Anna Kornakiewicz

Mechanisms of Acquired Resistance to Tyrosine Kinase Inhibitors in Clear - Cell Renal Cell Carcinoma (ccRCC)

Clear - cell renal cell carcinoma (ccRCC) is a histological subtype of renal cell carcinoma - the most prevalent adult kidney cancer. Causes of ccRCC are not completely understood and therefore number of available therapies is limited. As a consequence of tumor chemo- and radioresistance as well as restrictions in offered targeted therapies, overall response rate is still unsatisfactory. Moreover, a significant group of patients (circa 1/4) does not respond to the targeted first-line treatment, while in other cases, after an initial period of stable improvement, disease progression occurs. Owing to this, more data on resistance mechanisms are needed, especially those concerning widely used, relatively lately approved and more successful than previous therapies - tyrosine kinase inhibitors (TKIs). Up to date, five TKIs have been licensed for ccRCC treatment: sunitinib (SUTENT®, Pfizer Inc.), sorafenib (Nexavar®, Bayer HealthCare/Onyx Pharmaceuticals), pazopanib (Votrient®, GlaxoSmithKline), axitinib (Inlyta®, Pfitzer Inc.) and tivozanib (AV-951®, AVEO Pharmaceuticals). Researchers have specified different subsets of tyrosine kinase inhibitors potential resistance mechanisms in clear-cell renal cell carcinoma. In most papers published until now, drug resistance is divided into intrinsic and acquired, and typically multi-drug resistance (MDR) protein is described. Herein, the authors focus on molecular analysis concerning acquired, non-genetic resistance to TKIs, with insight into specific biological processes.

The Role of Hypoxia and Cancer Stem Cells in Renal Cell Carcinoma Pathogenesis

The cancer stem cell (CSC) model has recently been approached also in renal cell carcinoma (RCC). A few populations of putative renal tumor-initiating cells (TICs) were identified, but they are indifferently understood; however, the first and most thoroughly investigated are CD105-positive CSCs. The article presents a detailed comparison of all renal CSC-like populations identified by now as well as their presumable origin. Hypoxic activation of hypoxia-inducible factors (HIFs) contributes to tumor aggressiveness by multiple molecular pathways, including the governance of immature stem cell-like phenotype and related epithelial-to-mesenchymal transition (EMT)/de-differentiation, and, as a result, poor prognosis. Due to intrinsic von Hippel-Lindau protein (pVHL) loss of function, clear-cell RCC (ccRCC) develops unique pathological intra-cellular pseudo-hypoxic phenotype with a constant HIF activation, regardless of oxygen level. Despite satisfactory evidence concerning pseudo-hypoxia importance in RCC biology, its influence on putative renal CSC-like largely remains unknown. Thus, the article discusses a current knowledge of HIF-1α/2α signaling pathways in the promotion of undifferentiated tumor phenotype in general, including some experimental findings specific for pseudo-hypoxic ccRCC, mostly dependent from HIF-2α oncogenic functions. Existing gaps in understanding both putative renal CSCs and their potential connection with hypoxia need to be filled in order to propose breakthrough strategies for RCC treatment.

Deep brain stimulation for refractory epilepsy.

Deep brain stimulation (DBS) is a method of treatment utilized to control medically refractory epilepsy (RE). Patients with medically refractory epilepsy who do not achieve satisfactory control of seizures with pharmacological treatment or surgical resection of the epileptic focus and those who do not qualify for surgery could benefit from DBS. The most frequently used stereotactic targets for DBS are the anterior thalamic nucleus, subthalamic nucleus, central-medial thalamic nucleus, hippocampus, amygdala and cerebellum. The DBS is believed to be an effective method of treatment for various types of epilepsy among adults and adolescents. Side effects may be associated with implantation of electrodes and with the stimulation itself. An increasing number of publications and growing interest in DBS application for RE may result in standardization of the qualification and treatment protocol for RE with DBS.

Frontiers in clinical and molecular diagnostics and staging of metastatic clear cell renal cell carcinoma

The last few years have brought advances in the understanding of the molecular biology of metastatic clear cell renal cell carcinoma (RCC). Both preclinical research and clinical trials brought together results from the latest advancements in RCC diagnostic and staging. Understanding of the complex molecular alterations involved in the development and progression of RCC enables development of immunohistochemical and genetic diagnostic tools and is also opening the doors for experimental targeted therapies. At the same time, improvements of medical and molecular imaging improves the sensitivity and specificity of metastatic disease diagnosis. Moreover, independent validation of molecular profiles across high-throughput platforms, methods, laboratories and cancer populations has recently been successfully performed in RCC. Generation of informative, clinical diagnostic tools is likely to contribute to development of novel personalized diagnostic and treatment protocols and ensure prolonged survival of RCC patient in the near future.

Mammalian Target of Rapamycin Inhibitors Resistance Mechanisms in Clear Cell Renal Cell Carcinoma

Mammalian target of rapamycin (mTOR) is a kinase protein involved in PI3K/AKT signaling with a central role in the processes of cell growth, survival and angiogenesis. Frequent mutations of this pathway make upstream and downstream components novel targets for tailored therapy design. Two mTOR inhibitors – everolimus and temsirolimus - enable an increase in overall survival (OS) or progression-free survival (PFS) time in a treatment of renal cancer. Despite recent advances in renal cancer treatment, resistance to targeted therapy is common. Understanding of molecular mechanisms is the basis of drug resistance which can facilitate prediction of success or failure in combinational or sequential targeted therapy. The article provides current knowledge on the mTOR signaling network and gives insight into the mechanisms of resistance to mTOR inhibitors from the complex perspective of RCC biology. The mechanisms of resistance developed not only by cancer cells, but also by interactions with tumor microenvironment are analyzed to emphasize the role of angiogenesis in ccRCC pathogenesis. As recent studies have shown the role of PI3K/AKT-mTOR pathway in proliferation and differentiation of cancer stem cells, we discuss cancer stem cell hypothesis and its possible contribution to ccRCC resistance. In the context of drug resistance, we also elaborate on a new approach considering ccRCC as a metabolic disease. In conclusion we speculate on future developments in agents targeting the mTOR pathway taking into consideration the singular biology of ccRCC.

Pain perception in patients with Parkinson’s disease

Abnormalities in pain perception are a part of the clinical picture in Parkinsons disease (PD) and belong to the category of non-motor symptoms. Two groups of patients were included in this study: (i) an experimental group of 36 patients with PD who were eligible for subthalamic deep brain stimulation (the experimental group [EG]) and (ii) a control group (CG) of 34 patients with a space-occupying lesion who were admitted for a framed stereotactic biopsy. Stereotactic frame fixation was used in both groups as a nociceptive stimulus. All participants were assessed for pain perception with two kinds of visual analogue scales (VAS) (a non-color VAS [ncVAS] and a color VAS [cVAS]) immediately after the stimulus (EG - ncVAS 1 and cVAS 1; CG - ncVAS 3 and cVAS 3) and 24 hours later (EG - ncVAS 2 and cVAS 2; CG - ncVAS 4 and cVAS 4). The means for the two pain scores assessed directly after frame fixation were 3.59 (ncVAS 1) and 3.06 (cVAS 1) for patients in the EG, while the mean ncVAS was 3, and the mean cVAS 3 was 6.1 for those in the CG. The pain intensity was significantly lower for patients with PD (EG) compared to those in the CG for both ncVAS and cVAS (p<0.05 for each measure). The mean pain scores for ncVAS and cVAS measured 24 hours after the procedure were 3.18 and 2.79 for patients with PD (EG) and 6.10 and 5.77 for those in the CG, respectively. Pain intensity measured 24 hours after the procedure was significantly lower in those with PD (EG) compared to the CG. This study has demonstrated that pain perception in patients with PD is significantly lower than pain perception in non-parkinsonian patients.

Future perspectives for mTOR inhibitors in renal cell cancer treatment

Everolimus is a mTOR inhibitor that demonstrates antitumor and antiangiogenic activities. In a randomized Phase III trial, patients with metastatic renal cell carcinoma who progressed on sunitinib/sorafenib were treated with everolimus and showed significant improvement in progression-free survival compared with best supportive care. Novel approaches in treatment are expected to ensure less toxic therapies and increase efficacy of everolimus. To provide a new perspective for mTOR inhibitor research and therapy, we discuss renal cell carcinoma cancer stem cells as a potential target for mTOR inhibitors and present new concepts on emerging antiangiogenic therapies. Finally, we point why systems biology approach with reverse molecular engineering may also contribute to the field of drug discovery in renal cell carcinoma.

Tyrosine kinase inhibitors target cancer stem cells in renal cell cancer.

This study was designed to analyze the impact of multi-targeted tyrosine kinase inhibitors on the cancer stem cell subpopulation in renal cell cancer. The second objective was to evaluate the effect of tumor growth inhibition related to a tumor niche factor - oxygen deprivation - as hypoxia develops along with the anti-angiogenic activity of tyrosine kinase inhibitors in renal tumors. Cells were treated with tyrosine kinase inhibitors, sunitinib, sorafenib and axitinib, in 2D and 3D culture conditions. Cell proliferation along with drug toxicity were evaluated. It was shown that the proliferation rate of cancer stem cells was decreased by the tyrosine kinase inhibitors. The efficacy of the growth inhibition was limited by hypoxic conditions and 3D intratumoral cell-cell interactions. We conclude that understanding the complex molecular interaction feedback loops between differentiated cancer cells, cancer stem cells and the tumor microenvironment in 3D culture should aid the identification of novel treatment targets and to evalute the efficacy of renal cancer therapies. Cell-cell interaction may represent a critical microenvironmental factor regulating cancer stem cell self-renewal potential, enhancing the stem cell phenotype and limiting drug toxicity. At the same time the role of hypoxia in renal cancer stem cell biology is also significant.

Clinical and molecular prognostic and predictive biomarkers in clear cell renal cell cancer

The natural history of clear cell renal cell cancer is highly unpredictable with various progressors and with populations where small renal masses may be accompanied by metastatic disease. Currently, there is a critical need to determine patient risk and optimize treatment regimes. For these patients, molecular markers may offer significant information in terms of prognostic and predictive values, as well as determination of valid therapeutic targets. Until now, only a few of the many identified clear cell renal cell cancer biomarkers have been clinically validated in large cohorts. And only several biomarkers are integrated in predictive or prognostic models. Therefore, a large cohesive effort is required to advance the field of clear cell renal cell cancer prognostic biomarkers through systematic discovery, verification, validation and clinical implementation.