108 research outputs found
Abstract 5732: PI3K/Akt activity regulates androgen receptor expression and predicts poor clinical outcome in non-metastatic hormone-naïve prostate cancer
No full textAbstract
Activation of PI3K/Akt pathway is associated with adverse outcome and aggressive disease in many cancers. In prostate cancer (PCa), the activity of this pathway has been shown to promote disease progression and metastasis. However, it is still controversial how PI3K/Akt regulates androgen receptor (AR), a central signaling molecule in prostate pathophysiology, and whether it has an active role in hormone naïve non-metastatic PCa. Here, we show using immunohistochemistry (IHC) and advanced quantitative multiplexed IHC that the expression of phosphorylated-Akt(S473) and AR are highly correlated in clinical PCa, even at the cellular level. Furthermore, we found that high expression of p-Akt(S473) predicts poor clinical outcome in two independent hormone-naïve non-metastatic PCa cohorts. To study whether PI3K/Akt regulates AR expression, we performed an in vitro drug screen with 32 PI3K/Akt/mTOR inhibitors in PC346C, an AR expressing cell line derived from a hormone-naïve primary tumor of prostate. We observed a strong correlation between p-Akt(S473) and AR also in vitro in individual cells independent of the inhibitor used. Although both PI3K and Akt specific inhibition reduced cell viability, the response in nuclear expression of AR was highly dependent on the target of inhibition: Akt specific inhibition reduced AR nuclear expression and resulted in large, spindle-shaped cells, whereas PI3K specific inhibition increased AR nuclear expression and resulted in smaller, round-shaped cells. These data suggest that PI3K and Akt have different roles in sustaining AR activity in PCa as perturbations of the two components leads to differential responses in terms of AR nuclear expression and cell morphology. In conclusion, activated Akt associates with AR expression and predicts poor clinical outcome in hormone-naïve non-metastatic PCa. Furthermore, the differing roles of PI3K and Akt in AR regulation warrants for further studies as it may have implications in the design of PCa therapy targeting PI3K/Akt, especially when the inhibitors are administered in combination with anti-androgens.
Citation Format: Sami Blom, Petra Mäki-Teeri, Andrew Erickson, Lassi Paavolainen, Tuomas Mirtti, Antti Rannikko, Swapnil Potdar, Päivi Östling, Wytske van Weerden, Olli Kallioniemi, Teijo Pellinen. PI3K/Akt activity regulates androgen receptor expression and predicts poor clinical outcome in non-metastatic hormone-naïve prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5732. doi:10.1158/1538-7445.AM2017-5732</jats:p
Abstract 3854: Precision medicine approach: analysis of renal cancer patient-derived cells with phenomics, genomics and drug sensitivity profiling
No full textAbstract
We have built up the precision medicine approach for solid tumors to understand biological heterogeneity and driver signalling pathways in cancer, to develop pharmacogenomic biomarkers and to ultimately tailor effective treatments for patients. In addition to genetic profiling of original tumor tissues, we have developed patient -derived tumor cell (PDC) models, and characterized these models with genomics, image-based phenotyping (phenomics) and high throughput drug profiling.
Here, we describe our approach for a clear cell renal cell carcinoma (ccRCC) patient. PDC cultures were initiated using conditional reprogramming method from fresh primary tumor, protrusion to vena cava, and the benign tissue samples. The exome-sequencing of tissues and PDCs showed that several copy number variations and somatic driver mutations were shared between the cancer tissue and corresponding cell models, including TSC2 and VHL mutations. Using image-based phenotyping, the PDCs from the benign tissue were observed to be strongly positive to cytokeratin 7 (CK7), while original tumor tissue and PDCs from tumor tissue were predominantly CK7 negative. The PDCs expressed vimentin, a mesenchymal marker, but the epithelial marker E-cadherin was downregulated, suggesting for epithelial-mesenchymal transition. The PDCs from primary tumor were exposed to drug sensitivity profiling with a library of 525 approved and investigational oncology compounds in five different concentrations and imaged for proliferation with Ki-67. PI3K/mTOR pathway inhibitors were found to be among the drugs inhibiting the cell proliferation, in agreement with detected somatic mutations affecting these pathways. In addition, our image-based drug sensitivity testing revealed the intra-sample heterogeneity in drug responses and resistance, and we are now further investigating the mechanisms of most potent drugs and their combinations in PDCs at single cell level.
As a conclusion, our results implicate the importance of comprehensive characterization of PDCs and their drug responses in translational research. We also foresee that these approaches may potentially improve the translation of results back to clinic and support the design of combination therapies in cancer.
Citation Format: Vilja M. Pietiäinen, Piia Mikkonen, Khalid Saeed, Lassi Paavolainen, Teijo Pellinen, Swapnil Potdar, John Mpindi, Harry Nisén, Antti Rannikko, Tuomas Mirtti, Peter Horvath, Päivi Östling, Olli Kallioniemi. Precision medicine approach: analysis of renal cancer patient-derived cells with phenomics, genomics and drug sensitivity profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3854. doi:10.1158/1538-7445.AM2017-3854</jats:p
Abstract 4207: Selective drug sensitivity score (DSS) for indolent and aggressive prostate cancer cell lines
No full textAbstract
Prostate cancer (PC) is the most common malignancy in men and the second leading cause of cancer-related deaths. The majority of the PCs are classified as adenocarcinomas characterized by the expression of androgen receptor (AR) and prostate-specific antigen (PSA). Two of the most commonly used cell lines are LNCaP and PC-3 cells, derived from lymph node and bone metastases, respectively. Also VCaP cells, derived from vertebral metastases, are widely used in prostate cancer research. It has been well established that LNCaP and VCaP cells represent the conventional indolent form of PC expressing AR and PSA and are androgen-dependent. PC-3 cells, on the other hand, do not express AR and PSA, are androgen-independent, and represent the highly aggressive form.
The drug sensitivity of the cell lines was assessed by applying a large panel of drugs covering cancer chemotherapeutics and clinically available and emerging drugs including conventional chemotherapy, kinase inhibitors, metabolic modifiers, rapalogs, differentiating/epigenetic modifiers, kinesin inhibitors, apoptotic modulators, NSAIDs, hormone therapy, immunomodulators and HSP inhibitors. A panel of 460 compounds was tested in five concentrations covering a 10.000-fold drug-relevant concentration range in 384-well format. Cells were seeded to pre-drugged plates, followed by cell viability measurements (CellTiter-Glo) after 72 hours. Maximal and minimal responses to drugs were analyzed, the EC50 values were calculated and Drug Sensitivity Score (DSS) was calculated for each drug as a measure of reduced viability. A selective Drug Sensitivity Score (sDSS) was calculated to identify the selective drug response pattern of each three cancer cell lines.
As expected, the results indicate that LNCaP and VCaP cells in general were more sensitive to drugs of different categories than PC-3 cells. According to DSS analysis, all three cell lines showed sensitivity to conventional chemotherapy and kinase inhibitors. However, PC-3 cells were more sensitive to kinase inhibitors than conventional chemotherapy. Determining sDSS revealed specific sensitivities of each cell line. LNCaP cells were sensitive to kinase inhibitors, such as mTOR and AKT inhibitors. Also VCaP cells showed selective sensitivity to kinase inhibitors, especially Aurora kinase and IGF1R inhibitors. In addition to kinase inhibitors, VCaP cells were selectively sensitive to HDAC inhibitors. Furthermore, PC-3 cells were sensitive to e.g. CDK inhibitors.
We conclude that the cell-based compound screening combined with DSS and sDSS analysis provides a possibility to profile cellular responses to an extensive collection of anti-cancer compounds enabling repurposing of existing drugs to new indications, identification of vulnerabilities in different types of cancer cells and functional investigation of cellular pathways behind drug sensitivity or resistance.
Citation Format: Jenni Mäki-Jouppila, Jenni Bernoulli, Johanna Tuomela, Mari I. Suominen, Jussi M. Halleen, Sanna Timonen, Elina Huovari, Katja Suomi, Swapnil Potdar, Päivi Östling, Jani Saarela, Katja M. Fagerlund. Selective drug sensitivity score (DSS) for indolent and aggressive prostate cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4207. doi:10.1158/1538-7445.AM2017-4207</jats:p
Online Trajectory Planning and Control of a MAV Payload System in Dynamic Environments: A Non-Linear Model Predictive Control Approach
No full textMicro Aerial Vehicles (MAVs) are increasingly being used for aerial transportation in remote and urban spaces where portability can be exploited to reach previously inaccessible and inhospitable spaces. Current approaches to MAV swung payload system path planning have primarily focused on pre-generating (agile) collision-free, or conservative minimal-swing trajectories in static environments. However, these approaches have failed to address the prospect of online re-planning in uncertain and dynamic environments which is a prerequisite for real-world deployability. This article describes a novel Non-Linear Model Predictive Controller (NMPC) for online, agile and closed-loop local trajectory planning and control addressing the limitations mentioned of contemporary approaches. We integrate the controller in a full system framework and demonstrate the algorithm’s effectiveness in simulation and experimental studies. Results show the scalability and adaptability of our method to various dynamic setups with repeatable performance over several complex tasks which include flying through a narrow opening and avoiding moving humans.Aerospace Engineering | Control & Simulatio
Abstract 3838: Drug sensitivity profile of 5TGM1 murine multiple myeloma cell line emphasizes the translational potential of the syngeneic <i>in vivo</i> model
No full textAbstract
Multiple myeloma (MM) is the second most common hematologic malignancy that originates from B-cells (plasma cells) and causes 2% of cancer-related deaths. Symptoms of MM include bone pain caused by multiple osteolytic lesions, pathologic fractures, and hypercalcemia. Typically, MM has a low growth fraction and it is highly dependent on the microenvironment. These properties have made it hard to target by conventional chemotherapy, but could now be exploited by novel stroma-targeting drugs and immunotherapy. These new approaches underline the need for well characterized models with functional immune system and appropriate tumor microenvironment. To gain additional information supporting the use of the syngeneic 5TGM1 murine multiple myeloma model in drug development, we tested drug sensitivity of 5TGM1 cells by screening an extensive panel of drugs.
The compound library consisting of 460 compounds included conventional chemotherapy, kinase inhibitors, metabolic modifiers, rapalogs, differentiating/epigenetic modifiers, kinesin inhibitors, apoptotic modulators, NSAIDs, hormone therapy, immunomodulators and HSP inhibitors. The compounds were tested in five concentrations covering a 10.000-fold drug-relevant concentration range in 384-well format. Cells were seeded to plates with a compound library, followed by cell viability measurements (CellTiter-Glo) after 72 hours. Maximal and minimal responses to drugs were analyzed, and the EC50 values were calculated. Drug Sensitivity Score (DSS) was calculated for each drug as a measure of reduced viability.
According to DSS analysis, 5TGM1 cells showed sensitivity to conventional chemotherapy, such as antimitotic drugs, and kinase inhibitors, such as MEK1/2 inhibitors. In addition, the cells showed particular sensitivity to several HSP90 inhibitors currently in phase I/II clinical development for MM. Lenalidomide and pomalidomide, efficient in treating multiple myeloma in humans, both gave low DSS value indicating that 5TGM1 cells are not sensitive to these drugs, which is expected because they do not bind to murine form of the target cereblon. In contrast, 5TGM1 cells were highly sensitive to the proteasome inhibitor bortezomib (DSS 32.2), which is currently in clinical use.
In conclusion, the murine 5TGM1 cells show sensitivity to various MM drugs used in the clinic and under development. Evaluating the effects of the microenvironment on the growth and drug sensitivity of 5TGM1 cells in vitro and in vivo will be essential. Furthermore, the cell-based compound screening combined with DSS analysis provides a possibility to profile cellular responses to an extensive collection of anti-cancer compounds enabling identification of vulnerabilities in cancer cells and functional investigation of cellular pathways behind drug sensitivity or resistance.
Citation Format: Jenni Mäki-Jouppila, Jenni Bernoulli, Mari I. Suominen, Tiina Kähkönen, Jussi M. Halleen, Sanna Timonen, Elina Huovari, Katja Suomi, Swapnil Potdar, Maria Nurmi, Päivi Östling, Jani Saarela, Katja M. Fagerlund. Drug sensitivity profile of 5TGM1 murine multiple myeloma cell line emphasizes the translational potential of the syngeneic in vivo model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3838. doi:10.1158/1538-7445.AM2017-3838</jats:p
ChemInform Abstract: Coumarin Syntheses via Pechmann Condensation in Lewis Acidic Chloroaluminate Ionic Liquid.
No full text
Future-mapping technique for a non-profit organization
No full textOrganizations often find themselves in a difficult situation when strategizing for the future. This report aims to map the future of a non-profit organization. According to the author, future mapping means assessing the future possibilities, assessing the available options, and using these analyses to direct the organization. The work covers the gap between future studies and strategies for non-profit organizations as a by-product. The technique is applied in the case of a non-profit organization, Modus ry, which supports the handcrafting entrepreneurs and businesses in Finland. The work has two resulting outputs. One is the recommendations for the association, and the second is a technique for future mapping. When developing the technique, the work may also be described as a recombination of individual already existing concepts to get the most out of them. These concepts include scenario-based strategy, future wheels, and analysis tools like context diagram, why-why diagram, stakeholder map, analysis tables, etc. The technique is replicable and valid. Strategizing for long-term possibilities while at the same time integrating short-lasting trends and changes is the highlight of the technique
- …
