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Annual Review of Cancer Biology - Current Issue
Volume 8, 2024
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An Erratic Path Toward Discovery
Vol. 8 (2024), pp. 1–13More LessThrough a series of accidents of history, my career began just when the revolution in molecular biology was taking place. The allure of molecular biology attracted me to exploiting tumor viruses as experimental models of the nucleic acid metabolism of cells. The fact that these viruses cause cancer was incidental but eventually led to an interest in cancer pathogenesis, exploiting them to understand the mechanisms of cell transformation. This made it possible to test the speculation that cell transformation derived from the mutation of cellular genes and that cancer cell behavior is driven by the actions of resulting mutant alleles of these genes. In 1979, we showed that cells that had been transformed by 3-methylcholanthrene carried a mutant oncogenic allele. This work progressed so that by 1982 my research group and others demonstrated that human bladder carcinoma cells carried a point-mutated RAS oncogene, providing a direct proof of the mutational theory of cancer pathogenesis.
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Complex Roles of PTPN11/SHP2 in Carcinogenesis and Prospect of Targeting SHP2 in Cancer Therapy
Vol. 8 (2024), pp. 15–33More LessThe nonreceptor tyrosine phosphatase SHP2 has been at the center of cell signaling research for three decades. SHP2 is required to fully activate the RTK/RAS/ERK signaling cascade, although the underlying mechanisms are not completely understood. PTPN11, which encodes SHP2, is the first identified proto-oncogene that encodes a tyrosine phosphatase, with dominantly activating mutations detected in leukemias and solid tumors. However, SHP2 has pro- and antioncogenic effects, and the most recent data reveal opposite activities of SHP2 in tumor cells and microenvironment cells. Allosteric SHP2 inhibitors show promising antitumor effects and overcome resistance to inhibitors of RAS/ERK signaling in animal models. Many clinical trials with orally bioactive SHP2 inhibitors, alone or combined with other regimens, are ongoing for a variety of cancers worldwide, with therapeutic outcomes yet unknown. This review discusses the multifaceted functions of SHP2 in oncogenesis, preclinical studies, and clinical trials with SHP2 inhibitors in oncological treatment.
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Deciphering the Warburg Effect: Metabolic Reprogramming, Epigenetic Remodeling, and Cell Dedifferentiation
Albert M. Li, and Jiangbin YeVol. 8 (2024), pp. 35–58More LessA century ago, Otto Heinrich Warburg made a seminal discovery now known as the Warburg effect. This metabolic signature, prevalent across all cancer cells, is characterized by the prominent shift of glucose metabolism toward lactate production instead of oxidative respiration. Warburg's pioneering theory suggested that the induction of the Warburg effect instigates dedifferentiation and the process of tumorigenesis, illuminating a fundamental mechanism underlying cancer development. To celebrate the centennial anniversary of Warburg's monumental finding, it is an appropriate moment to reflect upon and commemorate his revolutionary contributions to the fields of metabolism and cancer research. In this review, we explore the role of mitochondria in epigenetic regulation and the decisions governing cell fate from an evolutionary standpoint. Moreover, we summarize metabolic and genetic factors that trigger the Warburg effect, underscoring the therapeutic potential of mitochondrial uncoupling as a strategy to counter this metabolic aberration. Our goal is to elucidate the means to induce tumor differentiation through metabolic therapy, thereby laying a foundation toward the cure for cancer.
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Basket Trials: Past, Present, and Future
Vol. 8 (2024), pp. 59–80More LessLarge-scale tumor molecular profiling has revealed that diverse cancer histologies are driven by common pathways with unifying biomarkers that can be exploited therapeutically. Disease-agnostic basket trials have been increasingly utilized to test biomarker-driven therapies across cancer types. These trials have led to drug approvals and improved the lives of patients while simultaneously advancing our understanding of cancer biology. This review focuses on the practicalities of implementing basket trials, with an emphasis on molecularly targeted trials. We examine the biologic subtleties of genomic biomarker and patient selection, discuss previous successes in drug development facilitated by basket trials, describe certain novel targets and drugs, and emphasize practical considerations for participant recruitment and study design. This review also highlights strategies for aiding patient access to basket trials. As basket trials become more common, steps to ensure equitable implementation of these studies will be critical for molecularly targeted drug development.
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Mechanisms of Resistance to Targeted Therapies in AML
Vol. 8 (2024), pp. 81–96More LessThe treatment of acute myeloid leukemia (AML) has historically relied on cytotoxic chemotherapy, but modern understanding of AML biology has paved the way for new treatments that target the molecular pathways that drive AML, in particular FLT3, IDH1/IDH2, and BCL2. Many of these targeted therapies are effective, but responses are typically short-lived and resistance remains a ubiquitous clinical problem. Understanding the mechanisms of resistance to targeted therapy is essential to continue improving AML therapy. Recent studies have shed new light on the ways in which AML evades targeted inhibition, including on-target resistance mutations, mutations in parallel molecular pathways, and plasticity in cellular state. In this review, we outline the mechanisms of resistance to commonly used targeted therapies in AML and discuss ideas to overcome the urgent problem of resistance.
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RAS and SHOC2 Roles in RAF Activation and Therapeutic Considerations
Vol. 8 (2024), pp. 97–113More LessMutations in RAS proteins play a pivotal role in the development of human cancers, driving persistent RAF activation and deregulating the mitogen-activated protein kinase (MAPK) signaling pathway. While progress has been made in targeting specific oncogenic RAS proteins, effective drug-based therapies for most RAS mutations remain limited. Recent investigations into RAS–RAF complexes and the SHOC2–MRAS–PP1C holoenzyme complex have provided crucial insights into the structural and functional aspects of RAF activation within the MAPK signaling pathway. Moreover, these studies have also unveiled new blueprints for developing inhibitors, allowing us to think beyond the current RAS and MEK inhibitors. In this review, we explore the roles of RAS and SHOC2 in activating RAF and discuss potential therapeutic strategies to target these proteins. A comprehensive understanding of the molecular interactions involved in RAF activation and their therapeutic implications can potentially drive innovative approaches in combating RAS-/RAF-driven cancers.
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Advances in Therapies Targeting Inhibitory Checkpoint Receptors: TIGIT, LAG-3, and Beyond
Vol. 8 (2024), pp. 115–133More LessProgress in our understanding of how tumor cells co-opt immune checkpoint receptor (ICR) regulation of the immune response to suppress T cell function and how these proteins interact in the tumor microenvironment has resulted in the development of a plethora of therapeutic ICR monoclonal antibodies. While anti-CTLA-4 and anti-PD-1/PD-L1 therapies have provided meaningful clinical benefit in patients with certain cancers, many patients either do not respond or experience disease progression. As such, dual blockade of PD-1/PD-L1 and ICRs with alternative mechanisms of action has the potential to improve outcomes in patients with cancer. In this review, we focus on the biology of and clinical investigations into two promising ICR targets: LAG-3 and TIGIT. The data suggest that blockade of these ICRs in combination with PD-1/PD-L1 in immune-sensitive tumors could enhance anti-PD-1 efficacy without increased toxicity, facilitate combinations with standard-of-care therapies, and extend treatment benefit to more patients.
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Extrachromosomal DNA: Biogenesis and Functions in Cancer
Vol. 8 (2024), pp. 135–153More LessIn cancer, oncogenes can untether themselves from chromosomes onto circular, extrachromosomal DNA (ecDNA) particles. ecDNA are common in many of the most aggressive forms of cancer of women and men and of adults and children, and they contribute to treatment resistance and shorter survival for patients. Hiding in plain sight and missing from cancer genome maps, ecDNA was not, until recently, widely recognized to be an important feature of cancer pathogenesis. However, extensive new data demonstrate that ecDNA is a frequent and potent driver of aggressive cancer growth and treatment failure that can arise early or late in the course of the disease. The non-Mendelian genetics of ecDNA lies at the heart of the problem. By untethering themselves from chromosomes, ecDNA are randomly distributed to daughter cells during cell division, promoting high oncogene copy number, intratumoral genetic heterogeneity, accelerated tumor evolution, and treatment resistance due to rapid genome change. Further, the circular shape of ecDNA, and its high level of chromatin accessibility, promotes oncogene transcription and generates unique enhancer–promoter interactions in cis, as well as cooperative regulatory interactions between ecDNA particles in trans. In this review, we discuss the state of the field and its implications for patients with oncogene-amplified cancers.
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Chemical Proteomics–Guided Discovery of Covalent Ligands for Cancer Proteins
Vol. 8 (2024), pp. 155–175More LessAdvances in genome sequencing and editing technologies have enriched our understanding of the biochemical pathways that drive tumorigenesis. Translating this knowledge into new medicines for cancer treatment, however, remains challenging, and many oncogenic proteins have proven recalcitrant to conventional approaches for chemical probe and drug discovery. Here, we discuss how innovations in chemical proteomics and covalent chemistry are being integrated to identify and advance first-in-class small molecules that target cancer-relevant proteins. Mechanistic studies have revealed that covalent compounds perturb protein functions in cancer cells in diverse ways that include the remodeling of protein–protein and protein–RNA complexes, as well as through alterations in posttranslational modification. We speculate on the attributes of chemical proteomics and covalent chemistry that have enabled targeting of previously inaccessible cancer-relevant pathways and consider technical challenges that remain to be addressed in order to fully realize the druggability of the cancer proteome.
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Relationships Between Regeneration, Wound Healing, and Cancer
Gianna Maggiore, and Hao ZhuVol. 8 (2024), pp. 177–197More LessRegeneration and cancer share genetic mechanisms and cellular processes. While highly regenerative cells are often the source of cancer, persistent injury or imperfect regeneration in the form of wound healing can lead to degenerative conditions that favor cancer development. Thus, the causal interplay between regeneration and cancer is complex. This article focuses on understanding how functional variation in regeneration and wound healing might influence the risk of cancer. Variation in regenerative capacity might create trade-offs or adaptations that significantly alter cancer risk. From this perspective, we probe the causal relationships between regeneration, wound healing, and cancer.
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Biological, Diagnostic, and Therapeutic Insights from (Epi)Genomic Profiling of Pediatric Brain Tumors
Vol. 8 (2024), pp. 199–226More LessPediatric brain tumors comprise a diverse set of diseases. (Epi)genomic analyses have provided insights into the biology of these tumors, stratifying them into distinct subtypes with different oncogenic driver mechanisms and developmental origins. A feature shared by these tumors is their initiation within neural stem or progenitor cells that undergo stalled differentiation in unique, niche-dependent ways. In this review, we provide an overview of how (epi)genomic characterization has revealed pediatric brain tumor origins and underlying biology. We focus on the best characterized tumor types—gliomas, ependymomas, medulloblastomas—as well as select rarer types such as embryonal tumors with multilayered rosettes, atypical teratoid/rhabdoid tumors, and choroid plexus carcinomas in which new insights have been made. The discovery of diverse developmental origins of these tumors and their defining molecular characteristics has led to a better understanding of their etiologies, with important implications for diagnostics, future therapy development, and clinical trial design.
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Allogeneic CAR T Cell Therapy for Cancer
Vol. 8 (2024), pp. 227–243More LessAutologous chimeric antigen receptor (CAR) T cell therapy, produced from the patient's own T cells, has changed the treatment landscape for hematologic malignancies but has some drawbacks that prevent large-scale clinical application, including logistical complexities in supply, patient T cell health, treatment delays, and limited manufacturing slots. Allogeneic, or off-the-shelf, CAR T cell therapies have the potential to overcome many of the limitations of autologous therapies, with the aim of bringing benefit to all patients eligible for treatment. This review highlights the progress and challenges of allogeneic cell therapies for cancer and the various approaches that are being evaluated preclinically and in clinical trials to enhance the persistence and antitumor efficacy of allogeneic CAR T cells, including new strategies to avoid immune rejection.
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Applications of Digital Pathology in Cancer: A Comprehensive Review
Vol. 8 (2024), pp. 245–268More LessDigital pathology, powered by whole-slide imaging technology, has the potential to transform the landscape of cancer research and diagnosis. By converting traditional histopathological specimens into high-resolution digital images, it paves the way for computer-aided analysis, uncovering a new horizon for the integration of artificial intelligence (AI) and machine learning (ML). The accuracy of AI- and ML-driven tools in distinguishing benign from malignant tumors and predicting patient outcomes has ushered in an era of unprecedented opportunities in cancer care. However, this promising field also presents substantial challenges, such as data security, ethical considerations, and the need for standardization. In this review, we delve into the needs that digital pathology addresses in cancer research, the opportunities it presents, its inherent potential, and the challenges it faces. The goal of this review is to stimulate a comprehensive discourse on harnessing digital pathology and AI in health care, with an emphasis on cancer diagnosis and research.
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Metabolic Rewiring During Metastasis: The Interplay Between the Environment and the Host
Vol. 8 (2024), pp. 269–290More LessFollowing escape from the primary tumor, cancer cells face diverse micro-environments during the metastatic cascade. To survive and establish outgrowth at a distant site, metastasizing cancer cells must undergo metabolic reprogramming to adapt to the changing conditions. However, the host in which the tumors grow also experiences metabolic adaptations in response to various environmental factors that can mediate cancer progression. In this review, we highlight the endogenous factors that determine host metabolism (nutrient availability at specific organs or the microbiome), as well as exogenous factors that influence host metabolism systemically or locally (diet, alcohol, physical activity, air pollution, and circadian rhythm). Furthermore, we elaborate on how these environment-induced metabolic changes can affect metastatic progression. Understanding the interplay between environmental factors, host metabolism, and metastatic progression may unveil potential targets for future therapeutic interventions.
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Therapeutic Targeting of the Menin–KMT2A Interaction
Vol. 8 (2024), pp. 291–307More LessThe direct targeting of chromatin-associated proteins is increasingly recognized as a potential therapeutic strategy for the treatment of cancer. In this review, we discuss a prominent example, namely, small-molecule inhibitors that target the menin–KMT2A interaction. These molecules are currently being investigated in clinical trials and showing significant promise. We describe the unique specificity of menin–KMT2A protein complexes for the transcriptional regulation of a small subset of genes that drive developmental and leukemic gene expression. We review the chromatin-associated KMT2A complex and the protein–protein interaction between menin and KMT2A that is essential for the maintenance of different types of cancer cells, but most notably acute myeloid leukemia (AML). We also summarize the development of menin inhibitors and their effects on chromatin. Finally, we discuss the promising early results from clinical trials in patients with AML and the recent discovery of therapy-resistant menin mutants that validate menin as a therapeutic target but also may present therapeutic challenges.
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Germline Predisposition to Hematopoietic Malignancies: An Overview
Vol. 8 (2024), pp. 309–329More LessDeleterious germline variants are now recognized as common drivers of hematopoietic malignancies (HMs) and bone marrow failure syndromes. With the increasing use of personalized medicine and the application of tumor-based profiling via next-generation sequencing, diagnosis of HM predisposition occurs with increasing frequency. Although deleterious germline variants can be readily identified by comprehensive clinical testing, numerous barriers exist for many clinicians. Observations regarding particular germline predisposition disorders challenge widely held assumptions about these conditions. Here, we review approaches to germline genetic testing, highlighting key points in a typical patient's course that present challenges for testing and interpreting results. Increasing awareness by health care providers of these conditions and improvements in testing platforms are crucial for enabling a proactive approach to tailoring a suitable treatment plan and surveillance program for the patient and their family members.
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YAP, TAZ, and Hippo-Dysregulating Fusion Proteins in Cancer
Vol. 8 (2024), pp. 331–350More LessGene fusions are well-known drivers of cancer and are potent targets for molecular therapy. An emerging spectrum of human tumors harbors recurrent and pathognomonic gene fusions that involve the transcriptional coactivator YAP1 (which encodes the protein YAP) or its paralog WWTR1 (which encodes the protein TAZ). YAP and TAZ are frequently activated in cancer and are the transcriptional effectors of the Hippo pathway, a highly conserved kinase cascade that regulates diverse functions such as organ size, development, and homeostasis. In this review, we discuss the tumors that have YAP, TAZ, or other Hippo-dysregulating fusion proteins; the mechanisms of these fusion proteins in driving their respective tumors; and the potential vulnerabilities of these chimeric oncoproteins across cancers of many origins. Furthermore, as new YAP1 and WWTR1 gene fusions are discovered, we provide a framework to predict whether the resulting protein product is likely to be oncogenic.
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Next-Generation Therapies for Multiple Myeloma
Vol. 8 (2024), pp. 351–371More LessRecent therapeutic advances have significantly improved the outcome for patients with multiple myeloma (MM). The backbone of successful standard therapy is the combination of Ikaros degraders, glucocorticoids, and proteasome inhibitors that interfere with the integrity of myeloma-specific superenhancers by directly or indirectly targeting enhancer-bound transcription factors and coactivators that control expression of MM dependency genes. T cell engagers and chimeric antigen receptor T cells redirect patients’ own T cells onto defined tumor antigens to kill MM cells. They have induced complete remissions even in end-stage patients. Unfortunately, responses to both conventional therapy and immunotherapy are not durable, and tumor heterogeneity, antigen loss, and lack of T cell fitness lead to therapy resistance and relapse. Novel approaches are under development to target myeloma-specific vulnerabilities, as is the design of multimodality immunological approaches, including and beyond T cells, that simultaneously recognize multiple epitopes to prevent antigen escape and tumor relapse.
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Therapeutic Discovery for Chromatin Complexes: Where Do We Stand?
Vol. 8 (2024), pp. 373–393More LessIn this review, we explore the current landscape of preclinical and clinical therapeutics targeting epigenetic complexes in cancer, focusing on targets with enzymatic inhibitors, degraders, or ligands capable of disrupting protein–protein interactions. Current strategies face challenges such as limited single-agent clinical efficacy due to insufficient disruption of chromatin complexes and incomplete dissociation from chromatin. Further complications arise from the adaptability of cancer cell chromatin and, in some cases, dose-limiting toxicity. The advent of targeted protein degradation (TPD) through degrader compounds such as proteolysis-targeting chimeras provides a promising approach. These innovative molecules exploit the endogenous ubiquitin–proteasome system to catalytically degrade target proteins and disrupt complexes, potentially amplifying the efficacy of existing epigenetic binders. We highlight the status of TPD-harnessing moieties in clinical and preclinical development, as these compounds may prove crucial for unlocking the potential of epigenetic complex modulation in cancer therapeutics.
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Small-Molecule Approaches to Target Transcription Factors
Vol. 8 (2024), pp. 395–415More LessDysregulated transcription factor activity is a defining feature of various cancer types. As such, targeting oncogenic transcriptional dependency has long been pursued as a potential therapeutic approach. However, transcription factors have historically been deemed as undruggable targets due to their highly disordered structures and lack of well-defined binding pockets. Nevertheless, interest in their pharmacologic inhibition and destruction has not dwindled in recent years. Here, we discuss new small-molecule-based approaches to target various transcription factors. Ligands with different mechanisms of action, such as inhibitors, molecular glue degraders, and proteolysis targeting chimeras, have recently seen success preclinically and clinically. We review how these strategies overcome the challenges presented by targeting transcription factors.
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Studying Progression from Chronic Injury to Esophageal Adenocarcinoma
Vol. 8 (2024), pp. 417–433More LessCancer research seeks to understand the biology underlying the progression to malignant transformation. Recently, the incidence of esophageal adenocarcinoma (EAC) has increased dramatically, and if we understand why and how, we will be better equipped for diagnosis, prognosis, detection, prevention, and intervention. The earliest steps in progression for most malignancies are the most difficult to study. The initiation of cancer is believed to be a relatively rare and sporadic event, the locations and timings of which are most often unknown. Of the trillions of somatic cells in our bodies, only a few ever find themselves on a path to malignancy. However, chronic inflammation generates a metaplastic lesion that is directly linked to increased incidence of EAC and thus alerts us to the time and place that progression is initiated and allows us to study the biology. We describe recent studies that identify coordinated actions between stromal and epithelial cells that progress to EAC.
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The Intestinal Microbiota and Therapeutic Responses to Immunotherapy
Vol. 8 (2024), pp. 435–452More LessThe intestinal microbiota, a complex ecosystem of microorganisms, has emerged as an important player in modulating various aspects of human health and disease. The microbiota is in a state of constant cross talk with itself and its host, and these interactions regulate several aspects of host homeostasis, including immune responses. Studies have demonstrated a relationship between the microbiota and outcomes of several cancer immunotherapies. This review explores the different roles of intestinal microbiota in shaping the efficacy and safety of cancer immunotherapies, including allogeneic hematopoietic cell transplantation, immune checkpoint blockade, and CAR T cell therapy.
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Histone H3 Variants in the Multiverse of Cancer
Vol. 8 (2024), pp. 453–474More LessOur understanding of cancer genomes has allowed for the integration of molecular data into histopathological classifications for routine stratification of patients. In the last 10–15 years, thanks to this systematic implementation of large-scale sequencing, the identification of hotspot somatic mutations in histone genes came into the limelight, underscoring the concept of oncohistones. As drivers in pediatric brain tumors, and in several other types of cancers, oncohistones brought a “new dimension of Strange” into the cancer multiverse, to paraphrase Marvel. An integrative approach to cancer complexity as a multidimensional projection is urgently needed to consider all relevant etiological, developmental, and evolutionary components. Here, we discuss recent progress on histone variants and chaperones, their regulation and alterations in cancers, the available in vivo models, and current treatment strategies. More specifically, we adopt a view through the lens of tissue-specific differences and means for genome expression and integrity maintenance.
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