ALBERT

Description: Decades of study on cell cycle regulation have provided great insight into human cellular life span barriers, as well as their dysregulation during tumorigenesis. Telomeres, the extremities of linear chromosomes, perform an essential role in implementing these proliferative boundaries and preventing the propagation of potentially cancerous cells. The tumor-suppressive function of telomeres relies on their ability to initiate DNA damage signaling pathways and downstream cellular events, ranging from cell cycle perturbation to inflammation and cell death. While the tumor-suppressor role of telomeres is undoubtable, recent advances have pointed to telomeres as a major source of many of the genomic aberrations found in both early- and late-stage cancers, including the most recently discovered mutational phenomenon of chromothripsis. Telomere shortening appears as a double-edged sword that can function in opposing directions in carcinogenesis. This review focuses on the current knowledge of the dual role of telomeres in cancer and suggests a new perspective to reconcile the paradox of telomeres and their implications in cancer etiology.

Description: 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.

Description: The use of ex vivo drug sensitivity testing to predict drug activity in individual patients has been actively explored for almost 50 years without delivering a generally useful predictive capability. However, extended failure should not be an indicator of futility. This is especially true in cancer research, where ultimate success is often preceded by less successful attempts. For example, both immune- and genetic-based targeted therapies for cancer underwent numerous failed attempts before biological understanding, improved targets, and optimized drug development matured to facilitate an arsenal of transformational drugs. Similarly, directly assessing drug sensitivity of primary tumor biopsies—and the use of this information to help direct therapeutic approaches—has a long history with a definitive learning curve. In this review, we survey the history of ex vivo testing and the current state of the art for this field. We present an update on methodologies and approaches, describe the use of these technologies to test cutting-edge drug classes, and describe an increasingly nuanced understanding of tumor types and models for which this strategy is most likely to succeed. We consider the relative strengths and weaknesses of predicting drug activity across the broad biological context of cancer patients and tumor types. This includes an analysis of the potential for ex vivo drug sensitivity testing to accurately predict drug activity within each of the biological hallmarks of cancer pathogenesis. 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.

Description: Many essential biological processes are regulated through proximity, from membrane receptor signaling to transcriptional activity. The ubiquitin-proteasome system controls protein degradation, with ubiquitin ligases as the rate-limiting step. Ubiquitin ligases are commonly controlled at the level of substrate recruitment and, therefore, by proximity. There are natural and synthetic small molecules that also operate through induced proximity. For example, thalidomide is effective in treating multiple myeloma and functions as a molecular glue that stabilizes novel protein-protein interactions between a ubiquitin ligase and proteins not otherwise targeted by the ligase, leading to neo-substrate degradation. Emerging data on new degrader molecules have uncovered diverse mechanisms distinct from molecular glues, which often mirror the regulatory mechanisms that control substrate-ligase proximity in nature. In this review, we summarize our current understanding of biological and synthetic regulation of protein degradation and share our view on how these diverse mechanisms have inspired novel therapeutic directions. 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.

Description: On June 16, 2020, Zena Werb, PhD, died suddenly at age 75. Zena was a faculty member of the Department of Anatomy at the University of California, San Francisco (UCSF) for over 40 years. She was one of the most cited scientists in the life sciences, with an H-index of 170. She was well known for discovering several matrix metalloproteinases and for defining their roles in development and disease. Zena Werb was a major contributor to the recent appreciation—and deeper understanding—of the importance of the tumor microenvironment. She achieved this by her scientific discoveries, by being a thought leader—responsible for several influential reviews in the field—and by mentoring several generations of researchers in the tumor microenvironment field. 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.

Description: Advances in immunotherapy have underscored the importance of antitumor immune responses in controlling cancer. However, the tumor microenvironment (TME) imposes several obstacles to the proper function of immune cells, including a metabolically challenging and immunosuppressive microenvironment. The increased metabolic activity of tumor cells can lead to the depletion of key nutrients required by immune cells and the accumulation of byproducts that hamper antitumor immunity. Furthermore, the presence of suppressive immune cells, such as regulatory T cells and myeloid-derived suppressor cells, and the expression of immune inhibitory receptors can negatively impact immune cell metabolism and function. This review summarizes the metabolic reprogramming that is characteristic of various immune cell subsets, discusses how the metabolism and function of immune cells is shaped by the TME, and highlights how therapeutic interventions aimed at improving the metabolic fitness of immune cells and alleviating the metabolic constraints in the TME can boost antitumor immunity. 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.

Description: 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.

Description: It is increasingly clear that the nectin family and its immunoreceptors shape the immune response to cancer through several pathways. Yet, even as antibodies against TIGIT, CD96, and CD112R advance into clinical development, biological and therapeutic questions remain unanswered. Here, we review recent progress, prospects, and challenges to understanding and tapping this family in cancer immunotherapy. 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.

Description: The capacity of the adaptive immune system to respond to antigenic challenges relies on rapid diversification, expansion, and functional specialization of mature B cells. To accomplish this, activated B cells are transiently endowed with phenotypes that would normally be suppressed in somatic cells, such as enhanced proliferative potential and tolerance for genomic instability. Acquisition of these traits, directed by immune signaling cues and orchestrated by transcriptional and epigenetic programs, sets the stage for malignant transformation, often due to somatic mutations targeting epigenetic machinery in B cell lymphomas. This review examines how such mutations hack the epigenome to reprogram the immune response in such a way as to facilitate the emergence of malignant traits, suppress immune surveillance, and ultimately drive transformation and progression of a diverse spectrum of B cell lymphomas. Importantly, these novel mechanisms reveal vulnerabilities that can be harnessed using new forms of epigenetic 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.

Description: 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.