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Annual Review of Cancer Biology - Volume 3, 2019
Volume 3, 2019
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A Joint Odyssey into Cancer Genetics
Vol. 3 (2019), pp. 1–19More LessThe war on cancer that began some 40 years ago with the discovery of oncogenes is starting to be won. We feel fortunate to have contributed to several advances. Here we recall how molecular biology became our scientific passion, how we met from opposite ends of the earth, and how our 50-year odyssey has taken us from gene expression through immunogenetics to exploring the molecular basis of cancer and cell death. We describe the scientific discoveries that motivated us and remarkable scientists who influenced us. We sketch our studies that clarified the role of chromosome translocations in cancer and established the value of genetically engineered mouse models of tumorigenesis. Finally, we outline how our findings with many talented close colleagues on cell death regulation stimulated the development of remarkable new anticancer agents called BH3 mimetics, which are encouraging hope that many more malignancies will become controllable and even curable.
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Targeting Therapies for the p53 Protein in Cancer Treatments
Vol. 3 (2019), pp. 21–34More LessHalf of all human cancers contain TP53 mutations, and in many other cancers, the function of the p53 protein is compromised. The diversity of these mutations and phenotypes presents a challenge to the development of drugs that target p53 mutant cancer cells. This review describes the rationale for many different approaches in the development of p53 targeted therapies: (a) viruses and gene therapies, (b) increased levels and activity of wild-type p53 proteins in cancer cells, (c) p53 protein gain-of-function inhibitors, (d) p53 protein loss-of-function structural correctors, (e) mutant p53 protein synthetic lethal drugs interfering with the p53 pathway, and (f) cellular immune responses to mutant p53 protein antigens. As these types of therapies are developed, tested, and evaluated, the best of them will have a significant impact upon cancer treatments and possibly prevention.
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The Hallmarks of Ferroptosis
Vol. 3 (2019), pp. 35–54More LessFerroptosis is a nonapoptotic, iron-dependent form of cell death that can be activated in cancer cells by natural stimuli and synthetic agents. Three essential hallmarks define ferroptosis, namely: the loss of lipid peroxide repair capacity by the phospholipid hydroperoxidase GPX4, the availability of redox-active iron, and oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids. Several processes including RAS/MAPK signaling, amino acid and iron metabolism, ferritinophagy, epithelial-to-mesenchymal transition, cell adhesion, and mevalonate and phospholipid biosynthesis can modulate susceptibility to ferroptosis. Ferroptosis sensitivity is also governed by p53 and KEAP1/NRF2 activity, linking ferroptosis to the function of key tumor suppressor pathways. Together these findings highlight the role of ferroptosis as an emerging concept in cancer biology and an attractive target for precision cancer medicine discovery.
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Cancer Immunotherapy: Beyond Checkpoint Blockade
Vol. 3 (2019), pp. 55–75More LessBlocking antibodies to the immune checkpoint receptors or their ligands have revolutionized the treatment of diverse malignancies. Many tumors are recognized by adaptive immunity, but these adaptive responses can be inhibited by immunosuppressive mechanisms within the tumor, often through pathways outside of the currently targeted checkpoints. For this reason, only a minority of cancer patients achieve durable responses to current immunotherapies. Multiple novel approaches strive to expand immunotherapy's reach. These may include targeting alternative immune checkpoints. However, many investigational strategies look beyond checkpoint blockade. These include cellular therapies to bypass endogenous immunity and efforts to stimulate new adaptive antitumor responses using vaccines, adjuvants, and combinations with cytotoxic therapy, as well as strategies to inhibit innate immune suppression and modulate metabolism within the tumor microenvironment. The challenge for immunotherapy going forward will be to select rational strategies for overcoming barriers to effective antitumor responses from the myriad possible targets.
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Natural Killer Cells in Cancer Immunotherapy
Vol. 3 (2019), pp. 77–103More LessNatural killer (NK) cells have evolved to complement T and B cells in host defense against pathogens and cancer. They recognize infected cells and tumors using a sophisticated array of activating, costimulatory, and inhibitory receptors that are expressed on NK cell subsets to create extensive functional diversity. NK cells can be targeted to kill with exquisite antigen specificity by antibody-dependent cellular cytotoxicity. NK and T cells share many of the costimulatory and inhibitory receptors that are currently under evaluation in the clinic for cancer immunotherapy. As with T cells, genetic engineering is being employed to modify NK cells to specifically target them to tumors and to enhance their effector functions. As the selective pressures exerted by immunotherapies to augment CD8+ T cell responses may result in loss of MHC class I, NK cells may provide an important fail-safe to eliminate these tumors by their capacity to eliminate tumors that are “missing self.”
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NAD+ Metabolism in Aging and Cancer
Vol. 3 (2019), pp. 105–130More LessAging is a major risk factor for many types of cancer, and the molecular mechanisms implicated in aging, progeria syndromes, and cancer pathogenesis display considerable similarities. Maintaining redox homeostasis, efficient signal transduction, and mitochondrial metabolism is essential for genome integrity and for preventing progression to cellular senescence or tumorigenesis. NAD+ is a central signaling molecule involved in these and other cellular processes implicated in age-related diseases and cancer. Growing evidence implicates NAD+ decline as a major feature of accelerated aging progeria syndromes and normal aging. Administration of NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) offer promising therapeutic strategies to improve health, progeria comorbidities, and cancer therapies. This review summarizes insights from the study of aging and progeria syndromes and discusses the implications and therapeutic potential of the underlying molecular mechanisms involved in aging and how they may contribute to tumorigenesis.
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PARP Trapping Beyond Homologous Recombination and Platinum Sensitivity in Cancers
Junko Murai, and Yves PommierVol. 3 (2019), pp. 131–150More LessPoly(ADP-ribose) polymerase inhibitors (PARPis) have recently been approved for the treatment of ovarian and breast cancers with BRCA mutations, as well as for maintenance therapies regardless of BRCA mutation for ovarian and primary peritoneal cancers that previously responded to platinum-based chemotherapy. The rationale of these indications is derived from the facts that cancer cells with BRCA mutations are defective in homologous recombination (HR), which confers synthetic lethality with PARPis, and that some of the sensitivity-determining factors for PARPis are shared with platinums. Although BRCA1 and BRCA2 are central for HR, more players within and beyond HR are emerging as response determinants to PARPis. Furthermore, there are similarities as well as differences in the DNA lesions and repair pathways induced by PARPis, platinums, and camptothecin topoisomerase 1 (TOP1) inhibitors. Here we review the sensitivity-determining factors for PARPis and the rationale for using PARPis as single agents and in combination therapy for cancers.
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Deciphering Human Tumor Biology by Single-Cell Expression Profiling
Itay Tirosh, and Mario L. SuvàVol. 3 (2019), pp. 151–166More LessHuman tumors are complex ecosystems where diverse cancer and noncancer cells interact to determine tumor biology and response to therapies. Genomic and transcriptomic methods have traditionally profiled these intricate ecosystems as bulk samples, thereby masking individual cellular programs and the variability among them. Recent advances in single-cell profiling have paved the way for studying tumors at the resolution of individual cells, providing a compelling strategy to bridge gaps in our understanding of human tumors. Here, we review methodologies for single-cell expression profiling of tumors and the initial studies deploying them in clinical contexts. We highlight how these studies uncover new biology and provide insights into drug resistance, stem cell programs, metastasis, and tumor classifications. We also discuss areas of technology development in single-cell genomics that provide new tools to address key questions in cancer biology. These emerging studies and technologies have the potential to revolutionize our understanding and management of human malignancies.
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Aberrant RNA Splicing in Cancer
Vol. 3 (2019), pp. 167–185More LessRNA splicing, the enzymatic process of removing segments of premature RNA to produce mature RNA, is a key mediator of proteome diversity and regulator of gene expression. Increased systematic sequencing of the genome and transcriptome of cancers has identified a variety of means by which RNA splicing is altered in cancer relative to normal cells. These findings, in combination with the discovery of recurrent change-of-function mutations in splicing factors in a variety of cancers, suggest that alterations in splicing are drivers of tumorigenesis. Greater characterization of altered splicing in cancer parallels increasing efforts to pharmacologically perturb splicing and early-phase clinical development of small molecules that disrupt splicing in patients with cancer. Here we review recent studies of global changes in splicing in cancer, splicing regulation of mitogenic pathways critical in cancer transformation, and efforts to therapeutically target splicing in cancer.
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Circulating Tumor DNA: Clinical Monitoring and Early Detection
Vol. 3 (2019), pp. 187–201More LessRoughly 70 years after the presence of cell-free DNA (cfDNA) in circulating blood was discovered, cfDNA has emerged as a transformative technology in clinical oncology. The ability to assess the presence, level, and composition of tumor DNA from a routine, noninvasive blood draw has opened the door to a broad array of high-impact clinical applications. While cfDNA is rapidly gaining clinical favor as a means of tumor mutational profiling without the need for an invasive biopsy, emerging applications in the areas of clinical monitoring and early cancer detection hold tremendous promise. These developing applications of cfDNA are reviewed herein.
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MiT/TFE Family of Transcription Factors, Lysosomes, and Cancer
Vol. 3 (2019), pp. 203–222More LessCancer cells have an increased demand for energy sources to support accelerated rates of growth. When nutrients become limiting, cancer cells may switch to nonconventional energy sources that are mobilized through nutrient scavenging pathways involving autophagy and the lysosome. Thus, several cancers are highly reliant on constitutive activation of these pathways to degrade and recycle cellular materials. Here, we focus on the MiT/TFE family of transcription factors, which control transcriptional programs for autophagy and lysosome biogenesis and have emerged as regulators of energy metabolism in cancer. These new findings complement earlier reports that chromosomal translocations and amplifications involving the MiT/TFE genes contribute to the etiology and pathophysiology of renal cell carcinoma, melanoma, and sarcoma, suggesting pleiotropic roles for these factors in a wider array of cancers. Understanding the interplay between the oncogenic and stress-adaptive roles of MiT/TFE factors could shed light on fundamental mechanisms of cellular homeostasis and point to new strategies for cancer treatment.
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Organoid Models for Cancer Research
Vol. 3 (2019), pp. 223–234More LessOrganoid cultures have emerged as powerful model systems accelerating discoveries in cellular and cancer biology. These three-dimensional cultures are amenable to diverse techniques, including high-throughput genome and transcriptome sequencing, as well as genetic and biochemical perturbation, making these models well suited to answer a variety of questions. Recently, organoids have been generated from diverse human cancers, including breast, colon, pancreas, prostate, bladder, and liver cancers, and studies involving these models are expanding our knowledge of the etiology and characteristics of these malignancies. Co-cultures of cancer organoids with non-neoplastic stromal cells enable investigation of the tumor microenvironment. In addition, recent studies have established that organoids have a place in personalized medicine approaches. Here, we describe the application of organoid technology to cancer discovery and treatment.
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Resistance to PARP Inhibitors: Lessons from Preclinical Models of BRCA-Associated Cancer
Vol. 3 (2019), pp. 235–254More LessInhibitors of poly(ADP-ribose) polymerase (PARP) have recently entered the clinic for the treatment of homologous recombination–deficient cancers. Despite the success of this approach, resistance to PARP inhibitors (PARPis) is a clinical hurdle, and it is poorly understood how cancer cells escape the deadly effects of PARPis without restoring BRCA1/2 function. By synergizing the advantages of next-generation sequencing with functional genetic screens in tractable model systems, novel mechanisms providing useful insights into DNA damage response (DDR) have been identified. BRCA1/2 models not only are tools to explore therapy escape mechanisms but also yield basic knowledge about DDR pathways and PARPis’ mechanism of action. Moreover, alterations that render cells resistant to targeted therapies may cause new synthetic dependencies that can be exploited to combat resistant disease.
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Dietary Fat and Sugar in Promoting Cancer Development and Progression
Vol. 3 (2019), pp. 255–273More LessThe uncontrolled cellular growth that characterizes tumor formation requires a constant delivery of nutrients. Since the 1970s, researchers have wondered if the supply of nutrients from the diet could impact tumor development. Numerous studies have assessed the impact of dietary components, specifically sugar and fat, to increased cancer risk. For the most part, data from these trials have been inconclusive; however, this does not indicate that dietary factors do not contribute to cancer progression. Rather, the dietary contribution may be dependent on tumor, patient, and context, making it difficult to detect in the setting of large trials. In this review, we combine data from prospective cohort trials with mechanistic studies in mice to argue that fat and sugar can play a role in tumorigenesis and disease progression. We find that certain tumors may respond directly to dietary sugar (colorectal and endometrial cancers) and fat (prostate cancer) or indirectly to the obese state (breast cancer).
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HSP90: Enabler of Cancer Adaptation
Vol. 3 (2019), pp. 275–297More LessThe stability and function of many oncogenic mutant proteins depend on heat shock protein 90 (HSP90). This unique activity has inspired the exploration of HSP90 as an anticancer target for over two decades. Unfortunately, while clinical trials of highly optimized HSP90 inhibitors have demonstrated modest benefit for patients with advanced cancers, most commonly stabilization of disease, no HSP90 inhibitor has demonstrated sufficient efficacy to achieve FDA approval to date. This review discusses potential reasons for the limited success of these agents and how our increasingly sophisticated understanding of HSP90 suggests alternative, potentially more effective strategies for targeting it to treat cancers. First, we focus on insights gained from model organisms that suggest a fundamental role for HSP90 in supporting the adaptability and heterogeneity of cancers, key factors underlying their ability to evolve and acquire drug resistance. Second, we examine how HSP90’s role in promoting the stability of mutant proteins might be targeted in genetically unstable tumor cells to reveal their aberrant, foreign proteome to the immune system. Both of these emerging aspects of HSP90 biology suggest that the most effective use of HSP90 inhibitors may not be at high doses with the intent to kill cancer cells, but rather in combination with other molecularly targeted therapies at modest, non-heat shock-inducing exposures that limit the adaptive capacity of cancers.
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Biology and Therapy of Dominant Fusion Oncoproteins Involving Transcription Factor and Chromatin Regulators in Sarcomas
Vol. 3 (2019), pp. 299–321More LessA third of soft tissue sarcomas have been shown to carry recurrent, characteristic chromosomal translocations, many of which generate fusion proteins that act as dominant transcription factors or as chromatin regulators. With routine use of massively parallel sequencing and advances in technology for the study of epigenetics and protein complexes, the last decade has seen a marked advancement in the identification of novel fusions and in our understanding of the mechanisms by which they contribute to the malignant state. Moreover, with new approaches in chemistry, such as the strategy of targeted protein degradation, we are now better poised to address these previously intractable targets. In this review, we describe three of the most common fusion-driven sarcomas (Ewing sarcoma, alveolar rhabdomyosarcoma, and synovial sarcoma), mechanistic themes emerging across these diseases, and novel approaches to their targeting.
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Roles of the cGAS-STING Pathway in Cancer Immunosurveillance and Immunotherapy
Vol. 3 (2019), pp. 323–344More LessCyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that initiates innate immune responses. DNA-bound cGAS produces cyclic GMP-AMP (cGAMP), which activates stimulator of interferon genes (STING) to induce inflammatory cytokines and other immune mediators. cGAS detects DNA without sequence specificity and responds to both cytosolic foreign DNA from pathogens and self-DNA leaked into the cytosol due to genome instability or cellular damage. Because of the diverse sources of cytosolic DNA, the cGAS-STING pathway plays a critical role during infection, autoimmune diseases, and senescence. Moreover, cGAS detects tumor-derived DNA and stimulates endogenous antitumor immunity. Thus, the cGAS-STING pathway is a promising target for cancer immunotherapy. Here, we review the role of the cGAS-STING pathway in various diseases and highlight various approaches targeting the cGAS-STING pathway for cancer therapy.
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Functional Genomics for Cancer Research: Applications In Vivo and In Vitro
Vol. 3 (2019), pp. 345–363More LessFunctional genomics holds great promise for the dissection of cancer biology. The elucidation of genetic cooperation and molecular details that govern oncogenesis, metastasis, and response to therapy is made possible by robust technologies for perturbing gene function coupled to quantitative analysis of cancer phenotypes resulting from genetic or epigenetic perturbations. Multiplexed genetic perturbations enable the dissection of cooperative genetic lesions as well as the identification of synthetic lethal gene pairs that hold particular promise for constructing innovative cancer therapies. Lastly, functional genomics strategies enable the highly multiplexed in vivo analysis of genes that govern tumorigenesis as well as of the complex multicellular biology of a tumor, such as immune response and metastasis phenotypes. In this review, we discuss both historical and emerging functional genomics approaches and their impact on the cancer research landscape.
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Targeting Cancer at the Intersection of Signaling and Epigenetics
Vol. 3 (2019), pp. 365–384More LessWhile mutations resulting in the chronic activation of signaling pathways drive human cancer, the epigenetic state of a cell ultimately dictates the biological response to any given oncogenic signal. Moreover, large-scale genomic sequencing efforts have now identified a plethora of mutations in chromatin regulatory genes in human tumors, which can amplify, modify, or complement traditional oncogenic events. Nevertheless, the co-occurrence of oncogenic and epigenetic defects appears to create novel therapeutic vulnerabilities, which can be targeted by specific drug combinations. Here we discuss general mechanisms by which oncogenic and epigenetic alterations cooperate in human cancer and synthesize the field's early efforts in developing promising therapeutic combinations. Collectively, these studies reveal common themes underlying potential chemical synthetic lethal interactions and support both the expansion and refinement of this type of therapeutic approach.
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Academic Discovery of Anticancer Drugs: Historic and Future Perspectives
Vol. 3 (2019), pp. 385–408More LessThe identification and prosecution of meritorious anticancer drug targets and the discovery of clinical candidates represent an extraordinarily time- and resource-intensive process, and the current failure rate of late-stage drugs is a critical issue that must be addressed. Relationships between academia and industry in drug discovery and development have continued to change over time as a result of technical and financial challenges and, most importantly, to the objective of translating impactful scientific discoveries into clinical opportunities. This Golden Age of anticancer drug discovery features an increased appreciation for the high-risk, high-innovation research conducted in the nonprofit sector, with the goals of infusing commercial drug development with intellectual capital and curating portfolios that are financially tenable and clinically meaningful. In this review, we discuss the history of academic-industry interactions in the context of antidrug discovery and offer a view of where these interactions are likely headed as we continue to reach new horizons in our understanding of the immense complexities of cancer biology.
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Aiding and Abetting: How the Tumor Microenvironment Protects Cancer from Chemotherapy
Vol. 3 (2019), pp. 409–428More LessDisease recurrence following cancer therapy remains an intractable clinical problem and represents a major impediment to reducing the mortality attributable to malignant tumors. While research has traditionally focused on the cell-intrinsic mechanisms and mutations that render tumors refractory to both classical chemotherapeutics and targeted therapies, recent studies have begun to uncover myriad roles for the tumor microenvironment (TME) in modulating therapeutic efficacy. This work suggests that drug resistance is as much ecological as it is evolutionary. Specifically, cancers resident in organs throughout the body do not develop in isolation. Instead, tumor cells arise in the context of nonmalignant cellular components of a tissue. While the roles of these cell-extrinsic factors in cancer initiation and progression are well established, our understanding of the TME's influence on therapeutic outcome is in its infancy. Here, we focus on mechanisms by which neoplastic cells co-opt preexisting or treatment-induced signaling networks to survive chemotherapy.
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Taming the Heterogeneity of Aggressive Lymphomas for Precision Therapy
Vol. 3 (2019), pp. 429–455More LessGenomic analyses of diffuse large B cell lymphoma (DLBCL) are revealing the genetic and phenotypic heterogeneity of these aggressive lymphomas. In part, this heterogeneity reflects the existence of distinct genetic subtypes that acquire characteristic constellations of somatic genetic alterations to converge on the DLBCL phenotype. In parallel, functional genomic screens and proteomic analyses have identified multiprotein assemblies that coordinate oncogenic survival signaling in DLBCL. In this review, we merge these recent insights into a unified conceptual framework with implications for the design of precision medicine trials in DLBCL.
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The Fanconi Anemia Pathway in Cancer
Vol. 3 (2019), pp. 457–478More LessFanconi anemia (FA) is a complex genetic disorder characterized by bone marrow failure (BMF), congenital defects, inability to repair DNA interstrand cross-links (ICLs), and cancer predisposition. FA presents two seemingly opposite characteristics: (a) massive cell death of the hematopoietic stem and progenitor cell (HSPC) compartment due to extensive genomic instability, leading to BMF, and (b) uncontrolled cell proliferation leading to FA-associated malignancies. The canonical function of the FA proteins is to collaborate with several other DNA repair proteins to eliminate clastogenic (chromosome-breaking) effects of DNA ICLs. Recent discoveries reveal that the FA pathway functions in a critical tumor-suppressor network to preserve genomic integrity by stabilizing replication forks, mitigating replication stress, and regulating cytokinesis. Homozygous germline mutations (biallelic) in 22 FANC genes cause FA, whereas heterozygous germline mutations in some of the FANC genes (monoallelic), such as BRCA1 and BRCA2, do not cause FA but significantly increase cancer susceptibility sporadically in the general population. In this review, we discuss our current understanding of the functions of the FA pathway in the maintenance of genomic stability, and we present an overview of the prevalence and clinical relevance of somatic mutations in FA genes.
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