Huarui Cui, Morgan Stilgenbauer, Angela N. Koehler
{"title":"Small-Molecule Approaches to Target Transcription Factors","authors":"Huarui Cui, Morgan Stilgenbauer, Angela N. Koehler","doi":"10.1146/annurev-cancerbio-062722-012209","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062722-012209","url":null,"abstract":"Dysregulated 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.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139462118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Next-Generation Therapies for Multiple Myeloma","authors":"Erin W. Meermeier, P. L. Bergsagel, M. Chesi","doi":"10.1146/annurev-cancerbio-061421-014236","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061421-014236","url":null,"abstract":"Recent 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. Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139438800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mohamed Omar, Mohammad K. Alexanderani, Itzel Valencia, Massimo Loda, Luigi Marchionni
{"title":"Applications of Digital Pathology in Cancer: A Comprehensive Review","authors":"Mohamed Omar, Mohammad K. Alexanderani, Itzel Valencia, Massimo Loda, Luigi Marchionni","doi":"10.1146/annurev-cancerbio-062822-010523","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-010523","url":null,"abstract":"Digital 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.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139084612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pablo R. Freire, Jevon A. Cutler, Scott A. Armstrong
{"title":"Therapeutic Targeting of the Menin–KMT2A Interaction","authors":"Pablo R. Freire, Jevon A. Cutler, Scott A. Armstrong","doi":"10.1146/annurev-cancerbio-062822-021934","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-021934","url":null,"abstract":"The 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.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139084371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Barbra Johnson Sasu, Elvin James Lauron, Thomas Schulz, Hsin-Yuan Cheng, Cesar Sommer
{"title":"Allogeneic CAR T Cell Therapy for Cancer","authors":"Barbra Johnson Sasu, Elvin James Lauron, Thomas Schulz, Hsin-Yuan Cheng, Cesar Sommer","doi":"10.1146/annurev-cancerbio-062822-023316","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-023316","url":null,"abstract":"Autologous 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.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138744321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Antonella De Cola, Amelia Foss, Richard Gilbertson, Manav Pathania
{"title":"Biological, Diagnostic, and Therapeutic Insights from (Epi)Genomic Profiling of Pediatric Brain Tumors","authors":"Antonella De Cola, Amelia Foss, Richard Gilbertson, Manav Pathania","doi":"10.1146/annurev-cancerbio-062722-034650","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062722-034650","url":null,"abstract":"Pediatric 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.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138744263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Relationships Between Regeneration, Wound Healing, and Cancer","authors":"Gianna Maggiore, Hao Zhu","doi":"10.1146/annurev-cancerbio-062822-123558","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-062822-123558","url":null,"abstract":"Regeneration 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.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138744173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ellis J. Curtis, John C. Rose, Paul S. Mischel, Howard Y. Chang
{"title":"Extrachromosomal DNA: Biogenesis and Functions in Cancer","authors":"Ellis J. Curtis, John C. Rose, Paul S. Mischel, Howard Y. Chang","doi":"10.1146/annurev-cancerbio-070620-092730","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-070620-092730","url":null,"abstract":"In 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.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138692417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yonina R. Murciano-Goroff, Manik Uppal, Monica Chen, Guilherme Harada, Alison M. Schram
{"title":"Basket Trials: Past, Present, and Future","authors":"Yonina R. Murciano-Goroff, Manik Uppal, Monica Chen, Guilherme Harada, Alison M. Schram","doi":"10.1146/annurev-cancerbio-061421-012927","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061421-012927","url":null,"abstract":"Large-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.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138534860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jane A. Healy, Jin-Hwan Han, David Bauché, Tanya E. Keenan, Jose Casasnovas-Nieves, Konstantin Dobrenkov
{"title":"Advances in Therapies Targeting Inhibitory Checkpoint Receptors: TIGIT, LAG-3, and Beyond","authors":"Jane A. Healy, Jin-Hwan Han, David Bauché, Tanya E. Keenan, Jose Casasnovas-Nieves, Konstantin Dobrenkov","doi":"10.1146/annurev-cancerbio-061521-093717","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061521-093717","url":null,"abstract":"Progress 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.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":501431,"journal":{"name":"Annual Review of Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138534864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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