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Celebrating the 10th Anniversary

A Decade of Discoveries in Cancer Discovery. For the Community. By the Community.


Featured

photos of Lewis C. Cantley, PhD and Luis A. Diaz, MD

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 Symposium

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

Special Anniversary Edition of Cancer Discovery April 2021

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.

image for Ribas, et al. article

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.

Read more…

image for Soria, et al. article

Featured Article from June 2017


Early Promise for Genome-Driven Therapy

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.

Read more…

image for Evans, et al. article

Featured Articles from August 2015 and July 2018


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.

Read more…

Featured Article from December 2015


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.

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artwork for article 'Microsatellite Instability Turns Up the Heat'

Featured Article from January 2015


Microsatellite Instability Turns Up the Heat

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).

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artwork for article 'Halting a Hallmark: BCL-2 Inhibition Moves from Bench to Bedside in AML'

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.

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Featured Article from February 2013


A New Opportunity for an Old Target

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.

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Image for article on Osimertinib and its impact on NSCLC treatment

Featured Article from September 2014


Osimertinib Enters the Scene

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.

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Featured Article from May 2012


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.

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Featured Articles from March 2012 and April 2018


Not All BRAF-Mutant Cancers Are Created Equal

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.

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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.

Read more…

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.

Read more…

 
 

Authors

Their impactful studies. In their words.


Christophe Massard, MD, PhD
Fabrice André, MD, PhD and
Jean-Charles Soria, MD, PhD

High-Throughput Genomics and Clinical Outcome in Hard-to-Treat Advanced Cancers: Results of the MOSCATO 01 Trial

A Q&A with authors Christophe Massard, MD, PhD, Gustave Roussy, Fabrice André, MD, PhD, Gustave Roussy, and Jean-Charles Soria, MD, PhD, Gustave Roussy

Read the interview

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

Read the interview

Elena Sotillo, PhD
Andrei Thomas-Tikhonenko, PhD

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

Read the interview

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

Read the interview

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

Read the interview

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.

Read the interview

Remembering the late Waun Ki Hong and his extraordinary contribution to Cancer Discovery’s first clinical trial research article.

Go to Comments by
Senior Author Scott Lippman

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.

Read the interview

Darren A.E. Cross, PhD
and William Pao, MD, PhD

AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer

A Q&A with authors Darren A.E. Cross, PhD, AstraZeneca and William Pao, MD, PhD, Roche

Read the interview

Lisa Coussens, PhD
and David DeNardo, PhD

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

Read more

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

Read the interview

photos of Nikolaus Schultz, PhD and Ethan Cerami, PhD

Nikolaus Schultz, PhD
and Ethan Cerami, PhD

The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data

A Q&A with authors Nikolaus Schultz, PhD Memorial Sloan Kettering Cancer Center and Ethan Cerami, PhD Dana-Farber Cancer Institute

Read the interview

 
 

Research Community

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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