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Diagnosis and Pathobiology
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
In general, phylogenetic and other theoretical models help simplify analysis and data interpretation. Rather than describing the studied processes directly, they assist in organizing the knowledge and outcomes obtained and help bring to mind new interpretations and recognition of previously unknown, unseen, and undiscovered relationships and connections [18]. Phylogenetic reconstruction through next-generation sequencing (NGS) modalities has contributed to our understanding of the varying modes of cancer evolution and life history [166]. These studies suggest the existence of a trade-off between genome instability and tumor fitness, and that cancer evolution can encounter a wide range of pressures [166]. Classically, neoplastic disease was presumed to accompany a multiphase affair that included activation of oncogenes, loss of tumor-suppressor genes, and ensuing clonal sweeps by the fittest clone. Since then, various ways to describe and identify cancer evolution have been uncovered, and rudimentary hypotheses have been refined into an array of competing, interconnected, and/or complementing hypotheses [166]. Several hypotheses and theories currently exist to explain the causes of cancer initiation and progression [167]. Examples of models, hypotheses, and theories (i.e., paradigms) on cancer origin, progression, and evolution are briefly described in Table 2.2 and include: (i) linear, (ii) branching (trunk–branch), (iii) neutral/big bang, (iv) punctuated, (v) parallel, (vi) convergent and (vii) divergent evolution, (viii) braided cancer river model, (ix) atavistic model, (x) macroevolution, (xi) microevolution, (xii) gradual, (xiii) Darwinian, (xiv) stochastic/clonal, (xv) hierarchical evolution, (xvi) oncogene-induced DNA replication stress model [152, 165, 166, 168–180], (xvii) speciation theory, (xviii) somatic mutation theory, (xix) mitochondrial dysfunction and loss of energy model, (xx) environment and matter-based hypothesis, (xxi) gradual loss of cell/lineage identity and gain of characteristics of neural progenitor/stem cells model, (xxii) epistemology of the origin of cancer, (xxiii) integrative theory of cancer, (xxiv) intercellular cooperation theory, (xxv) thermodynamic laws-based entropy theory, (xxvi) tissue organization field theory, (xxvii) integrative model of breast carcinogenesis and tumor development, (xxviii) hypotheses of cancer weakening and origin, (xxix) physiomitotic theory of cancer, (xxx) mutator phenotype hypothesis [17, 167, 181–199], among others. The two models that assume the primary tumor plus its metastases being clonally related are the linear progression model and the parallel progression model and, additionally, are the commonly accepted models for metastatic dissemination [200]. The multitude of existing paradigms clearly highlights the complexity of cancer and further hints at the heterogenous nature of this malignant disease.
Defining and targeting wild-type BRCA high-grade serous ovarian cancer: DNA repair and cell cycle checkpoints
Published in Expert Opinion on Investigational Drugs, 2019
S. Percy Ivy, Charles A. Kunos, Fernanda I. Arnaldez, Elise C. Kohn
Figure 2. Drugs targeting cell cycle checkpoints and DNA replication stress. Progression through the cell cycle is one of the most tightly regulated processes as it assures the fidelity of replication of the genome. It allows DNA damage to be repaired and in certain circumstances stops DNA replication to prevent duplication of damaged DNA. This diagram represents the four phases of the cell cycle, G1, the gap/growth phase 1, S the synthetic DNA duplication phase, G2 the gap/growth phase 2, and M the mitosis, cell division phase. There are two checkpoints: G1/S that allows damaged DNA to collapse replication forks; and, G2/M that allow damaged DNA to bring about mitotic catastrophe, abnormal division or loss of vital DNA. By blocking cell cycle progression, or the G1/S and G2/M checkpoints can be accomplished using the inhibitors listed in the green boxes. These inhibitors block the cyclin-dependent kinases, CDK4, CDK6, CDK9 and CDK2, and DNA repair inhibitors including ATR, CHK1 and/or CHK2, WEE1, DNA-PKcs, MYT1 and RNR.
Targeted therapy to annihilate the immune-evading phenotype in cancer evolution
Published in Expert Opinion on Therapeutic Targets, 2018
We recently observed that a drug-induced MMR deficiency, fostering susceptibility to checkpoint blockade, may be achievable [5–7], considerably enhacing the interest of such immunotherapies as generic cancer treatments. To induce susceptibility to a checkpoint blocker utilizing a kinase inhibitor [5] requires that a drug is identified that impairs a major signaling pathway recruited to promote MMR [6]. So it happens that the α-isoform of anticancer target phosphoinositide 3-kinase (PI3Kα) is also a key transducer in MMR-related signaling, playing a metabolic role so that its inhibition results in nucleotide depletion [6]. This depletion is a consequence of reduced flux through glycolysis that results in a decrease in R5P needed for base ribosylation. This metabolic deficiency leads to ultimately compromising DNA synthesis in rapidly proliferating tumor cells that become subject to DNA replication stress as they enter the S phase. Thus, the metabolic effect of PI3Kα-inhibition results in error-prone DNA replication, likely to be specific to tumor cells. This is because tumor cells rely more heavily on de novo nucleotide biosynthesis than normal cells and because of their overloaded reliance on MMR. Tumor specificity as well as its central role in blocking cancer-related signaling pathways advocates for the therapeutic benefit of a PI3Kα inhibitor as inducer of susceptibility to checkpoint blockade [5].
Targeting angiogenesis in metastatic renal cell carcinoma
Published in Expert Review of Anticancer Therapy, 2019
Costanza Canino, Lorenzo Perrone, Eugenia Bosco, Giuseppe Saltalamacchia, Alessandra Mosca, Mimma Rizzo, Camillo Porta
SET domain-containing protein 2 (SETD2) is a two-hit tumor suppressor gene, located on chromosome 3p, and it is mutated in approximately 10% to 15% of the ccRCCs. SETD2 protein is a histone H3 lysine 36 trimethylating (H3K36me3) enzyme and, even if H3K36 methylation is usually associated with active transcription, it can also correlate with alternative splicing and transcriptional blockage. It was demonstrated that reduction of SETD2 is associated with DNA replication stress and alteration nucleosome components.