LKB1–Salt-Inducible Kinase Signaling Is Essential in MEF2C+ Leukemia Cancer Discov. (IF 20.011) Pub Date : 2018-03-16 American Association for Cancer Research
MEF2C activity in acute myeloid leukemia is dependent upon salt-inducible kinase (SIK) signaling.
The Kyn–AhR Pathway Upregulates PD-1 to Promote Tumor Immune Escape Cancer Discov. (IF 20.011) Pub Date : 2018-03-16 American Association for Cancer Research
Tumor-repopulating cells release Kyn, which activates AhR on T cells to promote PD-1 upregulation.
Group 3 Medulloblastomas Require a Photoreceptor Transcriptional Program Cancer Discov. (IF 20.011) Pub Date : 2018-03-16 American Association for Cancer Research
NRL and CRX are master regulators of the photoreceptor-specific differentiation program.
A Paralog-Selective Inhibitor May Allow for Targeting of GSK3α in AML Cancer Discov. (IF 20.011) Pub Date : 2018-03-16 American Association for Cancer Research
The GSK3α-selective inhibitor BRD0705 promotes AML cell differentiation without increasing β-catenin.
Tissue-Specific Immunoregulation: A Call for Better Understanding of the “Immunostat” in the Context of Cancer Cancer Discov. (IF 20.011) Pub Date : 2018-03-15 William Pao; Chia-Huey Ooi; Fabian Birzele; Astrid Ruefli-Brasse; Michael A. Cannarile; Bernhard Reis; Sebastian H. Scharf; David A. Schubert; Klas Hatje; Nadege Pelletier; Olivia Spleiss; John C. Reed
Checkpoint inhibitor therapy has been a breakthrough in cancer research, but only some patients with cancer derive substantial benefit. Although mechanisms underlying sensitivity and resistance to checkpoint inhibitors are being elucidated, the importance of organ-specific regulation of immunity is currently underappreciated. Here, we call for a greater understanding of tissue-specific immunoregulation, namely, “tissue-specific immunostats,” to make advances in treatments for cancer. A better understanding of how individual organs at baseline regulate the immune system could enable an improved precision medicine approach to cancer immunotherapy. Cancer Discov; 8(4); 1–8. ©2018 AACR.
Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAF V600E-Mutant Colorectal Cancer Cancer Discov. (IF 20.011) Pub Date : 2018-03-15 Ryan B. Corcoran; Thierry André; Chloe E. Atreya; Jan H.M. Schellens; Takayuki Yoshino; Johanna C. Bendell; Antoine Hollebecque; Autumn J. McRee; Salvatore Siena; Gary Middleton; Kei Muro; Michael S. Gordon; Josep Tabernero; Rona Yaeger; Peter J. O'Dwyer; Yves Humblet; Filip De Vos; A. Scott Jung; Jan C. Brase; Savina Jaeger; Severine Bettinger; Bijoyesh Mookerjee; Fatima Rangwala; Eric Van Cutsem
Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism. SIGNIFICANCE: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 1–16. ©2018 AACR. See related commentary by Janku, p. 389.
Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer Cancer Discov. (IF 20.011) Pub Date : 2018-03-15 Matti Annala; Gillian Vandekerkhove; Daniel Khalaf; Sinja Taavitsainen; Kevin Beja; Evan W. Warner; Katherine Sunderland; Christian Kollmannsberger; Bernhard J. Eigl; Daygen Finch; Conrad D. Oja; Joanna Vergidis; Muhammad Zulfiqar; Arun A. Azad; Matti Nykter; Martin E. Gleave; Alexander W. Wyatt; Kim N. Chi
Primary resistance to androgen receptor (AR)–directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers. SIGNIFICANCE: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice. Cancer Discov; 8(4); 1–14. ©2018 AACR. See related commentary by Jayaram et al., p. 392.
MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia Cancer Discov. (IF 20.011) Pub Date : 2018-03-15 Fiona C. Brown; Eric Still; Richard P. Koche; Christina Y. Yim; Sumiko Takao; Paolo Cifani; Casie Reed; Shehana Gunasekera; Scott B. Ficarro; Peter Romanienko; Willie Mark; Craig McCarthy; Elisa de Stanchina; Mithat Gonen; Venkatraman Seshan; Patrick Bhola; Conor O'Donnell; Barbara Spitzer; Crystal Stutzke; Vincent-Philippe Lavallée; Josée Hébert; Andrei V. Krivtsov; Ari Melnick; Elisabeth M. Paietta; Martin S. Tallman; Anthony Letai; Guy Sauvageau; Gayle Pouliot; Ross Levine; Jarrod A Marto; Scott A. Armstrong; Alex Kentsis
In acute myeloid leukemia (AML), chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that Mef2cS222A/S222A knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL–AF9. MEF2C phosphorylation was required for leukemia stem cell maintenance and induced by MARK kinases in cells. Treatment with the selective MARK/SIK inhibitor MRT199665 caused apoptosis and conferred chemosensitivity in MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C phosphorylation. These findings identify kinase-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease. SIGNIFICANCE: Functional proteomics identifies phosphorylation of MEF2C in the majority of primary chemotherapy-resistant AML. Kinase-dependent dysregulation of this transcription factor confers susceptibility to MARK/SIK kinase inhibition in preclinical models, substantiating its clinical investigation for improved diagnosis and therapy of AML. Cancer Discov; 8(4); 1–20. ©2018 AACR.
Convergent Therapeutic Strategies to Overcome the Heterogeneity of Acquired Resistance in BRAF V600E Colorectal Cancer Cancer Discov. (IF 20.011) Pub Date : 2018-03-15 Mehlika Hazar-Rethinam; Marianna Kleyman; G. Celine Han; David Liu; Leanne G. Ahronian; Heather A. Shahzade; Lifeng Chen; Aparna R. Parikh; Jill N. Allen; Jeffrey W. Clark; Eunice L. Kwak; Jason E. Faris; Janet E. Murphy; Theodore S. Hong; Emily E. Van Seventer; Brandon Nadres; Catriona B. Hong; Joseph M. Gurski; Nicholas A. Jessop; Dora Dias-Santagata; A. John Iafrate; Eliezer M. Van Allen; Ryan B. Corcoran
Clonal heterogeneity associated with acquired resistance presents a critical therapeutic challenge. Whole-exome sequencing of paired tumor biopsies and targeted sequencing of cell-free DNA (cfDNA) from patients with BRAFV600E colorectal cancer receiving BRAF inhibitor combinations identified 14 distinct alterations in MAPK pathway components driving acquired resistance, with as many as eight alterations in a single patient. We developed a pooled clone system to study clonal outgrowth during acquired resistance, in vitro and in vivo. In vitro, the dynamics of individual resistant clones could be monitored in real time in cfDNA isolated from culture media during therapy. Outgrowth of multiple resistant clones was observed during therapy with BRAF, EGFR, and MEK inhibitor combinations. However, ERK inhibition, particularly in combination with BRAF and EGFR inhibition, markedly abrogated clonal outgrowth in vitro and in vivo. Thus, convergent, up-front therapy may suppress outgrowth of heterogeneous clones harboring clinically observed resistance alterations, which may improve clinical outcome. SIGNIFICANCE: We observed heterogeneous, recurrent alterations in the MAPK pathway as key drivers of acquired resistance in BRAFV600E colorectal cancer, with multiple concurrent resistance alterations detectable in individual patients. Using a novel pooled clone system, we identify convergent up-front therapeutic strategies capable of intercepting multiple resistance mechanisms as potential approaches to suppress emergence of acquired resistance. Cancer Discov; 8(4); 1–11. ©2018 AACR. See related commentary by Janku, p. 389.
A Patient-Driven Model for Cancer Research Cancer Discov. (IF 20.011) Pub Date : 2018-03-14 American Association for Cancer Research
The Metastatic Prostate Cancer Project aims to gather genomic and phenotypic data from large numbers of men with prostate cancer, creating a database that scientists can use in their own research efforts. Any man with advanced disease who wants to participate may do so.
Direct-to-Consumer Test for BRCA Mutations Authorized Cancer Discov. (IF 20.011) Pub Date : 2018-03-14 American Association for Cancer Research
The FDA authorized 23andMe to market the first direct-to-consumer test to check for three BRCA1/2 mutations associated with a higher risk of developing breast, ovarian, and prostate cancers. The mutations are most commonly found in about 2% of women of Ashkenazi Jewish descent.
CSPG4 Shows Promise for Glioblastoma CAR T Therapy Cancer Discov. (IF 20.011) Pub Date : 2018-03-14 American Association for Cancer Research
CAR T cells directed against CSPG4 limit the growth of brain tumors in cultured neurospheres and glioma xenograft mouse models, with no signs of immune escape owing to loss of antigen expression.
BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor Cancer Discov. (IF 20.011) Pub Date : 2018-03-14 Hatice Gulcin Ozer; Dalia El-Gamal; Ben Powell; Zachary A. Hing; James S. Blachly; Bonnie Harrington; Shaneice Mitchell; Nicole R. Grieselhuber; Katie Williams; Tzung-Huei Lai; Lapo Alinari; Robert A. Baiocchi; Lindsey Brinton; Elizabeth Baskin; Matthew Cannon; Larry Beaver; Virginia M. Goettl; David M. Lucas; Jennifer A. Woyach; Deepa Sampath; Amy M. Lehman; Lianbo Yu; Jiazhong Zhang; Yan Ma; Ying Zhang; Wayne Spevak; Songyuan Shi; Paul Severson; Rafe Shellooe; Heidi Carias; Garson Tsang; Ken Dong; Todd Ewing; Adhirai Marimuthu; Christina Tantoy; Jason Walters; Laura Sanftner; Hamid Rezaei; Marika Nespi; Bernice Matusow; Gaston Habets; Prabha Ibrahim; Chao Zhang; Ewy A. Mathé; Gideon Bollag; John C. Byrd; Rosa Lapalombella
Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers. SIGNIFICANCE: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 1–20. ©2018 AACR.
Organoids May Point to Best Therapy Cancer Discov. (IF 20.011) Pub Date : 2018-03-13 American Association for Cancer Research
In a recent study, organoids derived from the metastatic tumors of patients with gastrointestinal cancers had a similar response to treatment as the original tumors. Eventually, organoids could become a useful tool for identifying the most effective therapy for each patient.
New Insights into Genomics of Pediatric Cancers Cancer Discov. (IF 20.011) Pub Date : 2018-03-12 American Association for Cancer Research
Two large studies show that the genetic events driving pediatric cancers are different from those underlying adult cancers. These findings may prove useful for identifying new treatments for childhood cancers, as well as for developing tests to aid in diagnosis and the selection of therapy.
METTL3 Increases m6A to Block Differentiation and Promote Leukemogenesis Cancer Discov. (IF 20.011) Pub Date : 2017-10-06 American Association for Cancer Research
METTL3 is upregulated in acute myeloid leukemia compared with other tumors and normal HSPCs.
SHP2 Inhibition May Resensitize NSCLC Tumors to ALK Inhibitors Cancer Discov. (IF 20.011) Pub Date : 2018-03-09 American Association for Cancer Research
Targeting SHP2 suppresses ALK inhibitor resistance caused by tyrosine kinase reactivation.
Engineered IL2/IL2Rβ Pairs May Enhance the Efficacy of T-cell Therapy Cancer Discov. (IF 20.011) Pub Date : 2018-03-09 American Association for Cancer Research
Orthogonal IL2/IL2Rβ pairs allow selective targeting of engineered autologously transferred T cells.
DNA Damage Response Alterations Predict Responses to Anti–PD-1/PD-L1 Cancer Discov. (IF 20.011) Pub Date : 2018-03-09 American Association for Cancer Research
DNA damage response alterations are linked to improved responses to anti–PD-1/PD-L1 in urothelial carcinoma.
SS18–SSX Induces the Expression of Neurogenic Genes to Drive Synovial Sarcoma Cancer Discov. (IF 20.011) Pub Date : 2018-03-09 American Association for Cancer Research
SS18–SSX usurps the PRC1.1 repressive complex to drive expression of a synovial sarcoma gene signature.
Kite, Sangamo Partner on Gene-Edited Cell Therapies Cancer Discov. (IF 20.011) Pub Date : 2018-03-06 American Association for Cancer Research
Kite and Sangamo signed a deal worth potentially more than $3 billion to jointly develop cellular immunotherapies using zinc finger nuclease gene-editing technologies.
Cross-cohort analysis identifies a TEAD4 ↔ MYCN positive-feedback loop as the core regulatory element of high-risk neuroblastoma Cancer Discov. (IF 20.011) Pub Date : 2018-03-06 Presha Rajbhandari; Gonzalo Lopez; Claudia Capdevila; Beatrice Salvatori; Jiyang Yu; Ruth Rodriguez-Barrueco; Daniel Martinez; Mark Yarmarkovich; Nina Weichert-Leahey; Brian J. Abraham; Mariano J. Alvarez; Archana Iyer; Jo Lynne Harenza; Derek Oldridge; Katleen De Preter; Jan Koster; Shahab Asgharzadeh; Robert C. Seeger; Jun S. Wei; Javed Khan; Jo Vandesompele; Pieter Mestdagh; Rogier Versteeg; A. Thomas Look; Richard A. Young; Antonio Iavarone; Anna Lasorella; Jose M. Silva; John M. Maris; Andrea Califano
High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator (MR) proteins that were conserved across independent cohorts. A 10 protein transcriptional module - centered around a TEAD4 ↔ MYCN positive-feedback loop - emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCNAmp) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo. Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional co-activators, YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN deregulated neuroblastomas.
Genetic mechanisms of immune evasion in colorectal cancer Cancer Discov. (IF 20.011) Pub Date : 2018-03-06 Catherine S. Grasso; Marios Giannakis; Daniel K. Wells; Tsuyoshi Hamada; Xinmeng Jasmine Mu; Michael Quist; Jonathan A. Nowak; Reiko Nishihara; Zhi Rong Qian; Kentaro Inamura; Teppei Morikawa; Katsuhiko Nosho; Gabriel Abril-Rodriguez; Charles Connolly; Helena Escuin-Ordinas; Milan S. Geybels; William M. Grady; Li Hsu; Siwen Hu-Lieskovan; Jeroen R. Huyghe; Yeon Joo Kim; Paige E. Krystofinski; Mark DM Leiserson; Dennis J. Montoya; Brian B. Nadel; Matteo Pellegrini; Colin C. Pritchard; Cristina Puig-Saus; Elleanor H. Quist; Benjamin J. Raphael; Stephen J. Salipante; Daniel Sanghoon Shin; Eve Shinbrot; Brian Shirts; Sachet Shukla; Janet L. Stanford; Wei Sun; Jennifer Tsoi; Alexander Upfill-Brown; David A. Wheeler; Catherine J. Wu; Ming Yu; Syed H. Zaidi; Jesse M. Zaretsky; Stacey B. Gabriel; Eric S Lander; Levi A. Garraway; Thomas J. Hudson; Charles S. Fuchs; Antoni Ribas; Shuji Ogino; Ulrike Peters
To understand the genetic drivers of immune recognition and evasion in colorectal cancer (CRC), we analyzed 1,211 CRC primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas CRC cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of CRC, had a high rate of significantly mutated genes in important immune modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy number alterations and copy-neutral loss of heterozygosity (CN-LOH). WNT/β-catenin signaling genes were significantly mutated in all CRC subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of CRC demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration, and furthermore, that CRC tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.
Colorectal tumors require NUAK1 for protection from oxidative stress Cancer Discov. (IF 20.011) Pub Date : 2018-03-02 Jennifer L. F. Port; Nathiya Muthalagu; Meera Raja; Fatih Ceteci; Tiziana Monteverde; Bjorn Kruspig; Ann Hedley; Gabriela Kalna; Sergio Lilla; Lisa Neilson; Martina Brucoli; Katarina Gyuraszova; Jacqueline Tait-Mulder; Mokdad Mezna; Silvija Svambaryte; Amy Bryson; David Sumpton; Allan McVie; Colin Nixon; Martin Drysdale; Hiroyasu Esumi; Graeme I. Murray; Owen J. Sansom; Sara Zanivan; Daniel J. Murphy
Exploiting oxidative stress has recently emerged as a plausible strategy for treatment of human Cancer and anti-oxidant defences are implicated in resistance to chemo- and radiotherapy. Targeted suppression of anti-oxidant defences could thus broadly improve therapeutic outcomes. Here we identify the AMPK-related kinase NUAK1 as a key component of the anti-oxidant stress response pathway and reveal a specific requirement for this role of NUAK1 in colorectal cancer. We show that NUAK1 is activated by oxidative stress and that this activation is required to facilitate nuclear import of the anti-oxidant master regulator NRF2: Activation of NUAK1 coordinates PP1β inhibition with AKT activation in order to suppress GSK3β-dependent inhibition of NRF2 nuclear import. Deletion of NUAK1 suppresses formation of colorectal tumors, while acute depletion of NUAK1 induces regression of pre-existing autochthonous tumors. Importantly, elevated expression of NUAK1 in human colorectal cancer is associated with more aggressive disease and reduced overall survival.
A Small-Molecule Splicing Modulator Targets Spliceosome-Mutant Cells Cancer Discov. (IF 20.011) Pub Date : 2018-03-02 American Association for Cancer Research
The small molecule H3B-8800 binds to and modulates the SF3b complex to kill spliceosome-mutant cells.
SETD1A Interacts with Cyclin K to Promote Leukemia Cell Survival Cancer Discov. (IF 20.011) Pub Date : 2018-03-02 American Association for Cancer Research
SETD1A enhances leukemic cell growth and survival independent of its methyltransferase activity.
Umbralisib Inhibits PI3Kδ with Less Toxicity Than Previous Inhibitors Cancer Discov. (IF 20.011) Pub Date : 2018-03-02 American Association for Cancer Research
Umbralisib is well tolerated and has activity against relapsed or refractory hematologic cancers.
Medulloblastoma Circulating Tumor Cells Form Leptomeningeal Metastases Cancer Discov. (IF 20.011) Pub Date : 2018-03-02 American Association for Cancer Research
NCAM+CD45+ medulloblastoma cells were shown to be medulloblastoma circulating tumor cells (CTC).
Oncogenes Induce Replication Stress via Intragenic Replication Origins Cancer Discov. (IF 20.011) Pub Date : 2018-03-02 American Association for Cancer Research
Oncogenes induce premature S phase, resulting in replication–transcription conflicts and replication stress.
In This Issue Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
See article, p. 276 Autophagy is increased in pancreatic ductal adenocarcinoma (PDAC) and supports tumor growth. However, the mechanisms by which autophagy promotes tumorigenesis have not been fully elucidated, and mouse models to investigate these mechanisms are lacking. Further, it is not clear if therapeutic inhibition of autophagy will be feasible. To determine the effects of targeting autophagy on PDACs, Yang and colleagues developed a mouse model that allowed reversible inhibition of autophagy in mouse models of autochthonous PDAC by inducible expression of a dominant negative mutant of ATG4B, a cysteine protease required to form the autophagosome membrane. Using this system, inhibiting autophagy reduced the growth of established PDAC tumors, and even intermittent autophagy inhibition was sufficient to suppress tumor growth and extend survival. Autophagy inhibition directly affected PDAC tumor cell growth, increasing apoptosis and reducing cell proliferation, but also increased intratumoral macrophages for an indirect effect on tumor growth. Accordingly, macrophage depletion reduced the antitumor effects of autophagy inhibition. Further, autophagy inhibition in the tumor stroma suppressed tumor seeding. In addition to delineating tumor cell intrinsic and extrinsic roles for autophagy in supporting PDAC maintenance, these results suggest that autophagy inhibitors warrant further investigation for the potential treatment of patients with PDAC.
Autophagy in the Tumor or in the Host: Which Plays a Greater Supportive Role? Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 Estela Noguera-Ortega; Ravi K. Amaravadi
Summary: Autophagy has been identified as a potential therapeutic target in pancreatic ductal adenocarcinoma, one of the most lethal cancers, with few therapeutic options. Yang and colleagues successfully created a genetically engineered mouse model focused on the autophagy gene Atg4b that allows the study of therapeutic autophagy inhibition in fully formed tumors. Using this tool, they demonstrated that selective autophagy inhibition in either the tumor cells, normal host cells, or both suppresses tumor growth. Cancer Discov; 8(3); 266–8. ©2018 AACR See related article by Yang et al., p. 276.
Digital Circulating Tumor Cell Analyses for Prostate Cancer Precision Oncology Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 Ellen Heitzer; Michael R. Speicher
Summary: In this issue of Cancer Discovery, Miyamoto and colleagues adapted their microfluidic CTC-iChip isolation platform with a digital RNA-PCR readout for eight prostate-specific transcripts and two assays for the androgen receptor mRNA splice variant ARV7 and the TMPRSS2–ERG translocation transcript. In patients with metastatic castrate-resistant prostate cancer at initiating abiraterone therapy in a first-line setting, the resulting RNA-based digital circulating tumor cell signatures identified patients with a shorter overall survival, and in patients with clinically localized disease, the signatures identified those with seminal vesicle invasion and pelvic lymph node involvement. Cancer Discov; 8(3); 269–71. ©2018 AACR. See related article by Miyamoto et al., p. 288.
Driver Oncogenes but Not as We Know Them: Targetable Fusion Genes in Breast Cancer Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 Rachael Natrajan; Andrew N.J. Tutt; Christopher J. Lord
Summary: Two reports in this issue of Cancer Discovery outline how the genomic composition of tumors, including the presence of intragenic gene fusions, could inform the selection of treatment approaches in aggressive forms of the disease. Cancer Discov; 8(3); 272–5. ©2018 AACR. See related article by Matissek et al., p. 336. See related article by Liu et al., p. 354.
Autophagy Sustains Pancreatic Cancer Growth through Both Cell-Autonomous and Nonautonomous Mechanisms Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 Annan Yang; Grit Herter-Sprie; Haikuo Zhang; Elaine Y. Lin; Douglas Biancur; Xiaoxu Wang; Jiehui Deng; Josephine Hai; Shenghong Yang; Kwok-Kin Wong; Alec C. Kimmelman
Autophagy has been shown to be elevated in pancreatic ductal adenocarcinoma (PDAC), and its role in promoting established tumor growth has made it a promising therapeutic target. However, due to limitations of prior mouse models as well as the lack of potent and selective autophagy inhibitors, the ability to fully assess the mechanistic basis of how autophagy supports pancreatic cancer has been limited. To test the feasibility of treating PDAC using autophagy inhibition and further our understanding of the mechanisms of protumor effects of autophagy, we developed a mouse model that allowed the acute and reversible inhibition of autophagy. We observed that autophagy inhibition causes significant tumor regression in an autochthonous mouse model of PDAC. A detailed analysis of these effects indicated that the tumor regression was likely multifactorial, involving both tumor cell–intrinsic and host effects. Thus, our study supports that autophagy inhibition in PDAC may have future utility in the treatment of pancreatic cancer and illustrates the importance of assessing complex biological processes in relevant autochthonous models. Significance: This work demonstrates that autophagy is critical pancreatic tumor maintenance through tumor cell–intrinsic and –extrinsic mechanisms. These results have direct clinical relevance to ongoing clinical trials as well as drug-development initiatives. Cancer Discov; 8(3); 276–87. ©2018 AACR. See related commentary by Noguera-Ortega and Amaravadi, p. 266. This article is highlighted in the In This Issue feature, p. 253
An RNA-Based Digital Circulating Tumor Cell Signature Is Predictive of Drug Response and Early Dissemination in Prostate Cancer Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 David T. Miyamoto; Richard J. Lee; Mark Kalinich; Joseph A. LiCausi; Yu Zheng; Tianqi Chen; John D. Milner; Erin Emmons; Uyen Ho; Katherine Broderick; Erin Silva; Sarah Javaid; Tanya Todorova Kwan; Xin Hong; Douglas M. Dahl; Francis J. McGovern; Jason A. Efstathiou; Matthew R. Smith; Lecia V. Sequist; Ravi Kapur; Chin-Lee Wu; Shannon L. Stott; David T. Ting; Anita Giobbie-Hurder; Mehmet Toner; Shyamala Maheswaran; Daniel A. Haber
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
Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 Oliver M.T. Pearce; Robin M. Delaine-Smith; Eleni Maniati; Sam Nichols; Jun Wang; Steffen Böhm; Vinothini Rajeeve; Dayem Ullah; Probir Chakravarty; Roanne R. Jones; Anne Montfort; Tom Dowe; John Gribben; J. Louise Jones; Hemant M. Kocher; Jonathan S. Serody; Benjamin G. Vincent; John Connelly; James D. Brenton; Claude Chelala; Pedro R. Cutillas; Michelle Lockley; Conrad Bessant; Martin M. Knight; Frances R. Balkwill
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
MYC Drives a Subset of High-Risk Pediatric Neuroblastomas and Is Activated through Mechanisms Including Enhancer Hijacking and Focal Enhancer Amplification Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 Mark W. Zimmerman; Yu Liu; Shuning He; Adam D. Durbin; Brian J. Abraham; John Easton; Ying Shao; Beisi Xu; Shizhen Zhu; Xiaoling Zhang; Zhaodong Li; Nina Weichert-Leahey; Richard A. Young; Jinghui Zhang; A. Thomas Look
The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here, we show that the family member MYC is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (∼10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas. Significance: Amplification of the MYCN oncogene is a recognized hallmark of high-risk pediatric neuroblastoma. Here, we demonstrate that MYC is also activated as a potent oncogene in a distinct subset of neuroblastoma cases through either focal amplification of distal enhancers or enhancer hijacking mediated by chromosomal translocation. Cancer Discov; 8(3); 320–35. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 253
Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor–Positive Breast Cancer Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 Karina J. Matissek; Maristela L. Onozato; Sheng Sun; Zongli Zheng; Andrew Schultz; Jesse Lee; Kristofer Patel; Piiha-Lotta Jerevall; Srinivas Vinod Saladi; Allison Macleay; Mehrad Tavallai; Tanja Badovinac-Crnjevic; Carlos Barrios; Nuran Beşe; Arlene Chan; Yanin Chavarri-Guerra; Marcio Debiasi; Elif Demirdögen; Ünal Egeli; Sahsuvar Gökgöz; Henry Gomez; Pedro Liedke; Ismet Tasdelen; Sahsine Tolunay; Gustavo Werutsky; Jessica St. Louis; Nora Horick; Dianne M. Finkelstein; Long Phi Le; Aditya Bardia; Paul E. Goss; Dennis C. Sgroi; A. John Iafrate; Leif W. Ellisen
We sought to uncover genetic drivers of hormone receptor–positive (HR+) breast cancer, using a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identified intergenic fusions involving driver genes, including PIK3CA, AKT3, RAF1, and ESR1, in 14% (24/173) of unselected patients with advanced HR+ breast cancer. FISH confirmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in nontransformed cells deregulates phosphoprotein signaling, cell proliferation, and survival in three-dimensional culture, whereas expression in HR+ breast cancer models modulates estrogen-dependent growth and confers hormonal therapy resistance in vitro and in vivo. Strikingly, shorter overall survival was observed in patients with rearrangement-positive versus rearrangement-negative tumors. Correspondingly, fusions were uncommon (<5%) among 300 patients presenting with primary HR+ breast cancer. Collectively, our findings identify expressed gene fusions as frequent and potentially actionable drivers in HR+ breast cancer. Significance: By using a powerful clinical molecular diagnostic assay, we identified expressed intergenic fusions as frequent contributors to treatment resistance and poor survival in advanced HR+ breast cancer. The prevalence and biological and prognostic significance of these alterations suggests that their detection may alter clinical management and bring to light new therapeutic opportunities. Cancer Discov; 8(3); 336–53. ©2017 AACR. See related commentary by Natrajan et al., p. 272. See related article by Liu et al., p. 354. This article is highlighted in the In This Issue feature, p. 253
Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple-Negative Breast Cancer Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 Hui Liu; Charles J. Murphy; Florian A. Karreth; Kristina B. Emdal; Forest M. White; Olivier Elemento; Alex Toker; Gerburg M. Wulf; Lewis C. Cantley
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
Advancing Cancer Screening with Liquid Biopsies Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
A new liquid biopsy technique, CancerSEEK, that evaluates tumor mutations and cancer-linked proteins can detect 70% of cancers in patients who have one of eight tumor types. The technique can pinpoint the location of a tumor in 68% of cases. However, its sensitivity drops off at earlier disease stages.
First PARP Inhibitor Ok'd for Breast Cancer Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
The FDA has approved olaparib, a PARP inhibitor, for use in patients with metastatic breast cancer who also carry a germline BRCA1 or BRCA2 mutation. With the January 12 approval, olaparib becomes the first targeted therapy for patients with breast cancer with mutated BRCA.
Celgene Targets Blood Cancers with Major Buys Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
Celgene acquired Juno Therapeutics for $9 billion and is spending up to $7 billion on Impact Biomedicines in an effort to diversify its hematology portfolio with chimeric antigen receptor T-cell therapies and a JAK2 inhibitor before its best seller, lenalidomide, faces competition from generics.
Mutation Burden Predicts Anti–PD-1 Response Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
A new study finds that objective response rates to anti–PD-1 therapies correlate with tumor mutation burden for most of the 27 cancer types studied. Objective response rates were higher than expected for Merkel cell carcinoma and renal cell carcinoma, which may be particularly immunogenic. The objective response rate was unexpectedly low for colorectal cancer with mismatch repair proficiency.
Chromatin-Remodeling Genes Promote Immunotherapy Resistance Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
Two studies show that genes that encode a chromatin-remodeling complex foster resistance to checkpoint inhibitors. One study identified the proteins by using CRISPR/Cas9 to knock out genes in mouse melanoma cells. The other study converged on the same result by identifying mutations in patients with clear cell renal cell carcinoma who responded to PD-1 inhibitors.
E-cigarette Report Reveals Research Gaps Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
In a comprehensive analysis of existing studies, the U.S. National Academies of Sciences, Engineering, and Medicine concluded that electronic cigarettes are addictive, though less toxic than conventional cigarettes. The report also identified key areas for future research, including smoking cessation, adolescent use, and long-term health effects.
CNS Metastases Needn't Rule Out Trial Inclusion Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
New guidelines from an expert working group describe when to include or exclude patients with brain metastases from clinical trials. In the past, these patients have often been inappropriately excluded from trials, resulting in a dearth of information on the efficacy of cancer drugs in the central nervous system.
First Comprehensive Companion Diagnostic OK'd Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
The FDA has approved F1CDx, a comprehensive companion diagnostic test that can detect genetic alterations and two genomic signatures in any type of solid tumor. Patients with five common types of advanced cancer can be matched to one of 17 targeted therapies with this single test.
STINGing Antitumor Immunity into Action Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
Efforts to stimulate STING signaling, thereby turning immunologically “cold” tumors “hot” and receptive to immunotherapy, are gaining ground in the industry. To date, directly targeting the STING receptor with synthetic ligands is the main approach to have entered clinical trials, but indirect small-molecule modulators of the pathway are also being pursued.
Venetoclax Data Prompt Rethink of CLL Therapy Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
The BCL2 inhibitor venetoclax is approved in the United States for only a subset of patients with refractory chronic lymphocytic leukemia. However, in light of data presented at the American Society of Hematology 2017 Annual Meeting, clinicians are thinking ahead to administering the drug more broadly—in combinations and as a first-line therapy—for other patients with the disease.
Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
Nivolumab plus ipilimumab achieves higher response rates than previously reported for nivolumab alone.
LXR Agonism Depletes MDSCs to Promote Antitumor Immunity Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
LXR activation reduces immunosuppressive MDSCs to activate antitumor cytotoxic T cells.
Patients with Desmoplastic Melanoma May Respond to PD-1 Blockade Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
PD-1 blockade achieved responses in 70% of patients with desmoplastic melanoma in a retrospective analysis.
Blood Monocyte Frequency May Be a Biomarker for Response to Anti–PD-1 Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
CD14+CD16−HLA-DRhi monocyte frequency was linked to response to anti–PD-1 in patients with melanoma.
Dimerization Is Critical for the Functions of Wild-type and Mutant KRAS Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
Wild-type KRAS increases survival and resistance to MEK inhibitors in KRAS-mutant lung cancer cells.
Chromosomal Instability Drives Metastasis Independent of Aneuploidy Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
Chromosomal instability (CIN) promotes metastasis with little effect on primary tumor growth.
Enhancer-Driven Gene Expression Changes Facilitate Metastasis Cancer Discov. (IF 20.011) Pub Date : 2018-03-01 American Association for Cancer Research
Altered enhancer activity allows for dynamic gene expression to promote osteosarcoma metastasis.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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