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Saint Petersburg, Russia

Imyanitov E.N.,Nn Petrov Institute Of Oncology | Byrski T.,Pomeranian Medical University
Hereditary Cancer in Clinical Practice | Year: 2013

The history of specific therapy for hereditary tumors dates back to mid 1980s and involves a number of reports demonstrating regression of familial colon polyps upon administration of sulindac. Virtually no clinical studies on other hereditary cancer types were available until the year 2009, when Byrski et al. presented the data on unprecedented sensitivity of BRCA1-associated breast malignancies to cisplatin. This breakthrough has revived interest to the treatment of cancer in germ-line mutation carriers. Recent trials and clinical observations have confirmed the efficacy of platinating agents and PARP inhibitors in BRCA1/2-driven breast, ovarian and pancreatic carcinomas. Pegylated liposomal doxorubicin may be considered as a promising treatment option for BRCA1/2-related ovarian cancer after the failure of platinum-containing therapy. Several novel drugs have been recently introduced in the management of rare familial tumor syndromes. Vandetanib, a low-molecular weight RET kinase inhibitor, demonstrated substantial efficacy in the treatment of hereditary and sporadic medullary thyroid cancer. Vismodegib, an inhibitor of SMO oncoprotein, caused regression of basal-cell carcinomas in patients with Gorlin syndrome. Down-regulation of mTOR kinase by everolimus has been successfully used for the therapy of subependymal giant-cell astrocytomas in patients with tuberous sclerosis. The achievements in the prevention, diagnostics and treatment of hereditary cancers may serve as an excellent example of triumph of translational medicine. © 2013 Imyanitov and Byrski; licensee BioMed Central Ltd.

Malek A.,Nn Petrov Institute Of Oncology
Methods in Molecular Biology | Year: 2013

Specific biological properties of ovarian cancer cells can be modeled and studied using in vitro experiments. Any experimental setting can closely reflect some aspects of the native conditions; however, parameters that differ from in vivo aspects must be considered. Familiarity with existing and well-established, as well as new, cell culture techniques provides a basis for correct experimental design and production of reliable scientific results. This chapter presents a short comparative review of the techniques used for cell culture establishment and maintenance of ovarian cancer cells, as well as laboratory methods used to characterize malignant features of these cells, including the epithelial-mesechymal transition, cell motility and invasiveness, resistance to detachment-induced apoptosis, and stem cell content. © Springer Science+Business Media, New York 2013.

Imyanitov E.N.,Nn Petrov Institute Of Oncology
Arkhiv Patologii | Year: 2012

Individual life-time risk of melanoma in white residents of highly developed countries may be as high as 2%. Continuing rise of melanoma incidence is directly related to the improving life standards, especially to growing opportunities of attending sea resorts and getting tanned. Melanoma is usually highly aggressive and resistant to standard cytotoxic therapy, therefore 5-years survival of patients with the metastatic disease does not exceed 10-15%. Approximately 50% of melanomas contain point mutation in codon 600 of the BRAF kinase. Specific inhibitors of activated BRAF have demonstrated unprecedented therapeutic efficacy, thus BRAF testing has become a mandatory component of treatment planning for inoperable melanoma. This review discusses key issues, which are related to various clinical, morphological, and molecular genetic aspects of determination of BRAF status in metastatic melanoma.

Suspitsin E.N.,Nn Petrov Institute Of Oncology
Medical oncology (Northwood, London, England) | Year: 2014

Somatic inactivation of the remaining allele is a characteristic feature of cancers arising in BRCA1 and BRCA2 mutation carriers, which determines their unprecedented sensitivity to some DNA-damaging agents. Data on tumor-specific status of the involved gene in novel varieties of hereditary breast cancer (BC) remain incomplete. We analyzed 32 tumors obtained from 30 patients with non-BRCA1/2 BC-associated germ-line mutations: 25 women were single mutation carriers (7 BLM, 15 CHEK2 and 3 NBN/NBS1) and 5 were double mutation carriers (2 BLM/BRCA1, 1 CHEK2/BLM, 1 CHEK2/BRCA1 and 1 NBN/BLM). Losses of heterozygosity affecting the wild-type allele were detected in none of the tumors from BLM mutation carriers, 3/18 (17 %) CHEK2-associated BC and 1/4 (25 %) NBN/NBS1-driven tumors. The remaining 28 BC were subjected to the sequence analysis of entire coding region of the involved gene; no somatic mutations were identified. We conclude that the tumor-specific loss of the wild-type allele is not characteristic for BC arising in CHEK2, NBN/NBS1 and BLM mutation carriers. Rarity of "second-hit" inactivation of the involved gene in CHEK2-, NBN/NBS1- and BLM-associated BC demonstrates their substantial biological difference from BRCA1/2-driven cancers and makes them poorly suitable for the clinical trials with cisplatin and PARP inhibitors.

Imyanitov E.N.,Nn Petrov Institute Of Oncology
Methods in Molecular Biology | Year: 2013

Ovarian cancer (OC) is a relatively frequent malignant disease with a lifetime risk approaching to approximately 1 in 70. As many as 15-25 % OC arise due to known heterozygous germ-line mutations in DNA repair genes, such as BRCA1, BRCA2, RAD51C, NBN (NBS1), BRIP, and PALB2. Sporadic ovarian cancers often phenocopy the features of BRCA1-related hereditary disease (so-called BRCAness), i.e., show biallelic somatic inactivation of the BRCA1 gene. Tumor-specific BRCA1 deficiency renders selective sensitivity of transformed cells to platinating compounds and several other anticancer drugs, which explains high response rates of OC to systemic therapies. High-throughput molecular profiling of OC is instrumental for further progress in identification of novel OC diagnostic markers as well as for the development of new OC-specific treatments. However, interpretation of the huge bulk of incoming data may present a challenge. There is a critical need in the development of bioinformatic tools capable to integrate the multiplicity of available data sets into biologically and medically meaningful pieces of knowledge. © Springer Science+Business Media, New York 2013.

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