Tamoxifen is a first targeted drug that continues to be the gold standard in treatment of estrogen receptor positive breast cancer for almost 50 years. The current review is an update of the paper published in 2012. We provide the new data on the tamoxifen targets that are the key points of signaling cascades activating cellular proliferation, which determines aggressiveness of disease and chemotherapy resistance or sensitivity. Some inspiring clinical cases dealing with tamoxifen efficiency in treatment of different tumors are discussed. Additionally, the review includes data on antiviral, antibacterial, antifungal and antiparasitic activity of tamoxifen.
Along with advances in precision oncology, checkpoint inhibitors and targeted therapies have substantially improved outcomes for cancer patients. However, many patients still demonstrate a limited response to these therapies due to many biological factors, including genetic heterogeneity, unique molecular profiles, and the complex features of the tumor microenvironment (TME). Therefore, the selection of personalized effective treatment requires a comprehensive source of therapy response biomarkers, enabling precision medicine strategies for therapy selection. Here, we present a first-in-class automated biomarker analysis database, Astraea, that comprehensively describes genomic, transcriptomic, and TME biomarkers across a wide array of cancers. Automated daily literature reviews of the therapeutic efficacy of biomarkers provided the foundation of Astraea. To date, the database contains a total of 4,116 published biomarkers associated with genomic events, the TME, and targeted proteomic, transcriptomic, and gene signatures. To ensure accuracy of the final inclusion of biomarkers in the database, a multi-step quality control process was implemented that includes an automatic validation step and manual review. After selection, each biomarker is organized into a unique profile in the database which includes assay specifics, the biomarker-associated cancer type, therapy, primary study design, and statistical analysis. Data available from The Cancer Genome Atlas (TCGA) was then used to aggregate interrelated biomarkers into 25 biologically meaningful clusters, with the most prominent clusters identified as components of the TME (i.e., cytotoxic T cells, B cells, fibroblasts) and proliferation rate signatures. The aggregation enabled an easier interpretation and understanding of potentially actionable molecular findings as well as insight into unique neoplastic drivers. To apply Astraea in a clinical setting, we then developed a platform to match therapies to patients based on 1) identified biomarkers prioritized according to level of evidence, including both number of associated publications, statistical strength of individual studies, and cohort size and 2) therapies scored according to supporting biomarkers and associated relevance (resistance/response). By providing comprehensive, up-to-date biomarker identification and matching through utilization of a large automated multi-platform database, this technique aids in the identification and application of biomarkers unique to each patient. Taken together, our results show that Astraea, accompanied by a multi-step personalized cancer therapy-matching platform, could improve precision medicine strategies and help optimize therapeutic decisions. Citation Format: Azamat Gafurov, Ivan Mamichev, Elena V. Vasileva, Georgy D. Sagaradze, Maria S. Shitova, Grigorii Nos, Nikita Kotlov, Jessica H. Brown, Alexander Bagaev, Nathan Fowler. Astraea: A first-in-class biomarker database integrating genomic, transcriptomic, and tumor microenvironment properties for precision oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 205.
effective clinical therapy for patients with metastatic colorectal cancer (mCRC), particularly for those with KRAS, NRAS, BRAF and PI3KCA wild-type cancer. However, only a fraction of patients receives clinical benefit from therapy with anti-EGFR antibodies. The HER2 gene amplification has been implicated as one of the mechanisms for primary and acquired resistance to anti-EGFR therapies in mCRC. However, little is known about the role of HER2 in cancer resistance to anti-EGFR antibodies. Material and methods We transfected stably colon cancer cells, sensitive to anti-EGFR antibodies (LIM1215 and SW48), with HER2 plasmid. We characterised the transfected cells in terms of molecular profile and sensitivity to several drugs through cell proliferation assays and western blot analysis. Furthermore, HER2 amplified cells were engrafted into nude mice and treated to find the best therapeutic treatment. Results and discussions We observed a strong upregulation on the HER family receptors EGFR, HER3, and HER4 in cells with HER2 amplification, but also an over-expression of intracellular transducers such as AKT, MAPK, and MEK proteins compared to parental cells. Furthermore, we treated LIM1215-HER2 and SW48-HER2 cells with several combinations of antibodies and small molecules directed to HER receptor family, such as anti-EGFR receptor antibodies of first, second and third generation (cetuximab, SYM004 and MM151); trastuzumab, pertuzumab and lapatinib directed against HER2 receptor; and duligotuzumab as anti-HER3 receptor. We observed a strongest growth inhibition effect after treatment with trastuzumab in combination with lapatinib compared to other treatments. Moreover, we incubated the HER2 amplified cells with drugs directed to the downstream pathway, such as refametinib and pictilisib which are the MEK and PI3KCA inhibitors, respectively. Interestingly, cells with HER2 amplification are highly sensitive to refametinib and pictilisib and further, we observed higher antitumor activity when both drugs were administrated in combination compared to their single treatment and to therapy-based on anti-HER family antibodies. The antitumor activity has been confirmed by the in vivo xenografts CRC models. Conclusion These results suggest that the treatment with refamentinib and pictilisib could be a strategy for patients with HER2 amplification that do not receive clinical benefit from standard anti-EGFR therapies.
Белок микротрубочек бета-III тубулин (TUBB3) в норме не экспрессируется в эпителиальных клетках, но присутствует во многих опухолях эпителиального происхождения. Мы предположили, что выявление экспрессии TUBB3 в морфологически нормальной ткани за пределами первичной опухоли может использоваться для молекулярной диагностики местной распространенности опухолевого процесса, что особенно важно для локально рецидивирующих опухолей, в частности, для рака пищевода. Цель исследования-количественная оценка экспрессии TUBB3 в опухолевой и окружающей морфологически нормальной ткани пищевода, прилежащей к опухоли и отдаленной от нее. Материалы и методы. Методом проточной иммуноцитофлуориметрии исследована экспрессия белка TUBB3 в хирургических биопсийных образцах рака пищевода и морфологически нормальной ткани органа 40 оперированных больных. Результаты. Экспрессия TUBB3 выявлена в 35 из 40 исследованных образцов рака пищевода, в 10 из 13 образцов прилежащей к опухоли морфологически нормальной ткани пищевода и в 25 из 40 образцов максимально удаленной от опухоли ткани пищевода вблизи края резекции. В подавляющем большинстве случаев уровень и интенсивность экспрессии TUBB3 у каждого больного в опухоли превышали те же показатели в отдаленной морфологически нормальной ткани. Показано, что в ряду «норма → норма вблизи опухоли → опухоль» экспрессия TUBB3 растет, т. е. прослеживается положительный градиент уровня и интенсивности экспрессии белка по мере приближения к опухоли. Заключение. Экспрессия ассоциированного с опухолевым ростом белка TUBB3 за пределами первичной опухоли указывает на молекулярную вовлеченность в опухолевый процесс визуально нормальной ткани органа и может использоваться в качестве дополнительного показателя при стадировании заболевания и определении тактики послеоперационного ведения пациентов.
Background. Class III beta-tubulin (TUBB3) is one of the eight beta tubulin isotypes identified in human. It is constitutively expressed in brain and testis but not in lung tissue. TUBB3 is also known to appear in solid tumors, in particular in non-small cell lung cancer (NSCLC), and it is often associated with poor prognosis and resistance to taxanes and Vinka alkaloids. Objective: We have suggested that TUBB3 expression may cover not only the primary tumor but also a wide adjacent area of morphologically normal lung tissue. To check the hypothesis we have measured TUBB3 expression both in the non-small cell lung carcinoma (NSCLC) and remote lung tissue derived from the same lung. 60surgical biopsy specimens of NSCLC and morphologically normal lung tissue of 30patients were investigated. Materials and methods. Biopsy specimens were converted to suspension, fixed in 4 % formaldehyde and analyzed by flow cytometry using monoclonal antibodies to TUBB3. The method was developed in the laboratory of medicinal chemistry research Institute of experimental diagnostics and therapy of tumors (N.N. Blokhin Russian Cancer Research Center) and patented. Results. Fraction of TUBB3-positive cells in the group of adjacent lung tissue specimens was lower compared to NSCLC group but still positive in the majority of adjacent lung tissue specimens (25 of 30) and achieved up to 39 % of cells. Conclusion. We suggest that TUBB3 expression in adjacent morphologically normal lung tissue indicates presence of transformed and potentially malignant cells far from the primary site.
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