A Decade of Discoveries in Cancer Discovery. For the Community. By the Community.
Featured
Editors-in Chief: Lewis C. Cantley, PhD
and Luis A. Diaz, MD
Celebrating 10 Years of Discoveries: A Message from Our Editors-in-Chief
We could not be prouder of Cancer Discovery's success or more grateful to the community for its support of the Journal over the past decade. In a recent interview, we discussed the journal’s origins, its coverage of paradigm-shifting studies and our vision for the future. We will continue highlighting the most important studies published in Cancer Discovery since its launch and will look ahead to unanswered questions and new directions in cancer research that we think will be crucial for significant progress in the field in the decade to come. For more information, read the editorial, "A Decade of Cancer Discovery"
The BATTLE Trial: Personalizing Therapy for Lung Cancer
Cancer Discovery’s first clinical trial research article.
The inaugural issue includes the BATTLE Trial, which represented a major advance in clinical trial design that established the feasibility of performing core biopsies and real-time biomarker analysis to assign therapy. Read the author interview describing this impactful study.
Research
10th Anniversary Special April Issue
The Cancer Discovery editors are pleased to present this first-ever special issue commemorating the Journal’s 10th Anniversary. Leaders in rapidly evolving areas of the field discuss some of the biggest unanswered questions and look ahead to the next decade of discoveries.
Featured Articles from June 2020 and July 2020
First Insights into the Impact of COVID-19 on Patients with Cancer
Two studies published in 2020 from sites of the earliest outbreaks in China and the United States – Wuhan and New York City – represented the first large cohort studies addressing whether patients with cancer and COVID-19 had worse outcomes than age-matched noncancer patients with COVID-19. Dai, Liu, Liu, Santillana, Cai, and colleagues enrolled 105 patients with cancer from 14 hospitals in Wuhan, China. Compared with age-matched noncancer patients, patients with cancer had higher rates of death, ICU admission, invasive mechanical ventilation, and severe or critical symptoms. Patients with hematologic cancer, lung cancer, or stage IV metastatic cancer were at greatest risk. Mehta, Goel, Kabarriti, Halmos, Verma, and colleagues analyzed 218 patients with COVID-19 and cancer in New York City and observed a significantly increased case fatality rate among patients with cancer compared with noncancer patients. Patients with lung or hematologic cancers were also observed to have the worst outcomes.
Cancer-associated fibroblasts (CAF) are particularly abundant in PDAC stroma, with evidence suggesting a heterogeneous population of cells with distinct functions. In 2019, Elyada, Robson, Tuveson, and colleagues performed single-cell RNA sequencing on human PDAC tissue and normal pancreas and tumor tissue from genetically engineered PDAC mouse models, providing the first insights into CAF heterogeneity at single-cell resolution. They catalogued various nonmalignant stromal cell types in both human and mouse PDAC and several different subsets of CAFs, including a previously uncharacterized CAF subtype that expressed MHC class II family genes and could present antigens to T cells ex vivo. Dubbed antigen-presenting CAFs, or apCAFs, these cells differed from canonical antigen-presenting cells in that they did not express costimulatory molecules necessary to induce T- cell proliferation, suggesting that they might act as decoys to promote immune suppression in the PDAC microenvironment.
Featured Articles from March 2016 and January 2020
KRAS Becomes Druggable
In 2016, Patricelli, Janes, Liu, and colleagues demonstrated that KRASG12C is a hyperexcitable protein that rapidly cycles bound nucleotide [and] that a covalent mutant-specific inhibitor stabilizes the GDP-bound inactive state. These findings provided a framework for further development of KRASG12C inhibitors, and in 2020, Hallin, Christensen, and colleagues reported the preclinical characterization and early clinical proof-of-concept for the KRASG12C inhibitor MRTX849. MRTX849 blocked KRAS-dependent signaling and proliferation in vitro and induced regression of KRASG12C-mutant tumors in vivo. MRTX849, now known as adagrasib, was one of the first KRAS inhibitors to enter the clinic, and this study included the first-ever reported clinical responses to a KRAS inhibitor, in one patient with non–-small cell lung cancer (NSCLC) and one patient with metastatic colorectal cancer. Preclinical work also pointed to potential resistance mechanisms involving extrinsic regulation of KRAS nucleotide cycling and activation of bypass pathways and suggested potential combination treatment strategies that are currently being evaluated.
Featured Articles from August 2015, July 2018, and February 2017
Uncovering Genetic Underpinnings of Immune Checkpoint Blockade Resistance
In 2015, Skoulidis, Heymach, and colleagues performed an integrative analysis of KRAS-mutant non–small cell lung cancers (NSCLC) and found that these tumors could be classified into three subsets with distinct co-occurring mutations, underlying biology, and potential therapeutic vulnerabilities, one of which was a subgroup with co-occurring STK11 (also known as LKB1) mutations. A subsequent 2018 study by Skoulidis, Goldberg, Greenawalt, Geese, Albacker, Heymach, and colleagues showed that immune checkpoint blockade with PD-1 inhibitors was significantly less effective in [this] subgroup, and supportive data in a syngeneic mouse model of Kras-mutant lung adenocarcinoma showed that loss of Stk11/Lkb1 confers resistance to PD-1 blockade. Loss-of-function mutations in JAK1 and JAK2 also were found to be associated with primary resistance to PD-1 blockade in patients with melanoma or colorectal cancer with a high mutational load, as shown by Shin, Ribas, and colleagues in 2017.
In 2017, Massard, et al. presented results from the Molecular Screening for Cancer Treatment Optimization (MOSCATO) 01 trial, one of the first prospective clinical trials designed to address the question of whether genomic profiling of tumors could actually provide clinical benefit. Of 1,035 adult patients with advanced cancer enrolled, 843 had both a successful tumor biopsy and molecular profiling completed. An actionable target for which an approved therapy did not yet exist was detected in 411 of these patients, and ultimately 199 patients received a matched therapy as part of ongoing phase I/II trials. Though the number of patients who were eligible for matched therapy was relatively low due to limitations inherent to different molecular profiling approaches, incomplete annotation of gene variants, and clinical availability of therapies targeted to a specific alteration, this landmark trial provided the first evidence for the utility of genome-driven therapy as a treatment paradigm and inspiration for matched targeted therapy trials that followed in the years to come.
Turning the Tide against Non–Small Cell Lung Cancer
Mortality from non–small cell lung cancer (NSCLC) has sharply declined in recent years, a decrease that has coincided with a spate of FDA approvals for targeted therapies in patients whose tumors harbor various genetic alterations. In 2015, two papers by Frampton, et al., and Paik, et al., showed that MET exon 14 splice site mutations were recurrent and actionable in patients with NSCLC. In 2018, Subbiah, et al., presented the preclinical characterization and early demonstration of clinical activity for BLU-667, a next-generation small-molecule inhibitor of RET, which is activated by gene rearrangement in 1% to 2% of NSCLCs. BLU-667 potently inhibited RET-dependent cell growth and induced regression of RET-altered tumor models, and 2 patients with RET fusion–positive NSCLC treated with BLU-667 experienced partial responses. These findings paved the way for clinical trials in patients with NSCLC whose tumors harbored MET exon 14 mutations or RET fusions, and ultimately a number of FDA approvals in less than 5 years.
Converging on an Escape Route from CAR-T Cell Therapy
One of the major therapeutic advances in cancer research over the past decade has been the development of chimeric antigen receptor (CAR)-T cell therapy. In 2015, Sotillo, Thomas-Tikhonenko, et al., performed copy-number analysis and whole-exome and RNA sequencing on samples from patients with B-ALL who relapsed following CD19 CAR-T cell therapy and identified hemizygous deletions spanning the CD19 locus, acquired frameshift and missense mutations in exon 2 of CD19, and alternatively spliced CD19 mRNA species lacking exon 2. Following this first characterization, antigen escape due to loss or downregulation of the target antigen became widely appreciated as a general mechanism of resistance to CAR-T cell therapy, spurring efforts to develop strategies to engineer CAR-T cells to achieve multispecificity or respond to lower levels of target antigen.
As immune checkpoint blockade with anti-PD1 and anti-PD-L1 antibodies became a more widely used therapeutic strategy, understanding the expression patterns of immune checkpoint inhibitors and characterizing the composition of tumor immune microenvironment became especially important for attempting to predict which patients might respond. In 2015, Llosa, Pardoll, Housseau, and colleagues comprehensively analyzed the immune microenvironments of a large set of primary colorectal tumors and found dramatically higher levels of tumor-infiltrating CD8+ cytotoxic T lymphocytes and activated IFNγ-secreting T helper type 1 cells – features of what is now referred to as a “hot” immune microenvironment – in approximately 20% of tumors, nearly all of which were characterized by microsatellite instability (MSI) due to defective DNA mismatch repair (MMR).
Featured Articles from March 2014 and October 2016
Halting a Hallmark: BCL-2 Inhibition Moves from Bench to Bedside in AML
Resistance to cell death has long been appreciated as a "Hallmark of Cancer," and efforts to induce mitochondrial apoptosis in cancer cells by targeting antiapoptotic members of the BCL-2 family of proteins with small-molecule mimetics of proapoptotic BH3 domains were well underway by the late 2000s. In 2014, Pan, Hogdal, Letai, et al., found that venetoclax effectively killed AML cell lines, xenografts, and primary patient samples, and showed that addiction to BCL-2 could serve as a biomarker for venetoclax sensitivity. Inspired by these findings, Konopleva, Letai, et al, initiated a phase II study of venetoclax monotherapy in patients with high-risk relapsed/refractory AML and in 2016 reported an overall response rate of 19% and evidence of antileukemic activity in an additional 19% of patients.
One of the earliest successes of precision medicine was the development of HER2-targeted therapy in the late 1990s for the approximately 20% of breast cancers with HER2 gene amplification resulting in HER2 protein overexpression. In 2013, Bose, Ellis, and colleagues identified rare somatic mutations in HER2 in breast cancers lacking HER2 gene amplification, most of which would have been considered HER2-negative based on immunohistochemistry and FISH. These findings suggested that the population of patients with breast cancer considered eligible for HER2-targeted therapy could be expanded, and in later years patients harboring HER2 began to be included in clinical trials of HER2-targeted therapies.
In 2014, Cross, Pao, and colleagues reported the preclinical development of AZD9291, a third-generation irreversible EGFR TKI with selectivity for mutant forms of EGFR including T790M, along with proof of its clinical activity in two patients with advanced T790M-positive NSCLC. The development of AZD9291—now known as osimertinib—had an immediate impact on NSCLC treatment. Osimertinib received accelerated FDA approval in 2015 for patients with T790M mutation–positive NSCLC that progressed on or after EGFR TKI therapy and regular approval for this indication in 2017. In 2018, Osimertinib was approved for first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations, based on phase III trial results showing it was safer and more effective than standard-of-care first-generation EGFR TKIs.
An Essential Tool for the Cancer Research Community
At the beginning of the last decade, the field of cancer genomics blossomed as the cost of next-generation sequencing rapidly declined and large national and international consortia sequenced an increasing number of tumors, but data generated through these efforts was not easily or directly available to cancer researchers for their own analyses. In 2012, Cerami et al., introduced the cBioPortal for Cancer Genomics, a resource for integration and visualization of multidimensional cancer genomic datasets, including mutational data, copy number alternations, mRNA expression, DNA methylation, and protein and phosphoprotein levels. Researchers can use cBioPortal to visualize their own data, and they can download genomic datasets for their own use.
In 2012, Corcoran, Ebi, Engelman, and colleagues presented preclinical evidence that the insensitivity of BRAFV600E-mutant colorectal cancer cells to BRAF inhibition was due to EGFR-mediated MAPK pathway reactivation, which did not occur in BRAFV600E-mutant melanoma cells. These findings provided the rationale for subsequent clinical trials using doublet and triplet combination approaches in BRAFV600E-mutant colorectal cancer, including a phase I trial by Corcoran and colleagues in 2018 showing that a combination of BRAF and EGFR inhibitors led to confirmed responses in 10% of patients with BRAFV600E-mutant colorectal cancer and a combination of BRAF, MEK, and EGFR inhibitors led to confirmed responses in 21% of patients.
Featured Articles from the Inaugural Issue (June 2011)
Opening Shots in the BATTLE of Precision Medicine
The very first issue of Cancer Discovery featured the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial by Kim, Herbst, Wistuba, Lee, Lippman, the late Waun Ki Hong, and colleagues - the first completed prospective, biomarker-based, adaptively randomized clinical trial in patients with lung cancer. The BATTLE trial represented a major advance in clinical trial design that established the feasibility of performing core biopsies and real-time biomarker analysis to assign therapy. It paved the way for future trials as our understanding of lung cancer biology advanced and more specific drugs were developed.
Immune Microenvironment Composition Linked to Clinical Outcomes
Also in the first issue of Cancer Discovery, DeNardo, Coussens, and colleagues analyzed lymphocyte and macrophage density from treatment-naive patients with breast cancer and established that an immune signature of high CD68+ tumor-associated macrophage infiltration and low cytotoxic CD8+ T cell infiltration predicted decreased relapse-free survival and overall survival. This was among the first studies to establish that the overall composition of the immune microenvironment is a predictive biomarker of clinical outcomes. It presaged a host of future studies characterizing tumor immune cell composition in clinical samples and targeting the immunosuppressive tumor microenvironment to enhance therapeutic responses.
A Q&A with authors Mengyuan Dai, MD, PhD, Wuhan University, Dianbo Liu, Harvard Medical School, Miao Liu, MD, PhD, Harvard Medical School, Mauricio Santillana, PhD, Harvard University, Hongbing Cai, MD, Wuhan University, Vikas Mehta, MD, Sanjay Goel, MBBS, Rafi Kabarriti, MD, Balazs Halmos, MD, and Amit Verma, MBBS, Albert Einstein College of Medicine
Patients with Cancer Appear More Vulnerable to SARS-CoV-2: A Multicenter Study during the COVID-19 Outbreak
and
Case Fatality Rate of Cancer Patients with COVID-19 in a New York Hospital System
A Q&A with authors Ela Elyada, PhD, The Hebrew University of Jerusalem, Paul Robson, PhD, The Jackson Laboratory for Genomic Medicine, and David A. Tuveson, MD, PhD, FAACR, Cold Spring Harbor Laboratory.
A Q & A with authors Matthew P. Patricelli, PhD, Vividion Therapeutics, Matthew R. Janes, PhD, Kumquat Biosciences Inc, Yi Liu, PhD, Kumquat Biosciences, Jill Hallin, BS, Mirati Therapeutics, Inc and James G. Christensen, PhD, Mirati Therapeutics, Inc
Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State
and
The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients
A Q&A with Ferdinandos Skoulidis, MD, MD Anderson Cancer Center, John Heymach, MD, PhD, MD Anderson Cancer Center, Michael Goldberg, University of Washington, Danielle Greenawalt, PhD, Bristol-Meyers Squibb, William Geese, PhD, Bristol-Meyers Squibb, Lee Albacker, PhD, Foundation Medicine,
Daniel Shin, MD, PhD, UCLA Jonsson Comprehensive Cancer Center, and Antoni Ribas, MD, PhD, UCLA Jonsson Comprehensive Cancer Center, discussing their articles:
Co-occurring Genomic Alterations Define Major Subsets of KRAS-Mutant Lung Adenocarcinoma with Distinct Biology, Immune Profiles, and Therapeutic Vulnerabilities
and
STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma
and
Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations
A Q&A with Garrett Frampton, PhD, Foundation Medicine,
Paul K. Paik, MD, Memorial Sloan Kettering Cancer Center,
Vivek Subbiah, MD, MD Anderson Cancer Center,
Justin F. Gainor, MD, Mass General Cancer Center, and
Erica K. Evans, PhD, Blueprint Medicines, discussing their articles:
Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors, Response to MET Inhibitors in Patients with Stage IV Lung Adenocarcinomas Harboring MET Mutations Causing Exon 14 Skipping, Precision Targeted Therapy with BLU-667 for RET-Driven Cancers
Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy
A Q&A with authors Elena Sotillo PhD, Stanford University and Andrei Thomas-Tikhonenko, PhD, Children’s Hospital of Philadelphia and University of Pennsylvania
Nicolas J. Llosa, MD
Drew M. Pardoll, MD
Marina Konopleva, MD, PhD
Franck Housseau, PhD
The Vigorous Immune Microenvironment of Microsatellite Instable Colon Cancer Is Balanced by Multiple Counter-Inhibitory Checkpoints
A Q&A with authors Nicolas J. Llosa, MD, Johns Hopkins University, Drew M. Pardoll, MD, PhD, Johns Hopkins University, and Franck Housseau, PhD, Johns Hopkins University
Rongqing Pan, PhD
Leah J. Hogdal, PhD
Marina Konopleva, MD, PhD
Anthony G. Letai, MD, PhD
Selective BCL-2 Inhibition by ABT-199 Causes On-Target Cell Death in Acute Myeloid Leukemia
and
Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia
A Q&A with authors Rongqing Pan, PhD, Dana-Farber Cancer Institute, Leah J. Hogdal, PhD, AbbVie, Marina Konopleva, MD, PhD, MD Anderson Cancer Center, and, Anthony G. Letai, MD, PhD, Dana-Farber Cancer Institute
Edward Kim, MD
Roy Herbst, MD, PhD
Ignacio Wistuba, MD
and Jack Lee, PhD, MS, DDS
The BATTLE Trial: Personalizing Therapy for Lung Cancer
A Q&A with authors Edward Kim, MD, City of Hope, Roy Herbst, MD, PhD, Yale Cancer Center, Ignacio Wistuba, MD, MD Anderson Cancer Center, and Jack Lee, PhD, MS, DDS, MD Anderson Cancer Center.
Ron Bose, MD, PhD
Cynthia X. Ma, MD, PhD
and Matthew J. Ellis, MD, PhD
Activating HER2 Mutations in HER2 Gene Amplification Negative Breast Cancer
A Q&A with authors Ron Bose, MD, PhD, Washington University School of Medicine, St. Louis, Cynthia X. Ma, MD, PhD, Washington University School of Medicine, St. Louis, and Matthew J. Ellis, MD, PhD, Baylor College of Medicine.
Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy
A summary of the study with authors Lisa Coussens, PhD, Oregon Health & Science University and David DeNardo, PhD, Washington University School of Medicine
Ryan B. Corcoran, MD, PhD
Hiromichi Ebi, PhD
and Jeffrey A. Engelman, MD, PhD
EGFR-Mediated Reactivation of MAPK Signaling Contributes to Insensitivity of BRAF-Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib
and
Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer
A Q&A with authors Ryan B. Corcoran, MD, PhD Massachusetts General Hospital, Hiromichi Ebi, PhD Aichi Cancer Center and Jeffrey A. Engelman, M.D., Ph.D. Treeline Biosciences
Cancer Discovery 10th Anniversary Symposium: The Next Decade of Discoveries
Moderated by Editors-in-Chief, Lewis Cantley and Luis A. Diaz Jr., key thought leaders, Regina Barzilay, Katherine Janeway, Ross Levine, Ira Mellman, Tony S.K. Mok, Alice T. Shaw, Ashani T. Weeraratna, and Laurence Zitvogel discussed emerging cancer research areas that will significantly move the field forward in the next decade. Each presentation was followed by a question-and-answer segment, and each session concluded with a panel discussion.
Find out more about the program.
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