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- Volume 1, 2017
Annual Review of Cancer Biology - Volume 1, 2017
Volume 1, 2017
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Targeted Differentiation Therapy with Mutant IDH Inhibitors: Early Experiences and Parallels with Other Differentiation Agents
Eytan Stein, and Katharine YenVol. 1 (2017), pp. 379–401More LessSomatic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes have been described in multiple hematologic and solid tumors, and confer a gain of function, permitting the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). 2-HG accumulation induces DNA and histone hypermethylation and altered gene expression, ultimately resulting in a block in cellular differentiation. Proof-of-concept preclinical work demonstrated that targeted inhibition of the mutant IDH (mIDH) enzyme is a feasible therapeutic strategy, based on the hypothesis that inhibition of the mIDH enzyme blocks 2-HG production, resulting in an appropriate methylation state and the onset of cellular differentiation. Clinical development programs for targeted inhibitors are underway, and preliminary data in patients with mIDH acute myeloid leukemia suggest that these inhibitors act as differentiation agents. Here we review the use of differentiation agents for the treatment of hematologic and solid tumors and discuss the preclinical and early clinical evidence that mIDH inhibitors mediate antitumor effects through the induction of differentiation.
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Determinants of Organotropic Metastasis
Heath A. Smith, and Yibin KangVol. 1 (2017), pp. 403–423More LessThe spread of cancer from a primary tumor to distant organ sites is the most devastating aspect of malignancy. Dissemination to specific organs depends upon blood flow patterns and characteristics of the distant organ environment, such as the vascular architecture, stromal cell content, and the biochemical milieu of growth factors, signaling molecules, and metabolic substrates, which can be permissive or antagonistic to metastatic colonization. Metastatic tumor cells possess intrinsic cellular properties selected for adaptation to specific organ environments, where they co-opt growth and survival signals, undergo metabolic reprogramming, and subvert resident stromal cell activities to promote extravasation, immune evasion, angiogenesis, and overt metastatic growth. Recent work and new experimental models of metastatic organotropism are uncovering crucial details of how malignant cells metastasize to specific tissues, revealing key mediators that prepare metastatic niches in specific organs and identifying new targets that offer attractive options for therapeutic intervention.
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Multiple Roles for the MLL/COMPASS Family in the Epigenetic Regulation of Gene Expression and in Cancer
Vol. 1 (2017), pp. 425–446More LessThe mixed lineage leukemia (MLL) gene is involved in numerous chromosomal translocations that result in acute myeloid and acute lymphoid leukemias. The MLL protein belongs to a family of six methyltransferases in mammals that can methylate histone H3 on lysine 4 (H3K4). The methyltransferase activities of MLL and the other family members, SETD1A, SETD1B, MLL2, MLL3 and MLL4, depend on their participation within macromolecular complexes called COMPASS (complex of proteins associated with Set1). Functional diversity within the COMPASS family includes the propensity to mono-, di-, or trimethylate H3K4 and to regulate promoters or enhancers. Recent cancer genome sequencing and animal studies have identified MLL3 and MLL4 as cancer drivers in a wide variety of hematologic and solid tumors. MLL3 and MLL4 implement monomethylation of H3K4 at enhancer regions, whereas another enzyme in MLL3 and MLL4 COMPASS, UTX, which is also frequently mutated in multiple types of cancer, demethylates H3K27me3, a modification associated with transcription repression by the Polycomb group of proteins. Here, we review the different roles for the COMPASS family in cancer and suggest directions for future research toward elucidating the cellular pathways disregulated due to altered COMPASS functions.
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Chimeric Antigen Receptors: A Paradigm Shift in Immunotherapy
Vol. 1 (2017), pp. 447–466More LessCancer immunotherapy is emerging as an effective and dependable approach to induce durable responses and survival benefit in several cancers. Two approaches, one based on antibody therapy to block immune inhibitory checkpoints and the other on the genetic engineering of T lymphocytes, have yielded dramatic clinical results in recent years, earning cancer immunotherapy the title “breakthrough of the year” by the journal Science in 2013. Based on the success of targeting CD19 in B cell malignancies, chimeric antigen receptors (CARs) have established themselves as a powerful means to redirect and enhance the natural properties of both CD8+ and CD4+ T lymphocyte subsets. Dual-signaling CARs not only redirect and activate T cells but also reprogram their effector, metabolic, and survival functions, enabling the rapid manufacture of tumor-specific agents for any given cancer patient. This approach marks a major shift in cell-based therapy, which previously depended on the identification and expansion of rare naturally occurring T cells with therapeutic potential, but now relies on the genetic engineering and manufacturing of optimized T cell products. Several challenges remain to tailor this approach to tackle cell tumors, which will require identifying suitable CAR targets and overcoming multiple obstacles in a complex tumor microenvironment.
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