Tracing and Targeting the Origins of Childhood Cancer

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Tim H.H. Coorens ◽  
Sam Behjati
Keyword(s):  
Cancer Biology ◽  
Phylogenetic Analyses ◽  
Tumor Formation ◽  
Cytotoxic Agents ◽  
Annual Review ◽  
Publication Date ◽  
Pediatric Tumors ◽  
Childhood Cancers ◽  
Cell Of Origin ◽  
Novel Therapeutic Strategies

Despite the success of treating childhood cancers with cytotoxic agents, novel therapeutic strategies are required to achieve the next leap in cure rates. A promising avenue may be to target the origin of childhood cancers. Here, we review recent advances in tracing the origins of pediatric tumors. Cancer-to-normal cell comparisons by single-cell mRNA sequencing reveal the fetal state of cancer cells, as well as their cell of origin. Recent phylogenetic analyses have uncovered large tissue-resident precursor clones to childhood cancers, which already possess key genomic alterations leading to tumor formation. Both the transcriptional fetalness and genomic status of the premalignant tissue bed provide further avenues for targeted therapy. Overall, these advances begin to describe the precise origins of pediatric tumors and pave the way for novel methods in detecting, treating, and perhaps even preventing childhood cancers. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Molecular Biology of Childhood Leukemia

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Thomas B. Alexander ◽  
Charles G. Mullighan
Keyword(s):  
Cancer Biology ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Annual Review ◽  
Publication Date ◽  
Cell Of Origin ◽  
Histone Deacetylase Inhibition ◽  
Therapeutic Implications ◽  
Myeloid Leukemias ◽  
Prognostic Importance

Childhood hematological malignancies (HM) exhibit profound genetic and biological heterogeneity. Many sporadic and familial HM have a heritable predisposition. Genomic sequencing has revised the taxonomy of lymphoid and myeloid leukemias, indicating the importance of accurate molecular diagnosis in disease management. Notable examples include the identification of gene expression–based subtypes of acute lymphoblastic leukemia (ALL), identification of diverse rearrangements of NUP98 in high-risk acute myeloid leukemia (AML), characterization of the interplay of cell-of-origin and genomic alterations in lineage-ambiguous leukemias, and the prognostic importance of DNA methylation in juvenile myelomonocytic leukemias. These insights provide therapeutic opportunities, including kinase inhibition in Ph-like ALL, menin inhibition in KMT2A-rearranged AML, histone deacetylase inhibition in MEF2D-rearranged ALL, and FLT3 inhibition in T-lineage and myeloid leukemias. We provide an overview of the molecular foundation and classification of childhood leukemias, focusing on recent scientific advances, and discuss potential therapeutic implications. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Cancer Dependencies: PRMT5 and MAT2A in MTAP/p16-Deleted Cancers

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Katya Marjon ◽  
Peter Kalev ◽  
Kevin Marks
Keyword(s):  
Cancer Biology ◽  
Annual Review ◽  
Publication Date ◽  
Arginine Methyltransferase ◽  
Genetic Inactivation ◽  
Small Molecule Inhibition ◽  
Specific Tumor ◽  
Genomic Screening ◽  
Novel Therapeutic Strategies ◽  
Key Aspects

Discovery of targeted therapies that selectively exploit the genetic inactivation of specific tumor suppressors remains a major challenge. This includes the prevalent deletion of the CDKN2A/ MTAP locus, which was first reported nearly 40 years ago. The more recent advent of RNA interference and functional genomic screening technologies led to the identification of hidden collateral lethalities occurring with passenger deletions of MTAP in cancer cells. In particular, small-molecule inhibition of the type II arginine methyltransferase PRMT5 and the S-adenosylmethionine-producing enzyme MAT2A each presents a precision medicine approach for the treatment of patients whose tumors have homozygous loss of MTAP. In this review, we highlight key aspects of MTAP, PRMT5, and MAT2A biology to provide a conceptual framework for developing novel therapeutic strategies in tumors with MTAP deletion and to summarize ongoing efforts to drug PRMT5 and MAT2A. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Central Role of the Antigen-Presentation and Interferon-γ Pathways in Resistance to Immune Checkpoint Blockade

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Annette Paschen ◽  
Ignacio Melero ◽  
Antoni Ribas
Keyword(s):  
Antigen Presentation ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Cancer Biology ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Class I ◽  
Annual Review ◽  
Publication Date ◽  
Type I

Resistance to immunotherapy is due in some instances to the acquired stealth mechanisms of tumor cells that lose expression of MHC class I antigen–presenting molecules or downregulate their class I antigen–presentation pathways. Most dramatically, biallelic β2-microglobulin (B2M) loss leads to complete loss of MHC class I expression and to invisibility to CD8+ T cells. MHC class I expression and antigen presentation are potently upregulated by interferon-γ (IFNγ) in a manner that depends on IFNγ receptor (IFNGR) signaling via JAK1 and JAK2. Mutations in these molecules lead to IFNγ unresponsiveness and mediate loss of recognition and killing by cytotoxic T lymphocytes. Loss of MHC class I augments sensitivity of tumor cells to be killed by natural killer (NK) lymphocytes, and this mechanism could be exploited to revert resistance, for instance, with interleukin-2 (IL-2)-based agents. Moreover, in some experimental models, potent local type I interferon responses, such as those following intratumoral injection of Toll-like receptor 9 (TLR9) or TLR3 agonists, revert resistance due to mutations of JAKs. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

TGFβ: Signaling Blockade for Cancer Immunotherapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Szu-Ying Chen ◽  
Ons Mamäi ◽  
Rosemary J. Akhurst
Keyword(s):  
Cancer Biology ◽  
Transforming Growth Factor ◽  
Biological Activities ◽  
Tumor Stroma ◽  
Transforming Growth Factor Β ◽  
Therapeutic Window ◽  
Annual Review ◽  
Publication Date ◽  
Tgfβ Signaling ◽  
Mesenchymal Transformation

Discovered over four decades ago, transforming growth factor β (TGFβ) is a potent pleiotropic cytokine that has context-dependent effects on most cell types. It acts as a tumor suppressor in some cancers and/or supports tumor progression and metastasis through its effects on the tumor stroma and immune microenvironment. In TGFβ-responsive tumors it can promote invasion and metastasis through epithelial-mesenchymal transformation, the appearance of cancer stem cell features, and resistance to many drug classes, including checkpoint blockade immunotherapies. Here we consider the biological activities of TGFβ action on different cells of relevance toward improving immunotherapy outcomes for patients, with a focus on the adaptive immune system. We discuss recent advances in the development of drugs that target the TGFβ signaling pathway in a tumor-specific or cell type–specific manner to improve the therapeutic window between response rates and adverse effects. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Targeting KRAS G12C with Covalent Inhibitors

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Jonathan M.L. Ostrem ◽  
Kevan M. Shokat
Keyword(s):  
Clinical Trials ◽  
Cancer Biology ◽  
Phase Iii ◽  
Annual Review ◽  
Publication Date ◽  
Kras Mutations ◽  
Phase Iii Clinical Trials ◽  
Covalent Inhibitors ◽  
Novel Approaches ◽  
Early Phase Clinical Trials

KRAS is the most frequently mutated oncogene in cancer. Following numerous attempts to inhibit KRAS spanning multiple decades, recent efforts aimed at covalently targeting the mutant cysteine of KRAS G12C have yielded very encouraging results. Indeed, one such molecule, sotorasib, has already received accelerated US Food and Drug Administration approval with phase III clinical trials currently underway. A second molecule, adagrasib, has also progressed to phase III, and several others have entered early-phase clinical trials. The success of these efforts has inspired an array of novel approaches targeting KRAS, with some reporting extension to the two most common oncogenic KRAS mutations, G12V and G12D. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The Coevolution of Placentation and Cancer

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Günter P. Wagner ◽  
Kshitiz ◽  
Anasuya Dighe ◽  
Andre Levchenko
Keyword(s):  
Twentieth Century ◽  
Cancer Cells ◽  
Immune Evasion ◽  
Online Publication ◽  
Cancer Biology ◽  
Annual Review ◽  
Publication Date ◽  
Trophoblast Cells ◽  
Cancer Hallmarks ◽  
Placental Invasion

Analogies between placentation, in particular the behavior of trophoblast cells, and cancer have been noted since the beginning of the twentieth century. To what degree these can be explained as a consequence of the evolution of placentation has been unclear. In this review, we conclude that many similarities between trophoblast and cancer cells are shared with other, phylogenetically older processes than placentation. The best candidates for cancer hallmarks that can be explained by the evolution of eutherian placenta are mechanisms of immune evasion. Another dimension of the maternal accommodation of the placenta with an impact on cancer malignancy is the evolution of endometrial invasibility. Species with lower degrees of placental invasion tend to have lower vulnerability to cancer malignancy. We finally identify several areas in which one could expect to see coevolutionary changes in placental and cancer biology but that, to our knowledge, have not been explored. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 10 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Reeling in the Zebrafish Cancer Models

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Alicia M. McConnell ◽  
Haley R. Noonan ◽  
Leonard I. Zon
Keyword(s):  
Cancer Biology ◽  
Model Organism ◽  
Transgenic Animals ◽  
Annual Review ◽  
Transgenic Zebrafish ◽  
Publication Date ◽  
Cancer Therapies ◽  
Cancer Models ◽  
Cancer Types ◽  
New Cancer Therapies

Zebrafish are rapidly becoming a leading model organism for cancer research. The genetic pathways driving cancer are highly conserved between zebrafish and humans, and the ability to easily manipulate the zebrafish genome to rapidly generate transgenic animals makes zebrafish an excellent model organism. Transgenic zebrafish containing complex, patient-relevant genotypes have been used to model many cancer types. Here we present a comprehensive review of transgenic zebrafish cancer models as a resource to the field and highlight important areas of cancer biology that have yet to be studied in the fish. The ability to image cancer cells and niche biology in an endogenous tumor make zebrafish an indispensable model organism in which we can further understand the mechanisms that drive tumorigenesis and screen for potential new cancer therapies. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Nutritional Preconditioning in Cancer Treatment in Relation to DNA Damage and Aging

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Winnie M.C. van den Boogaard ◽  
Marry M. van den Heuvel-Eibrink ◽  
Jan H.J. Hoeijmakers ◽  
Wilbert P. Vermeij
Keyword(s):  
Dna Damage ◽  
Cancer Treatment ◽  
Cancer Biology ◽  
Accelerated Aging ◽  
Nutritional Intervention ◽  
Annual Review ◽  
Publication Date ◽  
Short And Long Term ◽  
Resilience Mechanisms

Dietary restriction (DR) is the most successful nutritional intervention for extending life span and preserving health in numerous species. Reducing food intake triggers a protective response that shifts energy resources from growth to maintenance and resilience mechanisms. This so-called survival response has been shown to particularly increase life and health span and decrease DNA damage in DNA repair–deficient mice exhibiting accelerated aging. Accumulation of DNA damage is the main cause of aging, but also of cancer. Moreover, radiotherapies and most chemotherapies are based on damaging DNA, consistent with their ability to induce toxicity and accelerate aging. Since fasting and DR decrease DNA damage and its effects, nutritional preconditioning holds promise for improving (cancer) therapy and preventing short- and long-term side effects of anticancer treatments. This review provides an overview of the link between aging and cancer, highlights important preclinical studies applying such nutritional preconditioning, and summarizes the first clinical trials implementing nutritional preconditioning in cancer treatment. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Mutant Allele Imbalance in Cancer

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Craig M. Bielski ◽  
Barry S. Taylor
Keyword(s):  
Cancer Biology ◽  
Mutant Allele ◽  
Tumor Biology ◽  
Cellular Level ◽  
Driver Mutations ◽  
Annual Review ◽  
Publication Date ◽  
Cancer Evolution ◽  
Allele Imbalance ◽  
And Function

The search for somatic mutations that drive the initiation and progression of human tumors has dominated recent cancer research. While much emphasis has been placed on characterizing the prevalence and function of driver mutations, comparatively less is known about their serial genetic evolution. Indeed, study of this phenomenon has largely focused on tumor-suppressor genes recessive at the cellular level or mechanisms of resistance in tumors with mutant oncogenes targeted by therapy. There is, however, a growing appreciation that despite a decades-old presumption of heterozygosity, changes in mutant oncogene zygosity are common and drive dosage and stoichiometry changes that lead to selective growth advantages. Here, we review the recent progress in understanding mutant allele imbalance and its implications for tumor biology, cancer evolution, and response to anticancer therapy. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals The Multifaceted Role of Regulatory T Cells in Breast Cancer

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Kevin Kos ◽  
Karin E. de Visser
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Tumor Progression ◽  
Immune Cells ◽  
Cancer Biology ◽  
Immune Escape ◽  
Breast Cancer Subtype ◽  
Annual Review ◽  
Publication Date

The microenvironment of breast cancer hosts a dynamic cross talk between diverse players of the immune system. While cytotoxic immune cells are equipped to control tumor growth and metastasis, tumor-corrupted immunosuppressive immune cells strive to impair effective immunity and promote tumor progression. Of these, regulatory T cells (Tregs), the gatekeepers of immune homeostasis, emerge as multifaceted players involved in breast cancer. Intriguingly, clinical observations suggest that blood and intratumoral Tregs can have strong prognostic value, dictated by breast cancer subtype. Accordingly, emerging preclinical evidence shows that Tregs occupy a central role in breast cancer initiation and progression and provide critical support to metastasis formation. Here, Tregs are not only important for immune escape but also promote tumor progression independent of their immune regulatory capacity. Combining insights into Treg biology with advances made across the rapidly growing field of immuno-oncology is expected to set the stage for the design of more effective immunotherapy strategies. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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