Cancer discoveryPub Date : 2024-10-04DOI: 10.1158/2159-8290.CD-24-0100
Katelyn L Donahue, Hannah R Watkoske, Padma Kadiyala, Wenting Du, Kristee Brown, Michael K Scales, Ahmed M Elhossiny, Carlos E Espinoza, Emily L Lasse Opsahl, Brian D Griffith, Yukang Wen, Lei Sun, Ashley Velez-Delgado, Nur M Renollet, Jacqueline Morales, Nicholas M Nedzesky, Rachael K Baliira, Rosa E Menjivar, Paola I Medina-Cabrera, Arvind Rao, Benjamin Allen, Jiaqi Shi, Timothy L Frankel, Eileen S Carpenter, Filip Bednar, Yaqing Zhang, Marina Pasca di Magliano
{"title":"Oncogenic KRAS-Dependent Stromal Interleukin-33 Directs the Pancreatic Microenvironment to Promote Tumor Growth.","authors":"Katelyn L Donahue, Hannah R Watkoske, Padma Kadiyala, Wenting Du, Kristee Brown, Michael K Scales, Ahmed M Elhossiny, Carlos E Espinoza, Emily L Lasse Opsahl, Brian D Griffith, Yukang Wen, Lei Sun, Ashley Velez-Delgado, Nur M Renollet, Jacqueline Morales, Nicholas M Nedzesky, Rachael K Baliira, Rosa E Menjivar, Paola I Medina-Cabrera, Arvind Rao, Benjamin Allen, Jiaqi Shi, Timothy L Frankel, Eileen S Carpenter, Filip Bednar, Yaqing Zhang, Marina Pasca di Magliano","doi":"10.1158/2159-8290.CD-24-0100","DOIUrl":"10.1158/2159-8290.CD-24-0100","url":null,"abstract":"<p><p>Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer-associated fibroblasts (CAF). The mechanisms underlying this conversion, including the regulation and function of fibroblast-derived cytokines, are poorly understood. Thus, efforts to therapeutically target CAFs have so far failed. Herein, we show that signals from epithelial cells expressing oncogenic KRAS-a hallmark pancreatic cancer mutation-activate fibroblast autocrine signaling, which drives the expression of the cytokine IL33. Stromal IL33 expression remains high and dependent on epithelial KRAS throughout carcinogenesis; in turn, environmental stress induces interleukin-33 (IL33) secretion. Using compartment-specific IL33 knockout mice, we observed that lack of stromal IL33 leads to profound reprogramming of multiple components of the pancreatic tumor microenvironment, including CAFs, myeloid cells, and lymphocytes. Notably, loss of stromal IL33 leads to an increase in CD8+ T-cell infiltration and activation and, ultimately, reduced tumor growth. Significance: This study provides new insights into the mechanisms underlying the programming of CAFs and shows that during this process, expression of the cytokine IL33 is induced. CAF-derived IL33 has pleiotropic effects on the tumor microenvironment, supporting its potential as a therapeutic target.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1964-1989"},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490962","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}
Cancer discoveryPub Date : 2024-10-02DOI: 10.1158/2159-8290.CD-24-0134
Neibla Priego, Ana de Pablos-Aragoneses, Maria Perea-García, Valentina Pieri, Carolina Hernandez-Oliver, Laura Alvaro-Espinosa, Andrea Rojas, Oliva Sanchez, Ariane Steindl, Eduardo Caleiras, Fernando Garcia, Santiago Garcia-Martin, Osvaldo Grana-Castro, Sandra Garcia-Mulero, Diego Serrano, Paloma Velasco-Beltran, Borja Jimenez-Lasheras, Leire Egia-Mendikute, Luise Rupp, Antonia Stammberger, Matthias Meinhardt, Anas Chaachou-Charradi, Elena Martínez-Saez, Luca Bertero, Paola Cassoni, Luca Mangherini, Alessia Pellerino, Roberta Ruda, Riccardo Soffietti, Fatima Al-Shahrour, Paul Saftig, Rebeca Sanz-Pamplona, Marc Schmitz, Stephen J Crocker, Alfonso Calvo, Asis Palazon, Renacer Group, Manuel Valiente
{"title":"TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis acting on infiltrating CD8+ T cells.","authors":"Neibla Priego, Ana de Pablos-Aragoneses, Maria Perea-García, Valentina Pieri, Carolina Hernandez-Oliver, Laura Alvaro-Espinosa, Andrea Rojas, Oliva Sanchez, Ariane Steindl, Eduardo Caleiras, Fernando Garcia, Santiago Garcia-Martin, Osvaldo Grana-Castro, Sandra Garcia-Mulero, Diego Serrano, Paloma Velasco-Beltran, Borja Jimenez-Lasheras, Leire Egia-Mendikute, Luise Rupp, Antonia Stammberger, Matthias Meinhardt, Anas Chaachou-Charradi, Elena Martínez-Saez, Luca Bertero, Paola Cassoni, Luca Mangherini, Alessia Pellerino, Roberta Ruda, Riccardo Soffietti, Fatima Al-Shahrour, Paul Saftig, Rebeca Sanz-Pamplona, Marc Schmitz, Stephen J Crocker, Alfonso Calvo, Asis Palazon, Renacer Group, Manuel Valiente","doi":"10.1158/2159-8290.CD-24-0134","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0134","url":null,"abstract":"<p><p>Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here we dissect the heterogeneity in metastasis-associated astrocytes using scRNAseq and report a population that blocks the antitumoral activity of infiltrating T cells. This pro-tumoral activity is mediated by the secretion of TIMP1 from a cluster of pSTAT3+ astrocytes that acts on CD63+ CD8+ T cells to modulate their function. Using genetic and pharmacologic approaches in mouse and human brain metastasis models, we demonstrate that combining immune checkpoint blockade antibodies with the inhibition of astrocyte-mediated local immunosuppression may benefit patients with symptomatic brain metastases. We further reveal that the presence of TIMP1 in liquid biopsies provides a biomarker to select patients for this combined immunotherapy. Overall, our findings demonstrate an unexpected immunomodulatory role for astrocytes in brain metastases with clinical implications.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361163","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}
Cancer discoveryPub Date : 2024-09-30DOI: 10.1158/2159-8290.CD-24-0489
Yonghong Liu, Jincheng Han, Wen-Hao Hsu, Kyle A LaBella, Pingna Deng, Xiaoying Shang, Paulino Tallon de Lara, Li Cai, Shan Jiang, Ronald A DePinho
{"title":"Combined KRAS inhibition and immune therapy generates durable complete responses in an autochthonous PDAC model.","authors":"Yonghong Liu, Jincheng Han, Wen-Hao Hsu, Kyle A LaBella, Pingna Deng, Xiaoying Shang, Paulino Tallon de Lara, Li Cai, Shan Jiang, Ronald A DePinho","doi":"10.1158/2159-8290.CD-24-0489","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0489","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy. In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. Here, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust anti-tumor regression in iKPC mice bearing large autochthonous tumors. While untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in 36% of mice at 6 months. Mechanistic analyses revealed enhanced T cell infiltration and activation, depletion of immunosuppressive myeloid cells, and increased antigen cross-presentation by dendritic cells within the tumor core. These findings highlight the promise of KRAS* inhibitors alongside immunotherapy as a potential PDAC treatment avenue, warranting clinical investigation.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342164","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}
Cancer discoveryPub Date : 2024-09-30DOI: 10.1158/2159-8290.cd-24-0393
Jamie E. Medina, Akshaya V. Annapragada, Pien Lof, Sarah Short, Adrianna L. Bartolomucci, Dimitrios Mathios, Shashikant Koul, Noushin Niknafs, Michael Noe, Zachariah H. Foda, Daniel C. Bruhm, Carolyn Hruban, Nicholas A. Vulpescu, Euihye Jung, Renu Dua, Jenna V. Canzoniero, Stephen Cristiano, Vilmos Adleff, Heather Symecko, Daan van den Broek, Lori J. Sokoll, Stephen B. Baylin, Michael F. Press, Dennis J. Slamon, Gottfried E. Konecny, Christina Therkildsen, Beatriz Carvalho, Gerrit A. Meijer, Claus Lindbjerg. Andersen, Susan M. Domchek, Ronny Drapkin, Robert B. Scharpf, Jillian Phallen, Christine A.R. Lok, Victor E. Velculescu
{"title":"Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers","authors":"Jamie E. Medina, Akshaya V. Annapragada, Pien Lof, Sarah Short, Adrianna L. Bartolomucci, Dimitrios Mathios, Shashikant Koul, Noushin Niknafs, Michael Noe, Zachariah H. Foda, Daniel C. Bruhm, Carolyn Hruban, Nicholas A. Vulpescu, Euihye Jung, Renu Dua, Jenna V. Canzoniero, Stephen Cristiano, Vilmos Adleff, Heather Symecko, Daan van den Broek, Lori J. Sokoll, Stephen B. Baylin, Michael F. Press, Dennis J. Slamon, Gottfried E. Konecny, Christina Therkildsen, Beatriz Carvalho, Gerrit A. Meijer, Claus Lindbjerg. Andersen, Susan M. Domchek, Ronny Drapkin, Robert B. Scharpf, Jillian Phallen, Christine A.R. Lok, Victor E. Velculescu","doi":"10.1158/2159-8290.cd-24-0393","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0393","url":null,"abstract":"Ovarian cancer is a leading cause of death for women worldwide in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model with the combined features, we detected ovarian cancer with specificity &gt;99% and sensitivity of 72%, 69%, 87%, and 100% for stages I–IV, respectively. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I–IV. Our approach differentiated benign masses from ovarian cancers with high accuracy (AUC=0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"39 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329984","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}
Cancer discoveryPub Date : 2024-09-26DOI: 10.1158/2159-8290.cd-24-0634
Ilaria Gritti, Jinkai Wan, Vajira Weeresekara, Joel M. Vaz, Giuseppe Tarantino, Tenna Holgersen. Bryde, Vindhya Vijay, Ashwin V. Kammula, Prabhat Kattel, Songli Zhu, Phuong Vu, Marina Chan, Meng-Ju Wu, John D. Gordan, Krushna C. Patra, Vanessa S. Silveira, Robert T. Manguso, Marc N. Wein, Christopher J. Ott, Jun Qi, David Liu, Kei Sakamoto, Taranjit S. Gujral, Nabeel Bardeesy
{"title":"DNAJB1-PRKACA fusion drives fibrolamellar liver cancer through impaired SIK signaling and CRTC2/p300-mediated transcriptional reprogramming","authors":"Ilaria Gritti, Jinkai Wan, Vajira Weeresekara, Joel M. Vaz, Giuseppe Tarantino, Tenna Holgersen. Bryde, Vindhya Vijay, Ashwin V. Kammula, Prabhat Kattel, Songli Zhu, Phuong Vu, Marina Chan, Meng-Ju Wu, John D. Gordan, Krushna C. Patra, Vanessa S. Silveira, Robert T. Manguso, Marc N. Wein, Christopher J. Ott, Jun Qi, David Liu, Kei Sakamoto, Taranjit S. Gujral, Nabeel Bardeesy","doi":"10.1158/2159-8290.cd-24-0634","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0634","url":null,"abstract":"Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived FLC models, engineered systems, and patient samples. We show that a core function of DNAJB1-PRKACA is the phosphorylation and inactivation of Salt-inducible kinases (SIKs). This leads to deregulation of the CRTC2 transcriptional co-activator and p300 acetyltransferase, resulting in transcriptional reprogramming and increased global histone acetylation, driving malignant growth. Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest the potential of targeting CRTC2/p300 in FLC. Notably, these findings link this rare cancer’s signature fusion oncoprotein to more common cancer gene alterations involving STK11 and GNAS, which also function via SIK suppression.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"37 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325292","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}
Cancer discoveryPub Date : 2024-09-24DOI: 10.1158/2159-8290.CD-24-1288
{"title":"Advancing Global Health Equity in Oncology Clinical Trial Access.","authors":"","doi":"10.1158/2159-8290.CD-24-1288","DOIUrl":"10.1158/2159-8290.CD-24-1288","url":null,"abstract":"<p><p>Despite exponentially increased industry investment in oncology research and development with more than $80 billion spent annually, patient enrollment in clinical trials remains below 5% globally. Our multistakeholder international cancer coalition envisions ecosystem transformation with capacity building through a global \"hub-and-spoke\" network model to expand access to and accelerate clinical trials, thus ending cancer as a major cause of death in this lifetime.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"OF1-OF7"},"PeriodicalIF":29.7,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307101","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}
Cancer discoveryPub Date : 2024-09-16DOI: 10.1158/2159-8290.CD-24-0887
Brian Belmontes, Katherine K Slemmons, Chun Su, Siyuan Liu, Antonia N Policheni, Jodi Moriguchi, Hong Tan, Fang Xie, Daniel Andrew Aiello, Yajing Yang, Raul Lazaro, Famke Aeffner, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Mikkel Vestergaard, Sanne Cowland, Jan Andersson, Ian Sarvary, Qing Chen, Pooja Sharma, Patricia Lopez, Nuria Tamayo, Liping H Pettus, Sudipa Ghimire-Rijal, Susmith Mukund, Jennifer R Allen, Jason DeVoss, Angela Coxon, Jordi Rodon, Francois Ghiringhelli, Nicolas Penel, Hans Prenen, Sanne Glad, Chen-Hua Chuang, Kiana Keyvanjah, Danielle M Townsley, John R Butler, Matthew P Bourbeau, Sean Caenepeel, Paul E Hughes
{"title":"AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients With MTAP-Deleted Cancers.","authors":"Brian Belmontes, Katherine K Slemmons, Chun Su, Siyuan Liu, Antonia N Policheni, Jodi Moriguchi, Hong Tan, Fang Xie, Daniel Andrew Aiello, Yajing Yang, Raul Lazaro, Famke Aeffner, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Mikkel Vestergaard, Sanne Cowland, Jan Andersson, Ian Sarvary, Qing Chen, Pooja Sharma, Patricia Lopez, Nuria Tamayo, Liping H Pettus, Sudipa Ghimire-Rijal, Susmith Mukund, Jennifer R Allen, Jason DeVoss, Angela Coxon, Jordi Rodon, Francois Ghiringhelli, Nicolas Penel, Hans Prenen, Sanne Glad, Chen-Hua Chuang, Kiana Keyvanjah, Danielle M Townsley, John R Butler, Matthew P Bourbeau, Sean Caenepeel, Paul E Hughes","doi":"10.1158/2159-8290.CD-24-0887","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0887","url":null,"abstract":"<p><p>One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on PRMT5 in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust antitumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280594","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}
Cancer discoveryPub Date : 2024-09-13DOI: 10.1158/2159-8290.cd-24-0231
Jessica J. Lin, Joshua C. Horan, Anupong Tangpeerachaikul, Aurélie Swalduz, Augusto Valdivia, Melissa L. Johnson, Benjamin Besse, D. Ross Camidge, Toshio Fujino, Satoshi Yoda, Linh Nguyen-Phuong, Hayato Mizuta, Ludovic Bigot, Catline Nobre, Jii Bum Lee, Mi Ra Yu, Scot Mente, Yuting Sun, Nancy E. Kohl, James R. Porter, Matthew D. Shair, Viola W. Zhu, Enriqueta Felip, Byoung Chul Cho, Luc Friboulet, Aaron N. Hata, Henry E. Pelish, Alexander Drilon
{"title":"NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations","authors":"Jessica J. Lin, Joshua C. Horan, Anupong Tangpeerachaikul, Aurélie Swalduz, Augusto Valdivia, Melissa L. Johnson, Benjamin Besse, D. Ross Camidge, Toshio Fujino, Satoshi Yoda, Linh Nguyen-Phuong, Hayato Mizuta, Ludovic Bigot, Catline Nobre, Jii Bum Lee, Mi Ra Yu, Scot Mente, Yuting Sun, Nancy E. Kohl, James R. Porter, Matthew D. Shair, Viola W. Zhu, Enriqueta Felip, Byoung Chul Cho, Luc Friboulet, Aaron N. Hata, Henry E. Pelish, Alexander Drilon","doi":"10.1158/2159-8290.cd-24-0231","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0231","url":null,"abstract":"Three generations of tyrosine kinase inhibitors (TKI) have been approved for anaplastic lymphoma kinase (ALK) fusion–positive non–small cell lung cancer. However, none address the combined need for broad resistance coverage, brain activity, and avoidance of clinically dose-limiting TRK inhibition. NVL-655 is a rationally designed TKI with &gt;50-fold selectivity for ALK over 96% of the kinome tested. In vitro, NVL-655 inhibits diverse ALK fusions, activating alterations, and resistance mutations, showing ≥100-fold improved potency against ALKG1202R single and compound mutations over approved ALK TKIs. In vivo, it induces regression across 12 tumor models, including intracranial and patient-derived xenografts. NVL-655 inhibits ALK over TRK with 22-fold to &gt;874-fold selectivity. These preclinical findings are supported by three case studies from an ongoing first-in-human phase I/II trial of NVL-655 which demonstrate preliminary proof-of-concept clinical activity in heavily pretreated patients with ALK fusion–positive non–small cell lung cancer, including in patients with brain metastases and single or compound ALK resistance mutations. Significance: By combining broad activity against single and compound ALK resistance mutations, brain penetrance, and selectivity, NVL-655 addresses key limitations of currently approved ALK inhibitors and has the potential to represent a distinct advancement as a fourth-generation inhibitor for patients with ALK-driven cancers.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"30 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231297","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}
Cancer discoveryPub Date : 2024-09-13DOI: 10.1158/2159-8290.cd-24-0018
Gregoire Gessain, Ahmed-Amine Anzali, Marvin Lerousseau, Kevin Mulder, Mathilde Bied, Anne Auperin, Daniel Stockholm, Nicolas Signolle, Farah Sassi, Maria Eugenia Marques Da Costa, Antonin Marchais, Alexandre Sayadi, Daniela Weidner, Stefan Uderhardt, Quentin Blampey, Sumanth Reddy Nakkireddy, Sophie Broutin, Charles-Antoine Dutertre, Pierre Busson, Thomas Walter, Alix Marhic, Antoine Moya-Plana, Joanne Guerlain, Ingrid Breuskin, Odile Casiraghi, Philippe Gorphe, Marion Classe, Jean-Yves Scoazec, Camille Bleriot, Florent Ginhoux
{"title":"Trem2-expressing multinucleated giant macrophages are a biomarker of good prognosis in head and neck squamous cell carcinoma","authors":"Gregoire Gessain, Ahmed-Amine Anzali, Marvin Lerousseau, Kevin Mulder, Mathilde Bied, Anne Auperin, Daniel Stockholm, Nicolas Signolle, Farah Sassi, Maria Eugenia Marques Da Costa, Antonin Marchais, Alexandre Sayadi, Daniela Weidner, Stefan Uderhardt, Quentin Blampey, Sumanth Reddy Nakkireddy, Sophie Broutin, Charles-Antoine Dutertre, Pierre Busson, Thomas Walter, Alix Marhic, Antoine Moya-Plana, Joanne Guerlain, Ingrid Breuskin, Odile Casiraghi, Philippe Gorphe, Marion Classe, Jean-Yves Scoazec, Camille Bleriot, Florent Ginhoux","doi":"10.1158/2159-8290.cd-24-0018","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0018","url":null,"abstract":"Patients with head and neck squamous cell carcinomas (HNSCC) often have poor outcomes due to suboptimal risk-management and treatment strategies; yet integrating novel prognostic biomarkers into clinical practice is challenging. Here, we report the presence of multinucleated giant cells (MGC) – a type of macrophages – in tumors from patients with HNSCC, which are associated with a favorable prognosis in treatment-naive and preoperative-chemotherapy-treated patients. Importantly, MGC density increased in tumors following preoperative therapy, suggesting a role of these cells in the anti-tumoral response. To enable clinical translation of MGC density as a prognostic marker, we developed a deep-learning model to automate its quantification on routinely stained pathological whole slide images. Finally, we used spatial transcriptomic and proteomic approaches to describe the MGC-related tumor microenvironment and observed an increase in central memory CD4 T cells. We defined an MGC-specific signature resembling to TREM2-expressing mononuclear tumor associated macrophages, which co-localized in keratin tumor niches.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"2 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231296","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}
Cancer discoveryPub Date : 2024-09-09DOI: 10.1158/2159-8290.CD-24-0306
Birgit Wilding, Lydia Woelflingseder, Anke Baum, Krzysztof Chylinski, Gintautas Vainorius, Neil Gibson, Irene C Waizenegger, Daniel Gerlach, Martin Augsten, Fiona Spreitzer, Yukina Shirai, Masachika Ikegami, Sylvia Tilandyova, Dirk Scharn, Mark A Pearson, Johannes Popow, Anna C Obenauf, Noboru Yamamoto, Shunsuke Kondo, Frans L Opdam, Annemarie Bruining, Shinji Kohsaka, Norbert Kraut, John V Heymach, Flavio Solca, Ralph A Neumuller
{"title":"Zongertinib (BI 1810631), an irreversible HER2 TKI, spares EGFR signaling and improves therapeutic response in preclinical models and patients with HER2-driven cancers.","authors":"Birgit Wilding, Lydia Woelflingseder, Anke Baum, Krzysztof Chylinski, Gintautas Vainorius, Neil Gibson, Irene C Waizenegger, Daniel Gerlach, Martin Augsten, Fiona Spreitzer, Yukina Shirai, Masachika Ikegami, Sylvia Tilandyova, Dirk Scharn, Mark A Pearson, Johannes Popow, Anna C Obenauf, Noboru Yamamoto, Shunsuke Kondo, Frans L Opdam, Annemarie Bruining, Shinji Kohsaka, Norbert Kraut, John V Heymach, Flavio Solca, Ralph A Neumuller","doi":"10.1158/2159-8290.CD-24-0306","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0306","url":null,"abstract":"<p><p>Mutations in HER2 occur in 2-4% of non-small cell lung cancer (NSCLC) and confer poor prognosis. ERBB-targeting tyrosine kinase inhibitors, approved for treating other HER2-dependent cancers, are ineffective in HER2 mutant NSCLC due to dose-limiting toxicities or suboptimal potency. We report the discovery of zongertinib (BI 1810631), a covalent HER2 inhibitor. Zongertinib potently and selectively blocks HER2, while sparing EGFR, and inhibits the growth of cells dependent on HER2 oncogenic driver events, including HER2-dependent human cancer cells resistant to trastuzumab deruxtecan. Zongertinib displays potent anti-tumor activity in HER2-dependent human NSCLC xenograft models and enhances the activities of antibody-drug conjugates and KRASG12C inhibitors, without causing obvious toxicities. The preclinical efficacy of zongertinib translates in objective responses in patients with HER2-dependent tumors, including cholangiocarcinoma (SDC4-NRG1 fusion) and breast cancer (V777L HER2 mutation) thus supporting the ongoing clinical development of zongertinib.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153172","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}
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