The Evolution of Anticancer Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
There are several examples from animal models in which correction of a single oncogenic abnormality can bring about a therapeutic effect, even in the context of multiple genetic abnormalities. Examples include the knock-out of oncogenes such as RAS or MYC, or re-introduction of a lost tumor suppressor gene such as P53, APC, or PTEN. Oncogenes that are mutated and not simply overexpressed might also be potential targets for therapy since they reflect the “hard wiring” of cancer cells. Mutated oncogenes are more likely to be present in the stem cell population of tumors rather than just in the progeny cells. In the “house of cards” model, the tumor requires each of the molecular abnormalities to instigate malignancy. Removal of any one of these abnormalities could cause the cancer cell to collapse like a house of cards. Even so, sufficiently high doses of a therapeutic agent would have to be provided early enough to ensure that no subclones develop that might be resistant to the agent. A mathematical calculation shows that by the time there are 109 tumor stem cells, each replication of the stem cell compartment produces on average one stem cell containing a mutation for any base position selected in the tumor genome. Thus, even treatment of chronic phase CML with imatinib has not proved to be curative.
Diffuse Intrinsic Pontine Glioma
David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack in Brain and Spinal Tumors of Childhood, 2020
In contrast to adult high-grade gliomas43,44 and other pediatric CNS tumors such as medulloblastoma,45 the primary disease-determining aberrations in DIPG (histone mutations and their partners) appear to be spatially conserved, i.e., present in primary, contiguous, and metastatic sites of disease, and temporally preserved, present over the entire course of the disease.7,46 Tumor evolutionary studies suggest histone H3K27M mutations and their obligate partner mutations involving cell cycle or growth factor pathways arise first and remain present during tumor invasion and metastases.7 Whereas histologic-grade intratumoral heterogeneity is present and has no correlation with prognosis, genomic/molecular driver mutations are conserved, are spatially homogeneous, and do correlate with prognosis. This alleviates concerns about biopsy representation of tumor and is important when considering biopsy to determine treatment for patients. Additional oncogenic mutations may arise later and are subclonal.7
Breast And Reproductive Cancers
Jane M. Ussher, Joan C. Chrisler, Janette Perz in Routledge International Handbook of Women’s Sexual and Reproductive Health, 2019
Mutations in two classes of genes (i.e., tumor oncogenes, suppressor genes) have important roles in carcinogenesis. Mutations to oncogenes often amplify gene function and release restraints (e.g., exaggerated cell proliferation). For example, mutations of the Myc oncogene are associated with increased cell proliferation, whereas mutations in the Fas oncogene impair aging and death of cancer cells, effectively making them immortal. Some oncogene mutations are more destructive than others. An amplified expression of the oncogene RTKs promotes tumor growth and metastasis, as well as the ability to recruit a dedicated blood supply (Cell Signaling Technology, 2018). The Pik3CA oncogene is one of those commonly associated with breast cancer. Pik3CA mutations are associated with hormone-positive breast cancers and also may predict a poorer tumor response to trastuzumab-based therapies (Mukohara, 2015).
Insights into radiation carcinogenesis based on dose-rate effects in tissue stem cells
Published in International Journal of Radiation Biology, 2023
Kensuke Otsuka, Toshiyasu Iwasaki
As discussed in the previous Section 3.2, mutation is a prerequisite for cancer, and the dynamics of mutant clones in tissues are important factors that lead to increased oncogenic events. However, in parallel with the accumulation of mutations due to permanent endogenous errors, the sporadic accumulation of mutations due to low-dose exposure is dependent on the cell cycle (division frequency) of tissue stem cells; thus, dose rate is an effective factor in the expansion of mutated cell clones. When damaged cells escape apoptosis due to prolonged exposure, as in the case of low dose-rate radiation, the probability of survival of cells with accumulated damage and mutations increases, and this could lead to tumor promotion (Amundson et al. 2003). To address this problem, the quantitative relationship between endogenous error mutations and exogenous induced mutations should be investigated at the stem-cell level using advanced NGS technologies.
New insight into brain disease therapy: nanomedicines-crossing blood–brain barrier and extracellular space for drug delivery
Published in Expert Opinion on Drug Delivery, 2022
Ziqi Gu, Haishu Chen, Han Zhao, Wanting Yang, Yilan Song, Xiang Li, Yang Wang, Dan Du, Haikang Liao, Wenhao Pan, Xi Li, Yajuan Gao, Hongbin Han, Zhiqian Tong
For a long time, the traditional drugs for the treatment of brain tumors have high molecular weight and low histocompatibility, so it is difficult to pass through BBB and has a significant cytotoxic effect on normal cells. Compared with the BBB, although blood–tumor barrier (BTB) is leaky generally, but its penetration is not well-distributed. Furthermore, cancer cells exhibit the enhancement of oncogenic, pro-survival signaling. All of these reduce the therapeutic effect of tumor drugs. A variety of nanomedicines using the different mediation methods have developed to treat brain tumors and evaluate their effects. For example, the poly (ethylene glycol)-poly (butylene adipate)-poly (ethylene glycol) superparamagnetic iron oxide NPs loaded with temozolomide have the positive antitumor effect on C6 glioma cells in vitro [152]. The TfR-mediated peptide T12 and mannose-functionalized albumin nanoparticles can pass through BBB and be targeted and delivered into glioma [153]. A functionalized gold-iron oxide NPs containing therapeutic microRNA by intranasal administration can improve the survival time of mouse glioma model [154].
Mouse models for mesothelioma drug discovery and development
Published in Expert Opinion on Drug Discovery, 2021
Kenneth P. Seastedt, Nathanael Pruett, Chuong D. Hoang
MPM remains a fatal disease in need of highly effective targeted therapeutic agents and both in vitro and in vivo disease models for drug testing. Many unique murine models exist in this regard, each with their advantages and disadvantages depending on the drug study’s objective. Better models are needed to continue to understand human MPM biology, including closer anatomic representation of the disease, further delineation of genetic alterations, the importance of immunologic involvement in disease, interactions with the tumor microenvironment, mechanisms of carcinogenesis (e.g., the precise contribution of chronic inflammation), targeted drug responses, and tumor inter- and intra-heterogeneity. The ability to alter the genomic backgrounds of mice utilizing CRISPR-Cas genome editing technologies [86] has contributed significantly to the production of useful models with which to explore disease progression and for testing interventional therapies. However, initial studies have focused on gene knockout models that mainly predispose mice to develop mesothelioma (there is no known oncogenic driver mutation in human mesothelioma, as discussed previously). To better understand the oncogenic mechanisms superseding these mutational events, one must develop models that explore these initiating conditions.
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