Correction: PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain Metastases In Vitro and In Vivo

e20050 Background: In melanoma, the RAF-MEK-ERK and PI3K-AKT signaling pathways play a major role in melanoma progression and drug resistance. On the basis of significant improvement in overall survival, the BRAF inhibitor vemurafenib gained FDA approval for the treatment of patients with metastatic BRAFV600E mutated melanoma. However, vemurafenib appears to be less effective in melanoma brain metastases, and brain metastases are the most common cause of death in patients with metastatic melanoma. In our previous study we reported that the AKT survival pathway is hyperactivated in melanoma brain metastases. Methods: The current study aims to investigate the mechanisms of AKT hyperactivation and the antitumor activity of the PI3K inhibitor BKM120 in melanoma brain metastases in vitro and in vivo. Results: To simulate the tumor environment of brain metastases and extracerebral metastases, brain and matched extracerebral metastatic melanoma cells were stimulated by astrocyte- and fibroblast-conditioned medium, respectively. Both brain and extracerebral metastatic melanoma cells stimulated by astrocyte-conditioned medium showed higher AKT activation and invasiveness in a transwell matrigel invasion assay than cells stimulated by fibroblast-conditioned medium. The PI3K inhibitor BKM120 inhibited the phosphorylation of AKT and the growth of >10 newly isolated cell lines derived from melanoma brain metastases achieving growth inhibition rates of up to 80%. These effects did not depend on BRAF, NRAS or KIT mutation status. Furthermore, BKM120 potently induced apoptosis in brain metastatic melanoma cells and significantly inhibited the tumor growth of human brain metastatic melanoma cells in the brain of nude mice as shown by MRI scans. Conclusions: Brain-derived factors induce hyperactivation of the AKT survival pathway and promote invasiveness and drug resistance of melanoma cells in the brain. The PI3K inhibitor BKM120 inhibits activation of the AKT survival pathway and demonstrates potent antitumor activity in melanoma brain metastases in vitro and in vivo.

Download Full-text

CSIG-29. THE DUAL PI3K/mTOR-PATHWAY INHIBITOR GDC-0084 ACHIEVES ANTITUMOR ACTIVITY IN BREAST CANCER BRAIN METASTASES IN VITRO AND IN VIVO

Neuro-Oncology ◽

10.1093/neuonc/noy148.195 ◽

2018 ◽

Vol 20 (suppl_6) ◽

pp. vi49-vi49

Author(s):

Franziska Ippen ◽

Christopher Alvarez-Breckenridge ◽

Benjamin Kuter ◽

Alexandria Fink ◽

Ivanna Bihun ◽

...

Keyword(s):

Breast Cancer ◽

Antitumor Activity ◽

Brain Metastases ◽

Mtor Pathway ◽

Breast Cancer Brain Metastases

Download Full-text

PI3K-AKT-mTOR Pathway is Dominant over Androgen Receptor Signaling in Prostate Cancer Cells

Analytical Cellular Pathology ◽

10.1155/2010/290643 ◽

2010 ◽

Vol 32 (1-2) ◽

pp. 11-27

Author(s):

Mari Kaarbø ◽

Øyvind Løveseter Mikkelsen ◽

Lene Malerød ◽

Su Qu ◽

Viola H. Lobert ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cell Growth ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Pi3k Pathway ◽

Prostate Cancer Cells ◽

Pathway Inhibition

Background: Androgen receptor (AR) and the phosphatidylinositol-3 kinase (PI3K) signaling are two of the most important pathways implicated in prostate cancer. Previous work has shown that there is crosstalk between these two pathways; however, there are conflicting findings and the molecular mechanisms are not clear. Here we studied the AR–PI3K pathway crosstalk in prostate cancer cells in vitro as well as in vivo.Methods: Quantitative PCR, Western analysis, reporter assays, and proliferation analyses in vitro and in vivo were used to evaluate the effect of PI3K pathway inhibition on AR signaling and cell growth.Results: Transcriptional activity of AR was increased when the PI3K pathway was inhibited at different levels. In the androgen responsive prostate cancer cell line LNCaP, androgen and the mTOR inhibitor rapamycin synergistically activated androgen target genes. Despite increased androgen signaling, rapamycin treatment reduced LNCaP cell growth; the AR antagonist bicalutamide potentiated this effect. Furthermore, the rapamycin derivative CCI-779 reduced the growth of CWR22 prostate cancer xenografts while increasing AR target gene expression.Conclusions: These findings suggest that inhibition of the PI3K pathway activates AR signaling. Despite the increase in AR signaling which has proliferative effects, the result of PI3K pathway inhibition is antiproliferative. These findings suggest that the PI3K pathway is dominant over AR signaling in prostate cancer cells which should be considered in developing novel therapeutic strategies for prostate cancer.

Download Full-text

ANTITUMOR EFFECT OF COLLOIDAL SILVER BISILICATE IN EXPERIMENTAL IN VITRO AND IN VIVO STUDIES

Problems in oncology ◽

10.37469/0507-3758-2019-65-5-760-765 ◽

2019 ◽

Vol 65 (5) ◽

pp. 760-765

Author(s):

Margarita Tyndyk ◽

Irina Popovich ◽

A. Malek ◽

R. Samsonov ◽

N. Germanov ◽

...

Keyword(s):

Antitumor Activity ◽

Tumor Growth ◽

Tumor Cells ◽

Human Tumor ◽

Significant Inhibition ◽

In Vivo Studies ◽

Ehrlich Carcinoma ◽

In Vivo Experiments

The paper presents the results of the research on the antitumor activity of a new drug - atomic clusters of silver (ACS), the colloidal solution of nanostructured silver bisilicate Ag6Si2O7 with particles size of 1-2 nm in deionized water. In vitro studies to evaluate the effect of various ACS concentrations in human tumor cells cultures (breast cancer, colon carcinoma and prostate cancer) were conducted. The highest antitumor activity of ACS was observed in dilutions from 2.7 mg/l to 5.1 mg/l, resulting in the death of tumor cells in all studied cell cultures. In vivo experiments on transplanted Ehrlich carcinoma model in mice consuming 0.75 mg/kg ACS with drinking water revealed significant inhibition of tumor growth since the 14th day of experiment (maximally by 52% on the 28th day, p < 0.05) in comparison with control. Subcutaneous injections of 2.5 mg/kg ACS inhibited Ehrlich's tumor growth on the 7th and 10th days of the experiment (p < 0.05) as compared to control.

Download Full-text

In vivo-in vitro correlation of antitumor activity of heat shock protein 90 (HSP90) inhibitors with a pharmacokinetics/pharmacodynamics analysis using NCI-N87 xenograft mice

Xenobiotica ◽

10.1080/00498254.2021.1942588 ◽

2021 ◽

pp. 1-30

Author(s):

Noriaki Ohminato ◽

Miho Nagayasu ◽

Kazuhisa Ozeki ◽

Ryoichi Saitoh ◽

Naomi Ono ◽

...

Keyword(s):

Heat Shock ◽

Antitumor Activity ◽

Heat Shock Protein ◽

Heat Shock Protein 90 ◽

Hsp90 Inhibitors ◽

Xenograft Mice

Download Full-text

Surface Labeling with Adhesion Protein FimH Improves Binding of Immunotherapeutic Agent Salmonella Ty21a to the Bladder Epithelium

Bladder Cancer ◽

10.3233/blc-200382 ◽

2020 ◽

pp. 1-12

Author(s):

Maroeska J. Burggraaf ◽

Lisette Waanders ◽

Mariska Verlaan ◽

Janneke Maaskant ◽

Diane Houben ◽

...

Keyword(s):

Bladder Cancer ◽

Antitumor Activity ◽

Bladder Wall ◽

Bladder Epithelium ◽

Modest Improvement ◽

Adhesion Protein ◽

Survival Experiment ◽

Muscle Invasive

BACKGROUND: Bladder cancer is the ninth most common cancer in men. 70% of these tumors are classified as non-muscle invasive bladder cancer and those patients receive 6 intravesical instillations with Mycobacterium bovis BCG after transurethral resection. However, 30% of patients show recurrences after treatment and experience severe side effects that often lead to therapy discontinuation. Recently, another vaccine strain, Salmonella enterica typhi Ty21a, demonstrated promising antitumor activity in vivo. Here we focus on increasing bacterial retention in the bladder in order to reduce the number of instillations required and improve antitumor activity. OBJECTIVE: To increase the binding of Ty21a to the bladder wall by surface labeling of the bacteria with adhesion protein FimH and to study its effect in a bladder cancer mouse model. METHODS: Binding of Ty21a with surface-labeled FimH to the bladder wall was analyzed in vitro and in vivo. The antitumor effect of a single instillation of Ty21a+FimH in treatment was determined in a survival experiment. RESULTS: FimH-labeled Ty21a showed significant (p < 0.0001) improved binding to mouse and human cell lines in vitro. Furthermore, FimH labeled bacteria showed ∼5x more binding to the bladder than controls in vivo. Enhanced binding to the bladder via FimH labeling induced a modest improvement in median but not in overall mice survival. CONCLUSIONS: FimH labeling of Ty21a significantly improved binding to bladder tumor cells in vitro and the bladder wall in vivo. The improved binding leads to a modest increase in median survival in a single bladder cancer mouse study.

Download Full-text

Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity

Molecules ◽

10.3390/molecules26071838 ◽

2021 ◽

Vol 26 (7) ◽

pp. 1838

Author(s):

Naglaa M. Ahmed ◽

Mahmoud M. Youns ◽

Moustafa K. Soltan ◽

Ahmed M. Said

Keyword(s):

Molecular Modeling ◽

Antitumor Activity ◽

Cell Lines ◽

Cancer Cell ◽

Antiproliferative Activity ◽

Antitumor Agents ◽

Cancer Cell Lines ◽

Normal Cells

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1–4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC50 = 5.1, 5.02, and 6.6 μM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53–79 %) activity. Compound 4g was found to be the most active compound against EGFR (IC50 = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent.

Download Full-text

EXTH-07. TUMOR-HOMING INDUCED NEURAL STEM CELLS SECRETING A CYTOTOXIC PAYLOAD AS AN ADJUVANT TREATMENT FOR NON-SMALL CELL LUNG CANCER BRAIN METASTASES

Neuro-Oncology ◽

10.1093/neuonc/noaa215.361 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii88-ii88

Author(s):

Alison Mercer-Smith ◽

Wulin Jiang ◽

Alain Valdivia ◽

Juli Bago ◽

Scott Floyd ◽

...

Keyword(s):

Stem Cells ◽

Brain Metastases ◽

Neural Stem Cells ◽

Adjuvant Treatment ◽

Small Cell ◽

Small Cell Lung ◽

Tumor Homing ◽

Induced Neural Stem Cells

Abstract INTRODUCTION Non-small cell lung cancer (NSCLC) is the most common cancer to form brain metastases. Radiation treatment is standard-of-care, but recurrence is still observed in 40% of patients. An adjuvant treatment is desperately needed to track down and kill tumor remnants after radiation. Tumoritropic neural stem cells (NSCs) that can home to and deliver a cytotoxic payload offer potential as such an adjuvant treatment. Here we show the transdifferentiation of human fibroblasts into tumor-homing induced neural stem cells (hiNSCs) that secrete the cytotoxic protein TRAIL (hiNSC-TRAIL) and explore the use of hiNSC-TRAIL to treat NSCLC brain metastases. METHODS To determine the migratory capacity of hiNSCs, hiNSCs were infused intracerebroventricularly (ICV) into mice bearing established bilateral NSCLC H460 brain tumors. hiNSC accumulation at tumor foci was monitored using bioluminescent imaging and post-mortem fluorescent analysis. To determine synergistic effects of radiation with TRAIL on NSCLC, we performed in vitro co-culture assays and isobologram analysis. In vivo, efficacy was determined by tracking the progression and survival of mice bearing intracranial H460 treated with hiNSC-TRAIL alone or in combination with 2 Gy radiation. RESULTS/CONCLUSION Following ICV infusion, hiNSCs persisted in the brain for > 1 week and migrated from the ventricles to colocalize with bilateral tumor foci. In vitro, viability assays and isobologram analysis revealed the combination treatment of hiNSC-TRAIL and 2 Gy radiation induced synergistic killing (combination index=0.64). In vivo, hiNSC-TRAIL/radiation combination therapy reduced tumor volumes > 90% compared to control-treated animals while radiation-only and hiNSC-TRAIL-only treated mice showed 21% and 52% reduced volumes, respectively. Dual-treatment extended survival 40%, increasing survival from a median of 20 days in controls to 28 days in the treatment group. These results suggest hiNSC-TRAIL can improve radiation therapy for NSCLC brain metastases and could potentially improve outcomes for patients suffering from this aggressive form of cancer.

Download Full-text