bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition
Authors: Goodall Jane , Mateo Joaquin , Yuan Wei , Mossop Helen , Porta Nuria , Miranda Susana , Perez-Lopez Raquel , Dolling David , Robinson Dan R. , Sandhu Shahneen , Fowler Gemma , Ebbs Berni , Flohr Penny , Seed George , Rodrigues Daniel Nava , Boysen Gunther , Bertan Claudia , Atkin Mark , Clarke Matthew , Crespo Mateus , Figueiredo Ines , Riisnaes Ruth , Sumanasuriya Semini , Rescigno Pasquale , Zafeiriou Zafeiris , Sharp Adam , Tunariu Nina , Bianchini Diletta , Gillman Alexa , Lord Christopher J. , Hall Emma , Chinnaiyan Arul M. , Carreira Suzanne , de Bono Johann S.
Published: March 2024

Abstract
Biomarkers for more precise patient care are needed in metastatic prostate cancer. We have reported a phase II trial (TOPARP-A) of the PARP inhibitor olaparib in metastatic prostate cancer, demonstrating antitumor activity associating with homologous recombination DNA repair defects. We now report targeted and whole-exome sequencing of serial circulating cell-free DNA (cfDNA) samples collected during this trial. Decreases in cfDNA concentration independently associated with outcome in multivariable analyses (HR for overall survival at week 8: 0.19; 95% CI, 0.06–0.56; P = 0.003). All tumor tissue somatic DNA repair mutations were detectable in cfDNA; allele frequency of somatic mutations decreased selectively in responding patients (χ2 P < 0.001). At disease progression, following response to olaparib, multiple subclonal aberrations reverting germline and somatic DNA repair mutations (BRCA2, PALB2) back in frame emerged as mechanisms of resistance. These data support the role of liquid biopsies as a predictive, prognostic, response, and resistance biomarker in metastatic prostate cancer.

Significance: We report prospectively planned, serial, cfDNA analyses from patients with metastatic prostate cancer treated on an investigator-initiated phase II trial of olaparib. These analyses provide predictive, prognostic, response, and resistance data with “second hit” mutations first detectable at disease progression, suggesting clonal evolution from treatment-selective pressure and platinum resistance. Cancer Discov; 7(9); 1006–17. ©2017 AACR.

See related commentary by Domchek, p. 937.

See related article by Kondrashova et al., p. 984.

See related article by Quigley et al., p. 999.

This article is highlighted in the In This Issue feature, p. 920
Data from CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation
Authors: Deng Jiehui , Wang Eric S. , Jenkins Russell W. , Li Shuai , Dries Ruben , Yates Kathleen , Chhabra Sandeep , Huang Wei , Liu Hongye , Aref Amir R. , Ivanova Elena , Paweletz Cloud P. , Bowden Michaela , Zhou Chensheng W. , Herter-Sprie Grit S. , Sorrentino Jessica A. , Bisi John E. , Lizotte Patrick H. , Merlino Ashley A. , Quinn Max M. , Bufe Lauren E. , Yang Annan , Zhang Yanxi , Zhang Hua , Gao Peng , Chen Ting , Cavanaugh Megan E. , Rode Amanda J. , Haines Eric , Roberts Patrick J. , Strum Jay C. , Richards William G. , Lorch Jochen H. , Parangi Sareh , Gunda Viswanath , Boland Genevieve M. , Bueno Raphael , Palakurthi Sangeetha , Freeman Gordon J. , Ritz Jerome , Haining W. Nicholas , Sharpless Norman E. , Arthanari Haribabu , Shapiro Geoffrey I. , Barbie David A. , Gray Nathanael S. , Wong Kwok-Kin
Published: March 2024

Abstract
Immune checkpoint blockade, exemplified by antibodies targeting the PD-1 receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T-cell activation, contributing to antitumor effects in vivo, due in part to the derepression of NFAT family proteins and their target genes, critical regulators of T-cell function. Although CDK4/6 inhibitors decrease T-cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies.

Significance: Our results define previously unrecognized immunomodulatory functions of CDK4/6 and suggest that combining CDK4/6 inhibitors with immune checkpoint blockade may increase treatment efficacy in patients. Furthermore, our study highlights the critical importance of identifying complementary strategies to improve the efficacy of immunotherapy for patients with cancer. Cancer Discov; 8(2); 216–33. ©2017 AACR.

See related commentary by Balko and Sosman, p. 143.

See related article by Jenkins et al., p. 196.

This article is highlighted in the In This Issue feature, p. 127
Data from Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity
Authors: Patnaik Akash , Swanson Kenneth D. , Csizmadia Eva , Solanki Aniruddh , Landon-Brace Natalie , Gehring Marina P. , Helenius Katja , Olson Brian M. , Pyzer Athalia R. , Wang Lily C. , Elemento Olivier , Novak Jesse , Thornley Thomas B. , Asara John M. , Montaser Laleh , Timmons Joshua J. , Morgan Todd M. , Wang Yugang , Levantini Elena , Clohessy John G. , Kelly Kathleen , Pandolfi Pier Paolo , Rosenblatt Jacalyn M. , Avigan David E. , Ye Huihui , Karp Jeffrey M. , Signoretti Sabina , Balk Steven P. , Cantley Lewis C.
Published: March 2024

Abstract
Several kinase inhibitors that target aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in cancer clinical trial patients across several malignancies. Here, we show that cabozantinib rapidly eradicates invasive, poorly differentiated PTEN/p53-deficient murine prostate cancer. This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutralization or blockade of neutrophil chemotaxis with the CXCR4 inhibitor plerixafor. Collectively, these data demonstrate that cabozantinib triggers a neutrophil-mediated anticancer innate immune response, resulting in tumor clearance.

Significance: This study is the first to demonstrate that a tyrosine kinase inhibitor can activate neutrophil-mediated antitumor innate immunity, resulting in invasive cancer clearance. Cancer Discov; 7(7); 750–65. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 653
Data from An RNA-Based Digital Circulating Tumor Cell Signature Is Predictive of Drug Response and Early Dissemination in Prostate Cancer
Authors: Miyamoto David T. , Lee Richard J. , Kalinich Mark , LiCausi Joseph A. , Zheng Yu , Chen Tianqi , Milner John D. , Emmons Erin , Ho Uyen , Broderick Katherine , Silva Erin , Javaid Sarah , Kwan Tanya Todorova , Hong Xin , Dahl Douglas M. , McGovern Francis J. , Efstathiou Jason A. , Smith Matthew R. , Sequist Lecia V. , Kapur Ravi , Wu Chin-Lee , Stott Shannon L. , Ting David T. , Giobbie-Hurder Anita , Toner Mehmet , Maheswaran Shyamala , Haber Daniel A.
Published: March 2024

Abstract
Blood-based biomarkers are critical in metastatic prostate cancer, where characteristic bone metastases are not readily sampled, and they may enable risk stratification in localized disease. We established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTC) using microfluidic cell enrichment followed by digital quantitation of prostate-derived transcripts. In a prospective study of 27 patients with metastatic castration-resistant prostate cancer treated with first-line abiraterone, pretreatment elevation of the digital CTCM score identifies a high-risk population with poor overall survival (HR = 6.0; P = 0.01) and short radiographic progression-free survival (HR = 3.2; P = 0.046). Expression of HOXB13 in CTCs identifies 6 of 6 patients with ≤12-month survival, with a subset also expressing the ARV7 splice variant. In a second cohort of 34 men with localized prostate cancer, an elevated preoperative CTCL score predicts microscopic dissemination to seminal vesicles and/or lymph nodes (P < 0.001). Thus, digital quantitation of CTC-specific transcripts enables noninvasive monitoring that may guide treatment selection in both metastatic and localized prostate cancer.

Significance: There is an unmet need for biomarkers to guide prostate cancer therapies, for curative treatment of localized cancer and for application of molecularly targeted agents in metastatic disease. Digital quantitation of prostate CTC-derived transcripts in blood specimens is predictive of abiraterone response in metastatic cancer and of early dissemination in localized cancer. Cancer Discov; 8(3); 288–303. ©2018 AACR.

See related commentary by Heitzer and Speicher, p. 269.

This article is highlighted in the In This Issue feature, p. 253
Data from AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations
Authors: Yen Katharine , Travins Jeremy , Wang Fang , David Muriel D. , Artin Erin , Straley Kimberly , Padyana Anil , Gross Stefan , DeLaBarre Byron , Tobin Erica , Chen Yue , Nagaraja Raj , Choe Sung , Jin Lei , Konteatis Zenon , Cianchetta Giovanni , Saunders Jeffrey O. , Salituro Francesco G. , Quivoron Cyril , Opolon Paule , Bawa Olivia , Saada Véronique , Paci Angelo , Broutin Sophie , Bernard Olivier A. , de Botton Stéphane , Marteyn Benoît S. , Pilichowska Monika , Xu YingXia , Fang Cheng , Jiang Fan , Wei Wentao , Jin Shengfang , Silverman Lee , Liu Wei , Yang Hua , Dang Lenny , Dorsch Marion , Penard-Lacronique Virginie , Biller Scott A. , Su Shin-San Michael
Published: March 2024

Abstract
Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate–dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation–positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation–positive advanced hematologic malignancies.

Significance: Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. Cancer Discov; 7(5); 478–93. ©2017 AACR.

See related commentary by Thomas and Majeti, p. 459.

See related article by Shih et al., p. 494.

This article is highlighted in the In This Issue feature, p. 443
Data from VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma
Authors: Yao Xiaosai , Tan Jing , Lim Kevin Junliang , Koh Joanna , Ooi Wen Fong , Li Zhimei , Huang Dachuan , Xing Manjie , Chan Yang Sun , Qu James Zhengzhong , Tay Su Ting , Wijaya Giovani , Lam Yue Ning , Hong Jing Han , Lee-Lim Ai Ping , Guan Peiyong , Ng Michelle Shu Wen , He Cassandra Zhengxuan , Lin Joyce Suling , Nandi Tannistha , Qamra Aditi , Xu Chang , Myint Swe Swe , Davies James O. J. , Goh Jian Yuan , Loh Gary , Tan Bryan C. , Rozen Steven G. , Yu Qiang , Tan Iain Bee Huat , Cheng Christopher Wai Sam , Li Shang , Chang Kenneth Tou En , Tan Puay Hoon , Silver David Lawrence , Lezhava Alexander , Steger Gertrud , Hughes Jim R. , Teh Bin Tean , Tan Patrick
Published: March 2024

Abstract
Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel–Lindau (VHL) tumor suppressor. Roles for noncoding cis-regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profiles, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specific aspects of malignancy. Superenhancer profiling identified ZNF395 as a ccRCC-specific and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo. VHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α–HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter–enhancer interactions. Subtype-specific driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression.

Significance: Comprehensive epigenomic profiling of ccRCC establishes a compendium of somatically altered cis-regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL, a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specific promoter–enhancer complexes. Cancer Discov; 7(11); 1284–305. ©2017 AACR.

See related commentary by Ricketts and Linehan, p. 1221.

This article is highlighted in the In This Issue feature, p. 1201
Data from The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial
Authors: O'Leary Ben , Cutts Rosalind J. , Liu Yuan , Hrebien Sarah , Huang Xin , Fenwick Kerry , André Fabrice , Loibl Sibylle , Loi Sherene , Garcia-Murillas Isaac , Cristofanilli Massimo , Huang Bartlett Cynthia , Turner Nicholas C.
Published: March 2024

Abstract
CDK4/6 inhibition with endocrine therapy is now a standard of care for advanced estrogen receptor–positive breast cancer. Mechanisms of CDK4/6 inhibitor resistance have been described preclinically, with limited evidence from clinical samples. We conducted paired baseline and end-of-treatment circulating tumor DNA sequencing from 195 patients in the PALOMA-3 randomized phase III trial of palbociclib plus fulvestrant versus placebo plus fulvestrant. We show that clonal evolution occurs frequently during treatment, reflecting substantial subclonal complexity in breast cancer that has progressed after prior endocrine therapy. RB1 mutations emerged only in the palbociclib plus fulvestrant arm and in a minority of patients (6/127, 4.7%, P = 0.041). New driver mutations emerged in PIK3CA (P = 0.00069) and ESR1 after treatment in both arms, in particular ESR1 Y537S (P = 0.0037). Evolution of driver gene mutations was uncommon in patients progressing early on palbociclib plus fulvestrant but common in patients progressing later on treatment. These findings inform future treatment strategies to address resistance to palbociclib plus fulvestrant.

Significance: Acquired mutations from fulvestrant are a major driver of resistance to fulvestrant and palbociclib combination therapy. ESR1 Y537S mutation promotes resistance to fulvestrant. Clonal evolution results in frequent acquisition of driver mutations in patients progressing late on therapy, which suggests that early and late progression have distinct mechanisms of resistance. Cancer Discov; 8(11); 1390–403. ©2018 AACR.

See related commentary by Schiff and Jeselsohn, p. 1352.

This article is highlighted in the In This Issue feature, p. 1333
Data from Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma
Authors: Kondrashova Olga , Nguyen Minh , Shield-Artin Kristy , Tinker Anna V. , Teng Nelson N.H. , Harrell Maria I. , Kuiper Michael J. , Ho Gwo-Yaw , Barker Holly , Jasin Maria , Prakash Rohit , Kass Elizabeth M. , Sullivan Meghan R. , Brunette Gregory J. , Bernstein Kara A. , Coleman Robert L. , Floquet Anne , Friedlander Michael , Kichenadasse Ganessan , O'Malley David M. , Oza Amit , Sun James , Robillard Liliane , Maloney Lara , Bowtell David , Giordano Heidi , Wakefield Matthew J. , Kaufmann Scott H. , Simmons Andrew D. , Harding Thomas C. , Raponi Mitch , McNeish Iain A. , Swisher Elizabeth M. , Lin Kevin K. , Scott Clare L.
Published: March 2024

Abstract
High-grade epithelial ovarian carcinomas containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pretreatment and postprogression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase II study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed ovarian carcinoma. In 6 of 12 pretreatment biopsies, a truncation mutation in BRCA1, RAD51C, or RAD51D was identified. In five of six paired postprogression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations.

Significance: Analyses of primary and secondary mutations in RAD51C and RAD51D provide evidence for these primary mutations in conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance. PARPi resistance due to secondary mutations underpins the need for early delivery of PARPi therapy and for combination strategies. Cancer Discov; 7(9); 984–98. ©2017 AACR.

See related commentary by Domchek, p. 937.

See related article by Quigley et al., p. 999.

See related article by Goodall et al., p. 1006.

This article is highlighted in the In This Issue feature, p. 920
Data from Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells
Authors: Shum Thomas , Omer Bilal , Tashiro Haruko , Kruse Robert L. , Wagner Dimitrios L. , Parikh Kathan , Yi Zhongzhen , Sauer Tim , Liu Daofeng , Parihar Robin , Castillo Paul , Liu Hao , Brenner Malcolm K. , Metelitsa Leonid S. , Gottschalk Stephen , Rooney Cliona M.
Published: March 2024

Abstract
Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7R-coexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer.

Significance: The constitutively signaling C7R system developed here delivers potent IL7 stimulation to CAR T cells, increasing their persistence and antitumor activity against multiple preclinical tumor models, supporting its clinical development. Cancer Discov; 7(11); 1238–47. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 1201
Data from Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple-Negative Breast Cancer
Authors: Liu Hui , Murphy Charles J. , Karreth Florian A. , Emdal Kristina B. , White Forest M. , Elemento Olivier , Toker Alex , Wulf Gerburg M. , Cantley Lewis C.
Published: March 2024

Abstract
Triple-negative breast cancers (TNBC) are genetically characterized by aberrations in TP53 and a low rate of activating point mutations in common oncogenes, rendering it challenging in applying targeted therapies. We performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) to identify somatic genetic alterations in mouse models of TNBCs driven by loss of Trp53 alone or in combination with Brca1. Amplifications or translocations that resulted in elevated oncoprotein expression or oncoprotein-containing fusions, respectively, as well as frameshift mutations of tumor suppressors were identified in approximately 50% of the tumors evaluated. Although the spectrum of sporadic genetic alterations was diverse, the majority had in common the ability to activate the MAPK/PI3K pathways. Importantly, we demonstrated that approved or experimental drugs efficiently induce tumor regression specifically in tumors harboring somatic aberrations of the drug target. Our study suggests that the combination of WES and RNA-seq on human TNBC will lead to the identification of actionable therapeutic targets for precision medicine–guided TNBC treatment.

Significance: Using combined WES and RNA-seq analyses, we identified sporadic oncogenic events in TNBC mouse models that share the capacity to activate the MAPK and/or PI3K pathways. Our data support a treatment tailored to the genetics of individual tumors that parallels the approaches being investigated in the ongoing NCI-MATCH, My Pathway Trial, and ESMART clinical trials. Cancer Discov; 8(3); 354–69. ©2017 AACR.

See related commentary by Natrajan et al., p. 272.

See related article by Matissek et al., p. 336.

This article is highlighted in the In This Issue feature, p. 253
Data from FOXF1 Defines the Core-Regulatory Circuitry in Gastrointestinal Stromal Tumor
Authors: Ran Leili , Chen Yuedan , Sher Jessica , Wong Elissa W.P. , Murphy Devan , Zhang Jenny Q. , Li Dan , Deniz Kemal , Sirota Inna , Cao Zhen , Wang Shangqian , Guan Youxin , Shukla Shipra , Li Katie Yang , Chramiec Alan , Xie Yuanyuan , Zheng Deyou , Koche Richard P. , Antonescu Cristina R. , Chen Yu , Chi Ping
Published: March 2024

Abstract
The cellular context that integrates upstream signaling and downstream nuclear response dictates the oncogenic behavior and shapes treatment responses in distinct cancer types. Here, we uncover that in gastrointestinal stromal tumor (GIST), the forkhead family member FOXF1 directly controls the transcription of two master regulators, KIT and ETV1, both required for GIST precursor-interstitial cells of Cajal lineage specification and GIST tumorigenesis. Further, FOXF1 colocalizes with ETV1 at enhancers and functions as a pioneer factor that regulates the ETV1-dependent GIST lineage-specific transcriptome through modulation of the local chromatin context, including chromatin accessibility, enhancer maintenance, and ETV1 binding. Functionally, FOXF1 is required for human GIST cell growth in vitro and murine GIST tumor growth and maintenance in vivo. The simultaneous control of the upstream signaling and nuclear response sets up a unique regulatory paradigm and highlights the critical role of FOXF1 in enforcing the GIST cellular context for highly lineage-restricted clinical behavior and treatment response.

Significance: We uncover that FOXF1 defines the core-regulatory circuitry in GIST through both direct transcriptional regulation and pioneer factor function. The unique and simultaneous control of signaling and transcriptional circuitry by FOXF1 sets up an enforced transcriptional addiction to FOXF1 in GIST, which can be exploited diagnostically and therapeutically. Cancer Discov; 8(2); 234–51. ©2017 AACR.

See related commentary by Lee and Duensing, p. 146.

This article is highlighted in the In This Issue feature, p. 127
Data from Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer
Authors: Zou Min , Toivanen Roxanne , Mitrofanova Antonina , Floch Nicolas , Hayati Sheida , Sun Yanping , Le Magnen Clémentine , Chester Daniel , Mostaghel Elahe A. , Califano Andrea , Rubin Mark A. , Shen Michael M. , Abate-Shen Cory
Published: March 2024

Abstract
Current treatments for castration-resistant prostate cancer (CRPC) that target androgen receptor (AR) signaling improve patient survival, yet ultimately fail. Here, we provide novel insights into treatment response for the antiandrogen abiraterone by analyses of a genetically engineered mouse (GEM) model with combined inactivation of Trp53 and Pten, which are frequently comutated in human CRPC. These NPp53 mice fail to respond to abiraterone and display accelerated progression to tumors resembling treatment-related CRPC with neuroendocrine differentiation (CRPC-NE) in humans. Cross-species computational analyses identify master regulators of adverse response that are conserved with human CRPC-NE, including the neural differentiation factor SOX11, which promotes neuroendocrine differentiation in cells derived from NPp53 tumors. Furthermore, abiraterone-treated NPp53 prostate tumors contain regions of focal and/or overt neuroendocrine differentiation, distinguished by their proliferative potential. Notably, lineage tracing in vivo provides definitive and quantitative evidence that focal and overt neuroendocrine regions arise by transdifferentiation of luminal adenocarcinoma cells. These findings underscore principal roles for TP53 and PTEN inactivation in abiraterone resistance and progression from adenocarcinoma to CRPC-NE by transdifferentiation.

Significance: Understanding adverse treatment response and identifying patients likely to fail treatment represent fundamental clinical challenges. By integrating analyses of GEM models and human clinical data, we provide direct genetic evidence for transdifferentiation as a mechanism of drug resistance as well as for stratifying patients for treatment with antiandrogens. Cancer Discov; 7(7); 736–49. ©2017 AACR.

See related commentary by Sinha and Nelson, p. 673.

This article is highlighted in the In This Issue feature, p. 653
Data from Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism
Authors: Farge Thomas , Saland Estelle , de Toni Fabienne , Aroua Nesrine , Hosseini Mohsen , Perry Robin , Bosc Claudie , Sugita Mayumi , Stuani Lucille , Fraisse Marine , Scotland Sarah , Larrue Clément , Boutzen Héléna , Féliu Virginie , Nicolau-Travers Marie-Laure , Cassant-Sourdy Stéphanie , Broin Nicolas , David Marion , Serhan Nizar , Sarry Audrey , Tavitian Suzanne , Kaoma Tony , Vallar Laurent , Iacovoni Jason , Linares Laetitia K. , Montersino Camille , Castellano Rémy , Griessinger Emmanuel , Collette Yves , Duchamp Olivier , Barreira Yara , Hirsch Pierre , Palama Tony , Gales Lara , Delhommeau François , Garmy-Susini Barbara H. , Portais Jean-Charles , Vergez François , Selak Mary , Danet-Desnoyers Gwenn , Carroll Martin , Récher Christian , Sarry Jean-Emmanuel
Published: March 2024

Abstract
Chemotherapy-resistant human acute myeloid leukemia (AML) cells are thought to be enriched in quiescent immature leukemic stem cells (LSC). To validate this hypothesis in vivo, we developed a clinically relevant chemotherapeutic approach treating patient-derived xenografts (PDX) with cytarabine (AraC). AraC residual AML cells are enriched in neither immature, quiescent cells nor LSCs. Strikingly, AraC-resistant preexisting and persisting cells displayed high levels of reactive oxygen species, showed increased mitochondrial mass, and retained active polarized mitochondria, consistent with a high oxidative phosphorylation (OXPHOS) status. AraC residual cells exhibited increased fatty-acid oxidation, upregulated CD36 expression, and a high OXPHOS gene signature predictive for treatment response in PDX and patients with AML. High OXPHOS but not low OXPHOS human AML cell lines were chemoresistant in vivo. Targeting mitochondrial protein synthesis, electron transfer, or fatty-acid oxidation induced an energetic shift toward low OXPHOS and markedly enhanced antileukemic effects of AraC. Together, this study demonstrates that essential mitochondrial functions contribute to AraC resistance in AML and are a robust hallmark of AraC sensitivity and a promising therapeutic avenue to treat AML residual disease.

Significance: AraC-resistant AML cells exhibit metabolic features and gene signatures consistent with a high OXPHOS status. In these cells, targeting mitochondrial metabolism through the CD36–FAO–OXPHOS axis induces an energetic shift toward low OXPHOS and strongly enhanced antileukemic effects of AraC, offering a promising avenue to design new therapeutic strategies and fight AraC resistance in AML. Cancer Discov; 7(7); 716–35. ©2017 AACR.

See related commentary by Schimmer, p. 670.

This article is highlighted in the In This Issue feature, p. 653
Data from Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers
Authors: Pearce Oliver M.T. , Delaine-Smith Robin M. , Maniati Eleni , Nichols Sam , Wang Jun , Böhm Steffen , Rajeeve Vinothini , Ullah Dayem , Chakravarty Probir , Jones Roanne R. , Montfort Anne , Dowe Tom , Gribben John , Jones J. Louise , Kocher Hemant M. , Serody Jonathan S. , Vincent Benjamin G. , Connelly John , Brenton James D. , Chelala Claude , Cutillas Pedro R. , Lockley Michelle , Bessant Conrad , Knight Martin M. , Balkwill Frances R.
Published: March 2024

Abstract
We have profiled, for the first time, an evolving human metastatic microenvironment by measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, extracellular matrix organization, and biomechanical properties, all on the same sample. Using biopsies of high-grade serous ovarian cancer metastases that ranged from minimal to extensive disease, we show how nonmalignant cell densities and cytokine networks evolve with disease progression. Multivariate integration of the different components allowed us to define, for the first time, gene and protein profiles that predict extent of disease and tissue stiffness, while also revealing the complexity and dynamic nature of matrisome remodeling during development of metastases. Although we studied a single metastatic site from one human malignancy, a pattern of expression of 22 matrisome genes distinguished patients with a shorter overall survival in ovarian and 12 other primary solid cancers, suggesting that there may be a common matrix response to human cancer.

Significance: Conducting multilevel analysis with data integration on biopsies with a range of disease involvement identifies important features of the evolving tumor microenvironment. The data suggest that despite the large spectrum of genomic alterations, some human malignancies may have a common and potentially targetable matrix response that influences the course of disease. Cancer Discov; 8(3); 304–19. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 253
Data from TCR Repertoire Intratumor Heterogeneity in Localized Lung Adenocarcinomas: An Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence
Authors: Reuben Alexandre , Gittelman Rachel , Gao Jianjun , Zhang Jiexin , Yusko Erik C. , Wu Chang-Jiun , Emerson Ryan , Zhang Jianhua , Tipton Christopher , Li Jun , Quek Kelly , Gopalakrishnan Vancheswaran , Chen Runzhe , Vence Luis M. , Cascone Tina , Vignali Marissa , Fujimoto Junya , Rodriguez-Canales Jaime , Parra Edwin R. , Little Latasha D. , Gumbs Curtis , Forget Marie-Andrée , Federico Lorenzo , Haymaker Cara , Behrens Carmen , Benzeno Sharon , Bernatchez Chantale , Sepesi Boris , Gibbons Don L. , Wargo Jennifer A. , William William N. , Swisher Stephen , Heymach John V. , Robins Harlan , Lee J. Jack , Sharma Padmanee , Allison James P. , Futreal P. Andrew , Wistuba Ignacio I. , Zhang Jianjun
Published: March 2024

Abstract
Genomic intratumor heterogeneity (ITH) may be associated with postsurgical relapse of localized lung adenocarcinomas. Recently, mutations, through generation of neoantigens, were shown to alter tumor immunogenicity through T-cell responses. Here, we performed sequencing of the T-cell receptor (TCR) in 45 tumor regions from 11 localized lung adenocarcinomas and observed substantial intratumor differences in T-cell density and clonality with the majority of T-cell clones restricted to individual tumor regions. TCR ITH positively correlated with predicted neoantigen ITH, suggesting that spatial differences in the T-cell repertoire may be driven by distinct neoantigens in different tumor regions. Finally, a higher degree of TCR ITH was associated with an increased risk of postsurgical relapse and shorter disease-free survival, suggesting a potential clinical significance of T-cell repertoire heterogeneity.

Significance: The present study provides insights into the ITH of the T-cell repertoire in localized lung adenocarcinomas and its potential biological and clinical impact. The results suggest that T-cell repertoire ITH may be tightly associated to genomic ITH and disease relapse. Cancer Discov; 7(10); 1088–97. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 1047
Data from Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade
Authors: Gu Yi-Feng , Cohn Shannon , Christie Alana , McKenzie Tiffani , Wolff Nicholas , Do Quyen N. , Madhuranthakam Ananth J. , Pedrosa Ivan , Wang Tao , Dey Anwesha , Busslinger Meinrad , Xie Xian-Jin , Hammer Robert E. , McKay Renée M. , Kapur Payal , Brugarolas James
Published: March 2024

Abstract
Clear cell renal cell carcinoma (ccRCC) is characterized by BAP1 and PBRM1 mutations, which are associated with tumors of different grade and prognosis. However, whether BAP1 and PBRM1 loss causes ccRCC and determines tumor grade is unclear. We conditionally targeted Bap1 and Pbrm1 (with Vhl) in the mouse using several Cre drivers. Sglt2 and Villin proximal convoluted tubule drivers failed to cause tumorigenesis, challenging the conventional notion of ccRCC origins. In contrast, targeting with PAX8, a transcription factor frequently overexpressed in ccRCC, led to ccRCC of different grades. Bap1-deficient tumors were of high grade and showed greater mTORC1 activation than Pbrm1-deficient tumors, which exhibited longer latency. Disrupting one allele of the mTORC1 negative regulator, Tsc1, in Pbrm1-deficient kidneys triggered higher grade ccRCC. This study establishes Bap1 and Pbrm1 as lineage-specific drivers of ccRCC and histologic grade, implicates mTORC1 as a tumor grade rheostat, and suggests that ccRCCs arise from Bowman capsule cells.

Significance: Determinants of tumor grade and aggressiveness across cancer types are poorly understood. Using ccRCC as a model, we show that Bap1 and Pbrm1 loss drives tumor grade. Furthermore, we show that the conversion from low grade to high grade can be promoted by activation of mTORC1. Cancer Discov; 7(8); 900–17. ©2017 AACR.

See related commentary by Leung and Kim, p. 802.

This article is highlighted in the In This Issue feature, p. 783
Data from CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade
Authors: Chen Limo , Diao Lixia , Yang Yongbin , Yi Xiaohui , Rodriguez B. Leticia , Li Yanli , Villalobos Pamela A. , Cascone Tina , Liu Xi , Tan Lin , Lorenzi Philip L. , Huang Anfei , Zhao Qiang , Peng Di , Fradette Jared J. , Peng David H. , Ungewiss Christin , Roybal Jonathon , Tong Pan , Oba Junna , Skoulidis Ferdinandos , Peng Weiyi , Carter Brett W. , Gay Carl M. , Fan Youhong , Class Caleb A. , Zhu Jingfen , Rodriguez-Canales Jaime , Kawakami Masanori , Byers Lauren Averett , Woodman Scott E. , Papadimitrakopoulou Vassiliki A. , Dmitrovsky Ethan , Wang Jing , Ullrich Stephen E. , Wistuba Ignacio I. , Heymach John V. , Qin F. Xiao-Feng , Gibbons Don L.
Published: March 2024

Abstract
Although treatment with immune checkpoint inhibitors provides promising benefit for patients with cancer, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the upregulation of CD38, which is induced by all-trans retinoic acid and IFNβ in the tumor microenvironment. In vitro and in vivo studies demonstrate that CD38 inhibits CD8+ T-cell function via adenosine receptor signaling and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large data sets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T-cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment.

Significance: CD38 is a major mechanism of acquired resistance to PD-1/PD-L1 blockade, causing CD8+ T-cell suppression. Coinhibition of CD38 and PD-L1 improves antitumor immune response. Biomarker assessment in patient cohorts suggests that a combination strategy is applicable to a large percentage of patients in whom PD-1/PD-L1 blockade is currently indicated. Cancer Discov; 8(9); 1156–75. ©2018 AACR.

See related commentary by Mittal et al., p. 1066.

This article is highlighted in the In This Issue feature, p. 1047
Data from MYC Is Activated by USP2a-Mediated Modulation of MicroRNAs in Prostate Cancer
Authors: Benassi Barbara , Flavin Richard , Marchionni Luigi , Zanata Silvio , Pan Yunfeng , Chowdhury Dipanjan , Marani Marina , Strano Sabrina , Muti Paola , Blandino Giovanni , Loda Massimo
Published: March 2024

Abstract
Ubiquitin-specific protease 2a (USP2a) is overexpressed in almost half of human prostate cancers and c-Myc is amplified in one third of these tumor types. Transgenic MYC expression drives invasive adenocarcinomas in the murine prostate. We show that overexpression of USP2a downregulates a set of microRNAs that collectively increase MYC levels by MDM2 deubiquitination and subsequent p53 inactivation. By establishing MYC as a target of miR-34b/c, we demonstrate that this cluster functions as a tumor suppressor in prostate cancer cells. We identify a distinct mRNA signature that is enriched for MYC-regulated transcripts and transcription factor binding sites in USP2a overexpressing prostate cancer cells. We demonstrate that these genes are associated with an invasive phenotype in human prostate cancer and that the proliferative and invasive properties of USP2a overexpressing cells are MYC-dependent. These results highlight an unrecognized mechanism of MYC regulation in prostate cancer and suggest alternative therapeutic strategies in targeting MYC.

Significance: The deubiquitinating enzyme USP2a has previously been shown to be oncogenic, overexpressed in almost half of human prostate adenocarcinomas, and prolongs the half-life of targets such as fatty acid synthase, MDM2, and cyclin D1. Here, we highlight a new mechanism by which USP2a enhances MYC levels through the modulation of specific subsets of microRNAs in prostate cancer, suggesting alternative therapeutic strategies for targeting MYC. Cancer Discovery; 2(3); 236–47. ©2012 AACR.

Read the Commentary on this article by Nelson et al., p. 206

This article is highlighted in the In This Issue feature, p. 193
Data from A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles
Authors: Rebecca Vito W. , Nicastri Michael C. , McLaughlin Noel , Fennelly Colin , McAfee Quentin , Ronghe Amruta , Nofal Michel , Lim Chun-Yan , Witze Eric , Chude Cynthia I. , Zhang Gao , Alicea Gretchen M. , Piao Shengfu , Murugan Sengottuvelan , Ojha Rani , Levi Samuel M. , Wei Zhi , Barber-Rotenberg Julie S. , Murphy Maureen E. , Mills Gordon B. , Lu Yiling , Rabinowitz Joshua , Marmorstein Ronen , Liu Qin , Liu Shujing , Xu Xiaowei , Herlyn Meenhard , Zoncu Roberto , Brady Donita C. , Speicher David W. , Winkler Jeffrey D. , Amaravadi Ravi K.
Published: March 2024

Abstract
Lysosomes serve dual roles in cancer metabolism, executing catabolic programs (i.e., autophagy and macropinocytosis) while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQ) as potent anticancer compounds, which concurrently inhibit mTOR and autophagy. Central nitrogen methylation of the DQ linker enhances lysosomal localization and potency. An in situ photoaffinity pulldown identified palmitoyl-protein thioesterase 1 (PPT1) as the molecular target of DQ661. PPT1 inhibition concurrently impairs mTOR and lysosomal catabolism through the rapid accumulation of palmitoylated proteins. DQ661 inhibits the in vivo tumor growth of melanoma, pancreatic cancer, and colorectal cancer mouse models and can be safely combined with chemotherapy. Thus, lysosome-directed PPT1 inhibitors represent a new approach to concurrently targeting mTORC1 and lysosomal catabolism in cancer.

Significance: This study identifies chemical features of dimeric compounds that increase their lysosomal specificity, and a new molecular target for these compounds, reclassifying these compounds as targeted therapies. Targeting PPT1 blocks mTOR signaling in a manner distinct from catalytic inhibitors, while concurrently inhibiting autophagy, thereby providing a new strategy for cancer therapy. Cancer Discov; 7(11); 1266–83. ©2017 AACR.

See related commentary by Towers and Thorburn, p. 1218.

This article is highlighted in the In This Issue feature, p. 1201
Data from Age-Related Changes in HAPLN1 Increase Lymphatic Permeability and Affect Routes of Melanoma Metastasis
Authors: Ecker Brett L. , Kaur Amanpreet , Douglass Stephen M. , Webster Marie R. , Almeida Filipe V. , Marino Gloria E. , Sinnamon Andrew J. , Neuwirth Madalyn G. , Alicea Gretchen M. , Ndoye Abibatou , Fane Mitchell , Xu Xiaowei , Sim Myung Shin , Deutsch Gary B. , Faries Mark B. , Karakousis Giorgos C. , Weeraratna Ashani T.
Published: March 2024

Abstract
Older patients with melanoma have lower rates of sentinel lymph node (LN) metastases yet paradoxically have inferior survival. Patient age correlated with an inability to retain Technetium radiotracer during sentinel LN biopsy in more than 1,000 patients, and high Technetium counts correlated to better survival. We hypothesized that loss of integrity in the lymphatic vasculature due to extracellular matrix (ECM) degradation might play a role. We have implicated HAPLN1 in age-dependent ECM degradation in the dermis. Here, we queried whether HAPLN1 could be altered in the lymphatic ECM. Lymphatic HAPLN1 expression was prognostic of long-term patient survival. Adding recombinant HAPLN1 to aged fibroblast ECMs in vitro reduced endothelial permeability via modulation of VE-cadherin junctions, whereas endothelial permeability was increased following HAPLN1 knockdown in young fibroblasts. In vivo, reconstitution of HAPLN1 in aged mice increased the number of LN metastases, but reduced visceral metastases. These data suggest that age-related changes in ECM can contribute to impaired lymphatics.
Significance:
Our studies reveal that changes in the stroma during aging may influence the way tumor cells traffic through the lymphatic vasculature. Aging may dictate the route of metastatic dissemination of tumor cells, and understanding these changes may help to reveal targetable moieties in the aging tumor microenvironment.

See related commentary by Marie and Merlino, p. 19.

This article is highlighted in the In This Issue feature, p. 1
Data from Clinical and Biological Correlates of Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia
Authors: Santomasso Bianca D. , Park Jae H. , Salloum Darin , Riviere Isabelle , Flynn Jessica , Mead Elena , Halton Elizabeth , Wang Xiuyan , Senechal Brigitte , Purdon Terence , Cross Justin R. , Liu Hui , Vachha Behroze , Chen Xi , DeAngelis Lisa M. , Li Daniel , Bernal Yvette , Gonen Mithat , Wendel Hans-Guido , Sadelain Michel , Brentjens Renier J.
Published: March 2024

Abstract
CD19-specific chimeric antigen receptor (CAR) T-cell therapy is highly effective against relapsed or refractory acute lymphoblastic leukemia (ALL), but is hindered by neurotoxicity. In 53 adult patients with ALL, we found a significant association of severe neurotoxicity with high pretreatment disease burden, higher peak CAR T-cell expansion, and early and higher elevations of proinflammatory cytokines in blood. Patients with severe neurotoxicity had evidence of blood–cerebrospinal fluid (CSF) barrier disruption correlating with neurotoxicity grade without association with CSF white blood cell count or CAR T-cell quantity in CSF. Proinflammatory cytokines were enriched in CSF during severe neurotoxicity with disproportionately high levels of IL6, IL8, MCP1, and IP10, suggesting central nervous system–specific production. Seizures, seizure-like activity, myoclonus, and neuroimaging characteristics suggested excitatory neurotoxicity, and we found elevated levels of endogenous excitatory agonists in CSF during neurotoxicity.

Significance: We detail the neurologic symptoms and blood, CSF, and neuroimaging correlates of neurotoxicity associated with CD19 CAR T cells and identify neurotoxicity risk factors. Our findings implicate cellular components other than T cells and suggest novel links between systemic inflammation and characteristic neurotoxicity symptoms. Cancer Discov; 8(8); 958–71. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 899