While the rate of death from cancer has been declining since the 1990s, an estimated 9.6 million people died from cancer in 2018, making it the second-leading cause of death worldwide [1]. According to the NCI Cancer Trends Progress Report, in the United States, the incidence and death rates of some cancer types have also been increasing. Together, these facts indicate that despite tremendous recent progress, the research community unfortunately still has a long list of tasks to complete to end global suffering from cancer.
The clinical management of cancer has long been rooted in morphological and histopathological analyses for diagnosis, and the triad of surgery, chemotherapy, and radiation for treatment. However, we are quickly moving towards a pervasive reliance on high resolution, high throughput, molecular marker-based diagnostic as well as precision-targeted therapeutic modalities. The progressive development of the paradigm that defined molecular drivers of cancer has exposed therapeutic vulnerabilities; for example, the BCR-ABL1 gene fusion in chronic myeloid leukemia, KIT mutations in gastrointestinal stromal tumors, ERBB2 amplification in a subset of breast cancers, or EGFR mutations and ALK/ ROS/ RET gene fusions in lung cancers to name a few. Fueled by advances in high-throughput sequencing, it is increasingly practical (and arguably affordable) to systematically pursue Targeted Anticancer Therapies and Precision Medicine in Cancer.
PLOS ONE, together with PLOS Computational Biology, launched a Call for Papers earlier this year to increase understanding of this clinically important area. The scope of this call encompassed four areas: identification and classification of driver genes and somatic alterations; target and drug discovery; mechanisms of drug resistance; and early detection and screening.
Today, we are very happy to announce the launch of the resulting Collection. Featuring an initial set of nearly two dozen papers, with more to be added as they are published, these articles represent diverse facets of ongoing efforts in this area, where general knowledge of cancers serves to inform individual patients care, and at the same time particulars from individual cancer cases contribute to improved resolution of our general knowledge pool.
Somatic aberrations that are critical to the development, growth and progression of cancer are defined as drivers that are typically accompanied by large numbers of incidental aberrations referred to as passengers, acquired in the tumors due to the general chromosomal instability characteristic of advanced cancers. Distinguishing driver aberrations from passengers in individual tumors represents an active area of research that involves development of smarter analytical algorithms, as well as definitive functional characterization of candidate aberrations.
Emilie A. Chapeau et al. developed a conditional inducible transgenic JAK2V617F mouse model that recapitulates aspects of human myeloproliferative neoplasms, including splenomegaly, erythroid expansion and hyperproliferation of bone marrow, with some intriguing differences seen between male and female mice. Importantly, the disease phenotype was reversible when transgene expression was switched off. This work underscores the key role for JAK2V617F in the initiation and maintenance of myeloproliferative neoplasms, and suggests that inhibitors specific to this JAK2 mutation might be efficacious in this disease [2].
Using targeted exon sequencing and array comparative genomic hybridization (CGH), Gayle Pageau Pouliot et al. identified monoallelic mutations in Fanconi-BRCA pathway genes in samples collected from children with T cell acute lymphoblastic leukemia (T-ALL). These mutations appeared to arise in early stages of tumorigenesis, suggesting a potential role for Fanconi-BRCA pathway insufficiency in the initiation of T-ALL. Although PARP inhibitors did not affect viability of isolated T-ALL cells with monoallelic Fanconi-BRCA mutations, these cells were hypersensitive to UV irradiation in vitro or ATR inhibition in vivo, suggesting that ATR inhibitors might have therapeutic value in T-ALL [3].
Three papers in this Collection examine links between genetic alterations and prognosis. Sumadi Lukman Anwar et al. report that LINE-1 hypomethylation in human hepatocellular carcinoma samples correlates with malignant transformation, decreased overall survival and increased tumor size [4]. Investigating HER2-positive breast cancer specimens, Arsalan Amirfallah et al. found that high levels of vacuole membrane protein 1 (VMP1) could potentially contribute to cancer progression and might be a marker of poor prognosis [5]. Finally, in their systematic review and meta-analysis, Chia Ching Lee et al. identified low discordance rates in EGFR mutations between primary lung tumors and distant metastases, although they note some differences depending on metastatic site. Notably, discordance rates appear to be higher in bone metastases compared to central nervous system or lung metastases [6]. These studies provide much-needed leads for the potential development of new diagnostic tests or targeted therapies.
Precision therapy of cancers is premised on the identification of tumor-specific driver aberrations that are necessary for tumor growth and survival. These aberrations represent potential therapeutic targets. While matching therapeutics have been developed for some of the tumor-specific targets, particularly many oncogenic kinases, a large number of defined driver aberrations remain in search of effective therapies. Drug discovery efforts to match defined targets represent a vigorous area of ongoing research with implications for survival and quality of lives of cancer patients worldwide. The development of drugs to treat cancers driven by transcription factors, chromatin modifiers, and epigenetic modulators has proved particularly challenging. On the other hand, recent development of novel immunotherapeutic approaches has spurred research to identify potential targets and matching drug discovery efforts.
This Collection highlights several interesting new strategies to identify potential lead compounds for cancer treatment. Thomas W. Miller et al. describe the development of a biochemical quantitative high-throughput screen for small molecules that disrupt the interaction between CD47 and SIRP. Preclinical studies have shown that disrupting this interaction may provide a new approach for cancer immunotherapy. Small molecular inhibitors that specifically target the interaction between CD47 and SIRP are potentially advantageous over biologics that target CD47, because they might have less on target toxicologic issues and greater tissue penetrance [7].
Work from Gabrielle Choonoo, Aurora S. Blucher et al. examines the feasibility of repurposing existing cancer drugs for new indications. The authors compiled information about somatic mutations and copy-number alterations in over 500 cases of head and neck squamous cell carcinoma (HNSCC) and mapped these data to potential drugs listed in the Cancer Targetome [8]. This approach uncovered pathways that are routinely dysregulated in HNSCC and for which potential anti-cancer therapies are already available, as well as those for which no therapies exist. The work opens new therapeutic avenues in the treatment of this disease and also illuminates which pathways could be prioritized for the development of therapies [9].
Another important approach in extending the clinical utility of existing anti-cancer drugs is to determine whether they are effective in other settings. Indeed, Kirti Kandhwal Chahal et al. have demonstrated that the multi-tyrosine kinase inhibitor nilotinib, which is approved for use in chronic myeloid leukemia, binds the Smoothened receptor and inhibits Hedgehog pathway signaling. Nilotinib decreased viability of hedgehog-dependent medulloblastoma cell lines in vitro and in patient-derived xenografts in vivo, suggesting that nilotinib might be an effective therapy in Hedgehog-dependent cancer [10]. (Check out the authors preprint of this article on bioRxiv.) Darcy Welch, Elliot Kahen et al. took a different approach to identify new tricks for old drugs. By testing two-drug combinations of five established (doxorubicin, cyclophosphamide, vincristine, etoposide, irinotecan) and two experimental chemotherapeutics (the lysine-specific demethylase 1 (LSD1) inhibitor SP2509 and the HDAC inhibitor romidepsin), they found that combining SP2509 with topoisomerase inhibitors or romidepsin synergistically decreased the viability of Ewing sarcoma cell lines in vitro [11].
Two papers in this collection describe potential new therapeutic approaches in cancer. Vagisha Ravi et al. developed a liposome-based delivery mechanism for a small interfering RNA targeting ferritin heavy chain 1 (FTH1) and showed that this increased radiosensitivity and decreased viability in a subpopulation of glioma initiating cells (GICs) [12]. Yongli Li et al. identified 2-pyridinealdehyde hydrazone dithiocarbamate S-propionate podophyllotoxin ester, a podophyllotoxin derivative that inhibits matrix metalloproteinases and Topoisomerase II. Treatment with this compound decreased the migration and invasion of human liver cancer cell lines in vitro, as well as growth of HepG2-derived tumors in mouse xenografts [13].
The success of precision cancer therapy targeting defined somatic aberrations is hampered by an almost inevitable, eventual treatment failure due to the emergence of drug resistance. Resistance often involves new mutations in the therapeutic target itself, or it may result due to activation of alternative pathways. Identification and therapeutic targeting of drug resistant clones represents an ongoing research problem with important practical implications for the clinical management of cancer.
Afatinib is a pan-human epidermal growth factor receptor (HER) inhibitor under investigation as a potential therapeutic option for people with gastric cancer; however, preclinical studies have found that some gastric cancer cell lines are resistant to afatinib treatment. Karolin Ebert et al. identify a potential mechanism behind this lack of response, demonstrating that siRNA-mediated knockdown of the receptor tyrosine kinase MET increases afatinib sensitivity of a gastric cancer cell line containing a MET amplification. As upregulation of MET has been linked to resistance to anti-HER therapies in other cancers, these findings support a role for MET in afatinib resistance in gastric cancer and suggest that combined afatinib and anti-MET therapy might be clinically beneficial for gastric cancer patients [14].
Identifying mechanisms to circumvent drug resistance is critically important to improve response and extend survival, but it is equally important to identify individuals who could be at risk of not responding to anti-cancer therapeutics. Lucas Maahs, Bertha E. Sanchez et al. report progress towards this end, showing that high expression of class III -tubulin in metastatic castration-resistant prostate cancer (CRPC) correlated with decreased overall survival and worse response rate (as measured by changes in prostate-specific antigen (PSA) levels) in CRPC patients who received docetaxel therapy. The development of a biomarker indicating potential treatment resistance to docetaxel could help develop treatment plans with the best chance of success [15].
The converse approach identifying biomarkers that correlate with drug sensitivity could help distinguish subsets of patients who would benefit most from a certain anti-cancer therapy. Kevin Shee et al. mined publicly available datasets to identify genes whose expression correlate with sensitivity and response to chemotherapeutics and found that expression of Schlafen Family Member 11 (SLFN11) correlates with better response to a variety of DNA-damaging chemotherapeutics in several types of solid tumors [16]. Separately, Jason C. Poole et al. validated the use of the Target Selector ctDNA assay, a technology developed by their group that allows the specific amplification of very low frequency mutant alleles in circulating tumor DNA (ctDNA). Testing for EGFR, BRAF and KRAS mutations yielded a very high, >99% analytical sensitivity and specificity with the capability of single mutant copy detection, indicating that accurate molecular disease management over time is possible with this minimally invasive method [17].
Work from Georgios Kaissis, Sebastian Ziegelmayer, Fabian Lohfe et al. uses a machine learning algorithm to differentiate subtypes of pancreatic ductal adenocarcinoma based on 1,606 different radiomic features. Intriguingly, the subtypes identified in their analysis correlated with response to chemotherapeutic regimens and overall survival [18]. An imaging approach taken by Seo Young Kang et al. demonstrates the potential power of fluorodeoxyglucose (FDG) PET/CT scans in determining the response of people with metastatic differentiated thyroid cancer to radioactive iodine treatment [19].
Since cancer growth and development accrues progressive accumulation of somatic aberrations, early detection holds the promise of more effective interventions. Similarly, screening of at risk demographics has been found effective in preventing or better managing cancer care, as exemplified by the significant reduction in cases of cervical cancer after the introduction of the Pap smear as well as human papillomavirus (HPV) testing.
Biomarker development is also critically important for the early detection of cancer and metastatic disease; moreover, biomarkers are being identified that can provide insight into patient prognosis. Several papers in this Collection report interesting findings in the area of biomarker development. A report from Lingyun Xu et al. describes a magneto-nanosensor-based multiplex assay that measures circulating levels of PSA and four proteins associated with prostate cancer. This approach segregates people with prostate cancer from those with benign prostate hyperplasia with high sensitivity and specificity [20].
Two articles provide new insight into markers of disease progression and survival. Vidya Balagopal et al. report the development of a 22-gene hybrid-capture next generation sequencing panel to identify measurable residual disease in patients with acute myeloid leukemia (AML). In their retrospective study, the panel was effective at detecting evidence for residual disease. Importantly, it correctly identified patients who had never relapsed in that no evidence of residual disease was detected in any of these respective samples. Once validated, this approach could potentially be useful in monitoring patients with AML to ensure that recurrence or relapse is identified as soon as possible [21]. Separately, Yoon-Sim Yap et al. use a label-free microfluidic platform to capture circulating tumor cells (CTCs) from people with breast cancer and show that absolute numbers of CTCs predict progression-free survival with higher levels of CTCs correlating with a worse prognosis [22].
Finally, Lucia Suzuki et al. report findings into a potential role for the intestinal stem cell marker olfactomedin 4 (OLFM4) as a biomarker for metastasis in esophageal adenocarcinoma. The authors found that OLFM4 expression was not significantly associated with disease-free or overall survival; however, low OLFM4 expression was detected in poorly differentiated early and advanced-stage esophageal adenocarcinoma and was an independent prognostic variable for lymph node metastasis [23].
This collection of studies encompassing the range of research topics under the banner of targeted anticancer therapies highlights the diversity, complexity and inter-disciplinary nature of research efforts actively contributing to our collective knowledge base with the hope to positively impact the lives of all cancer patients.
We would like to thank all Academic Editors and reviewers for their expert evaluation of the articles in this Collection as well as the authors for their contributions to this field. Special thanks to Senior Editor, Team Manager Emily Chenette for her invaluable help and guidance in publishing this Collection.
Andrew Cherniack
Andrew Cherniack is a group leader in the Cancer Program at the Broad Institute of MIT and Harvard and in the Department of Medical Oncology at the Dana Farber Cancer Institute. He led the Broad Institutes effort to analyze somatic DNA copy number alterations for The Cancer Genome Atlas (TCGA) and is now co-principal investigator of the Broad Institutes copy number Genome Data Analysis Center for the National Cancer Institutes Genomic Data Analysis Network (GDAN). He also leads the oncoming effort to identify new cancer therapeutic targets for the partnership with Bayer. Prior to joining the Broad Institute in 2010, Dr. Cherniack worked in both academia and industry, with a 9-year tenure at the Abbott Bioresearch Center following a similar time period in the Program in Molecular Medicine at UMass Medical School, where he was a postdoctoral researcher and a research assistant professor. Dr. Cherniack holds a Ph.D. in molecular genetics from Ohio State University and a B.A. in biology from the University of Pennsylvania.
Anette Duensing
Anette Duensing is an Assistant Professor of Pathology at the University of Pittsburgh School of Medicine and a Member of the Cancer Therapeutics Program at the University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center. Dr. Duensings research focuses on bone and soft tissue sarcomas with the goal of identifying novel therapeutic approaches that target the underlying molecular biology of these malignancies. Her special interest and expertise are in gastrointestinal stromal tumors (GISTs), a sarcoma characterized by mutations in the KIT or PDGFRA receptor tyrosine kinases and the first solid tumor entity that was successfully treated with small molecule kinase inhibitors. Dr. Duensing holds an M.D. degree from the University of Hannover School of Medicine, Germany, and was a research scholar of the Dr. Mildred Scheel Stiftung fr Krebsforschung (German Cancer Aid/Deutsche Krebshilfe) at Brigham and Womens Hospital, Harvard Medical School. She is the recipient of an AACR Scholar-in-Training Award (AACR-AstraZeneca), a Young Investigator Award from The Liddy Shriver Sarcoma Initiative, a UPCI Junior Scholar Award, a Jeroen Pit Science Award, a Research Award from the GIST Group Switzerland and was named Hillman Fellow for Innovative Cancer Research. Dr. Duensing is co-founder and leader of the Pittsburgh Sarcoma Research Collaborative (PSaRC), a highly translational, interdisciplinary sarcoma research program. She is also affiliated with the Department of Urology at the University of Heidelberg, Germany. Dr. Duensing is an Academic Editor for PLOS ONE and author of nearly 70 original articles, reviews and book chapters.
Steven G. Gray
Steven Gray graduated from Trinity College Dublin in 1992. He joined the laboratory of Tomas J. Ekstrm at the Karolinska Institute (Sweden) in 1996 and received his PhD in 2000. He moved to the Van Andel Research Institute in Michigan, USA where he continued his studies on the therapeutic potential of histone deacetylase inhibitors in the treatment of cancer. He also spent time as a visiting fellow at Harvard Medical School, Boston working on epigenetic therapies for neurodegenerative disease. Returning to Europe, Dr. Gray spent some time at the German Cancer Research Centre (DKFZ Heidelberg), and subsequently moved to Copenhagen to work for Novo Nordisk as part of the research team of Prof Pierre De Meyts at the Hagedorn Research Institute working on epigenetic mechanisms underpinning diabetes pathogenesis. Dr. Gray is currently a senior clinical scientist at St Jamess Hospital at the Thoracic Oncology Research Group at St. Jamess Hospital. He holds adjunct positions at both Trinity College Dublin (senior clinical lecturer with the Dept. of Clinical Medicine), and at Technical University Dublin (adjunct senior lecturer, School of Biology DIT). Dr. Gray has published over 100 peer-reviewed articles, 15 book chapters and has edited 1 book. Research in Dr Grays laboratory focuses on Receptor Tyrosine Kinases as potential therapeutic targets for the treatment of mesothelioma; epigenetic mechanisms underpinning drug resistance in lung cancer; targeting epigenetic readers, writers and erasers for the treatment of mesothelioma and thoracic malignancy; circulating tumour cells; and non-coding RNA repertoires in mesothelioma and thoracic malignancy.
Sunil Krishnan
Sunil Krishnan is the Director of the Center for Radiation Oncology Research and the John E. and Dorothy J. Harris Professor of Gastrointestinal Cancer in the department of Radiation Oncology at MD Anderson Cancer Center. He received his medical degree from Christian Medical College, Vellore, India and completed a radiation oncology residency at Mayo Clinic, Rochester, Minnesota. In the clinic, he treats patients with hepatobiliary, pancreatic and rectal tumors with radiation therapy. His laboratory has developed new strategies and tools to define the roles and mechanisms of radiation sensitization with gold nanoparticles, chemotherapeutics, biologics and botanicals. Dr. Krishnan serves as the co-chair of the gastrointestinal scientific program committee of ASTRO, co-chair of the gastrointestinal translational research program of RTOG, consultant to the IAEA for rectal and liver cancers, chair of the NCI pancreatic cancer radiotherapy working group, and Fellow of the American College of Physicians. He has co-authored over 200 peer-reviewed scientific publications, co-authored 17 book chapters, and co-edited 3 books.
Chandan Kumar-Sinha
Chandan Kumar-Sinha is a Research Associate Scientist in the Department of Pathology at the University of Michigan. He obtained Masters in Biotechnology from Madurai Kamraj University, and PhD in Plant Molecular Biology from Indian Institute of Science. He completed a Postdoctoral Fellowship at the Department of Pathology, University of Michigan, where he worked on genomic profiling of cancers. Thereafter, he joined the Advanced Center for Treatment, Research and Education in Cancer in India as a faculty member. After establishing a cancer genomics group there, he moved back to the University of Michigan to pursue translational cancer research. Dr. Kumar-Sinhas current research involves integrative clinical sequencing using high-throughput genome and transcriptome analyses to inform precision oncology. He has authored over 50 peer-reviewed publications, two book chapters, and is named co-inventor on a patent on prostate cancer biomarkers.
Gayle E. Woloschak
Gayle Woloschak is Professor of Radiation Oncology, Radiology, and Cell and Molecular Biology in the Feinberg School of Medicine, Northwestern University. Dr. Woloschak received her Ph.D. in Medical Sciences from the University of Toledo (Medical College of Ohio). She did her postdoctoral training at the Mayo Clinic, and then moved to Argonne National Laboratory until 2001. Her scientific interests are predominantly in the areas of molecular biology, radiation biology, and nanotechnology studies, and she has authored over 200 papers. She is a member of the National Council on Radiation Protection, the International Commission on Radiation Protection and numerous other committees and also serves on the US delegation to the United National Scientific Committee on the Effects of Atomic Radiation.
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Introducing the Targeted Anticancer Therapies and Precision Medicine in Cancer Collection - PLoS Blogs