David L Spector, Scott K Lyons, David A Tuveson, Paolo Cifani, Christopher R Vakoc","doi":"10.1158/2159-8290.CD-23-1529","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-23-1529","url":null,"abstract":"<p><p>The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. Here, we used paralog co-targeting CRISPR screens to identify the kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show can regress established tumors in vivo. Together, these findings reveal MARK2/3 as powerful co-dependencies of YAP/TAZ in human cancer; targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The SCRUM-Japan MONSTAR-SCREEN consortium is a nationwide molecular profiling project employing artificial intelligence-driven multi-omics analyses for patients with advanced malignancies, aiming to develop novel therapeutics and diagnostics and deliver effective drugs to patients. Concurrently, studies assessing molecular residual disease-based precision medicine for resectable solid tumors, including CIRCULATE-Japan, are ongoing. The substantial data generated by these platforms are stored within a state-of-the-art supercomputing infrastructure, VAPOR CONE. Since 2015, our project has registered over 24,000 patients as of December 2023. Among 16,144 patients with advanced solid tumors enrolled in MONSTAR-SCREEN projects, 5.0% participated in matched clinical trials, demonstrating a 29.2% objective response rate and 14.8-month median survival (95% confidence interval, 13.4-16.3), for patients treated in the matched clinical trials. Notably, patients who received matched therapy demonstrated significantly prolonged overall survival compared with those who did not (hazard ratio 0.77; 95% confidence interval, 0.71-0.83).
{"title":"The SCRUM-MONSTAR Cancer-Omics Ecosystem: Striving for a Quantum Leap in Precision Medicine.","authors":"Tadayoshi Hashimoto, Yoshiaki Nakamura, Takao Fujisawa, Mitsuho Imai, Taro Shibuki, Naoko Iida, Hiroshi Ozaki, Norio Nonomura, Chigusa Morizane, Hiroji Iwata, Susumu Okano, Wataru Yamagami, Naoya Yamazaki, Shigenori Kadowaki, Hiroya Taniguchi, Makoto Ueno, Shogen Boku, Eiji Oki, Yoshito Komatsu, Satoshi Yuki, Akitaka Makiyama, Tomoyuki Otsuka, Hiroki Hara, Naohiro Okano, Tomohiro Nishina, Yasutoshi Sakamoto, Izumi Miki, Shin Kobayashi, Junichiro Yuda, Shun-Ichiro Kageyama, Michiko Nagamine, Shingo Sakashita, Naoya Sakamoto, Riu Yamashita, Yoshikatsu Koga, Hideaki Bando, Genichiro Ishii, Takeshi Kuwata, Woong-Yang Park, Atsushi Ohtsu, Takayuki Yoshino","doi":"10.1158/2159-8290.CD-24-0206","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0206","url":null,"abstract":"<p><p>The SCRUM-Japan MONSTAR-SCREEN consortium is a nationwide molecular profiling project employing artificial intelligence-driven multi-omics analyses for patients with advanced malignancies, aiming to develop novel therapeutics and diagnostics and deliver effective drugs to patients. Concurrently, studies assessing molecular residual disease-based precision medicine for resectable solid tumors, including CIRCULATE-Japan, are ongoing. The substantial data generated by these platforms are stored within a state-of-the-art supercomputing infrastructure, VAPOR CONE. Since 2015, our project has registered over 24,000 patients as of December 2023. Among 16,144 patients with advanced solid tumors enrolled in MONSTAR-SCREEN projects, 5.0% participated in matched clinical trials, demonstrating a 29.2% objective response rate and 14.8-month median survival (95% confidence interval, 13.4-16.3), for patients treated in the matched clinical trials. Notably, patients who received matched therapy demonstrated significantly prolonged overall survival compared with those who did not (hazard ratio 0.77; 95% confidence interval, 0.71-0.83).</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.1158/2159-8290.CD-23-1393
Ju-Fang Chang, Jack H Landmann, Tien-Ching Chang, Mehmet Emrah Selli, Yangdon Tenzin, John M Warrington, Julie Ritchey, Yu-Sung Hsu, Michael Slade, Deepesh Kumar Gupta, John F DiPersio, Alex S Holehouse, Nathan Singh
Chimeric antigen receptor (CAR)-based therapies have pioneered synthetic cellular immunity but remain limited in their long-term efficacy. Emerging data suggest that dysregulated CAR-driven T cell activation causes T cell dysfunction and therapeutic failure. To re-engage the precision of the endogenous T cell response, we designed MHC-independent T cell receptors (miTCRs) by linking antibody variable domains to TCR constant chains. Using predictive modeling, we observed that this standard "cut and paste" approach to synthetic protein design resulted in myriad biochemical conflicts at the hybrid variable-constant domain interface. Through iterative modeling and sequence modifications we developed structure-enhanced miTCRs which significantly improved receptor-driven T cell function across multiple tumor models. We found that 41BB costimulation specifically prolonged miTCR T cell persistence and enabled improved leukemic control in vivo compared to classic CAR T cells. Collectively, we have identified core features of hybrid receptor structure responsible for regulating function.
基于嵌合抗原受体(CAR)的疗法开创了合成细胞免疫疗法,但其长期疗效仍然有限。新出现的数据表明,CAR 驱动的 T 细胞活化失调会导致 T 细胞功能障碍和治疗失败。为了重新精确激活内源性 T 细胞反应,我们将抗体可变域与 TCR 常链连接,设计出了不依赖 MHC 的 T 细胞受体(miTCRs)。通过预测建模,我们发现这种标准的 "剪切和粘贴 "合成蛋白质设计方法会在可变结构域与恒定结构域的混合界面上产生无数的生化冲突。通过迭代建模和序列修改,我们开发出了结构增强型 miTCR,在多个肿瘤模型中显著改善了受体驱动的 T 细胞功能。我们发现,与传统的 CAR T 细胞相比,41BB 成本刺激特异性地延长了 miTCR T 细胞的存活时间,并改善了体内的白血病控制。总之,我们确定了混合受体结构中负责调节功能的核心特征。
{"title":"Rational protein engineering to enhance MHC-independent T cell receptors.","authors":"Ju-Fang Chang, Jack H Landmann, Tien-Ching Chang, Mehmet Emrah Selli, Yangdon Tenzin, John M Warrington, Julie Ritchey, Yu-Sung Hsu, Michael Slade, Deepesh Kumar Gupta, John F DiPersio, Alex S Holehouse, Nathan Singh","doi":"10.1158/2159-8290.CD-23-1393","DOIUrl":"10.1158/2159-8290.CD-23-1393","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-based therapies have pioneered synthetic cellular immunity but remain limited in their long-term efficacy. Emerging data suggest that dysregulated CAR-driven T cell activation causes T cell dysfunction and therapeutic failure. To re-engage the precision of the endogenous T cell response, we designed MHC-independent T cell receptors (miTCRs) by linking antibody variable domains to TCR constant chains. Using predictive modeling, we observed that this standard \"cut and paste\" approach to synthetic protein design resulted in myriad biochemical conflicts at the hybrid variable-constant domain interface. Through iterative modeling and sequence modifications we developed structure-enhanced miTCRs which significantly improved receptor-driven T cell function across multiple tumor models. We found that 41BB costimulation specifically prolonged miTCR T cell persistence and enabled improved leukemic control in vivo compared to classic CAR T cells. Collectively, we have identified core features of hybrid receptor structure responsible for regulating function.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-08DOI: 10.1158/2159-8290.CD-24-0421
Haniel A Araujo, Ximo Pechuan-Jorge, Teng Zhou, Minh Truong Do, Xin Hu, Frank R Rojas Alvarez, Maria E Salvatierra, Heladio P Ibarguen, Richard Lee, Rashi Raghulan, Harshit Shah, Mariela A Moreno Ayala, Kevin Chen, Nataliya Tovbis Shifrin, Shuhong Wu, Luisa M Solis Soto, Marcelo V Negrao, Don L Gibbons, David S Hong, Jack A Roth, John V Heymach, Jianjun Zhang, Jingjing Jiang, Mallika Singh, Jacqueline A M Smith, Elsa Quintana, Ferdinandos Skoulidis
Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the anti-tumor activity of the RAS(ON) multi-selective tri-complex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant NSCLC. Broad-spectrum, reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse co-mutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or (OFF) inhibitor resistance. Interrogation of time-resolved single cell transcriptional responses established an in vivo atlas of multi-modal acute and chronic RAS pathway inhibition in the NSCLC ecosystem and uncovered a regenerative mucinous transcriptional program that supports long-term tumor cell persistence. In patients with advanced KRASG12C-mutant NSCLC, the presence of mucinous histological features portended poor response to sotorasib or adagrasib. Our results have potential implications for personalized medicine and the development of rational RAS inhibitor-anchored therapeutic strategies.
{"title":"Mechanisms of response and tolerance to active RAS inhibition in KRAS-mutant NSCLC.","authors":"Haniel A Araujo, Ximo Pechuan-Jorge, Teng Zhou, Minh Truong Do, Xin Hu, Frank R Rojas Alvarez, Maria E Salvatierra, Heladio P Ibarguen, Richard Lee, Rashi Raghulan, Harshit Shah, Mariela A Moreno Ayala, Kevin Chen, Nataliya Tovbis Shifrin, Shuhong Wu, Luisa M Solis Soto, Marcelo V Negrao, Don L Gibbons, David S Hong, Jack A Roth, John V Heymach, Jianjun Zhang, Jingjing Jiang, Mallika Singh, Jacqueline A M Smith, Elsa Quintana, Ferdinandos Skoulidis","doi":"10.1158/2159-8290.CD-24-0421","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0421","url":null,"abstract":"<p><p>Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the anti-tumor activity of the RAS(ON) multi-selective tri-complex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant NSCLC. Broad-spectrum, reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse co-mutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or (OFF) inhibitor resistance. Interrogation of time-resolved single cell transcriptional responses established an in vivo atlas of multi-modal acute and chronic RAS pathway inhibition in the NSCLC ecosystem and uncovered a regenerative mucinous transcriptional program that supports long-term tumor cell persistence. In patients with advanced KRASG12C-mutant NSCLC, the presence of mucinous histological features portended poor response to sotorasib or adagrasib. Our results have potential implications for personalized medicine and the development of rational RAS inhibitor-anchored therapeutic strategies.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-08DOI: 10.1158/2159-8290.CD-24-0177
Julien Dilly, Megan T Hoffman, Laleh Abbassi, Ziyue Li, Francesca Paradiso, Brendan D Parent, Connor J Hennessey, Alexander C Jordan, Micaela Morgado, Shatavisha Dasgupta, Giselle A Uribe, Annan Yang, Kevin S Kapner, Felix P Hambitzer, Li Qiang, Hanrong Feng, Jacob Geisberg, Junning Wang, Kyle E Evans, Hengyu Lyu, Aislyn Schalck, Ningping Feng, Anastasia M Lopez, Christopher A Bristow, Michael P Kim, Kimal I Rajapakshe, Vahid Bahrambeigi, Jennifer A Roth, Kavita Garg, Paola A Guerrero, Ben Z Stanger, Simona Cristea, Scott W Lowe, Timour Baslan, Eliezer M Van Allen, Joseph D Mancias, Emily Chan, Abraham Anderson, Yuliya V Katlinskaya, Alex K Shalek, David S Hong, Shubham Pant, Jill Hallin, Kenna Anderes, Peter Olson, Timothy P Heffernan, Seema Chugh, James G Christensen, Anirban Maitra, Brian M Wolpin, Srivatsan Raghavan, Jonathan A Nowak, Peter S Winter, Stephanie K Dougan, Andrew J Aguirre
KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.
{"title":"Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer.","authors":"Julien Dilly, Megan T Hoffman, Laleh Abbassi, Ziyue Li, Francesca Paradiso, Brendan D Parent, Connor J Hennessey, Alexander C Jordan, Micaela Morgado, Shatavisha Dasgupta, Giselle A Uribe, Annan Yang, Kevin S Kapner, Felix P Hambitzer, Li Qiang, Hanrong Feng, Jacob Geisberg, Junning Wang, Kyle E Evans, Hengyu Lyu, Aislyn Schalck, Ningping Feng, Anastasia M Lopez, Christopher A Bristow, Michael P Kim, Kimal I Rajapakshe, Vahid Bahrambeigi, Jennifer A Roth, Kavita Garg, Paola A Guerrero, Ben Z Stanger, Simona Cristea, Scott W Lowe, Timour Baslan, Eliezer M Van Allen, Joseph D Mancias, Emily Chan, Abraham Anderson, Yuliya V Katlinskaya, Alex K Shalek, David S Hong, Shubham Pant, Jill Hallin, Kenna Anderes, Peter Olson, Timothy P Heffernan, Seema Chugh, James G Christensen, Anirban Maitra, Brian M Wolpin, Srivatsan Raghavan, Jonathan A Nowak, Peter S Winter, Stephanie K Dougan, Andrew J Aguirre","doi":"10.1158/2159-8290.CD-24-0177","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0177","url":null,"abstract":"<p><p>KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}