scholarly journals STEM-21. CLINICAL RELEVANCE OF CANCER STEM CELL CYTOTOXICITY ASSAY IN GUIDING TREATMENT FOR GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii200-ii200
Author(s):  
Claudio Pier Paolo ◽  
Tulika Ranjan ◽  
Candace Howard ◽  
Alexander Yu ◽  
Linda Xu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Clinical Investigation ◽  
Therapy Resistance ◽  
Chemotherapeutic Agents ◽  
Cytotoxicity Assay ◽  
Recurrence Time ◽  
Cell Cytotoxicity ◽  
Treatment Protocols ◽  
Time To Recurrence

Abstract BACKGROUND. The prognosis of glioblastoma (GBM) treated with standard-of-care regimens remains very poor with a median time to recurrence of 7-9 months, and a median survival of 15-18 months. GBMs contain a small, but resilient population of cancer stem cells (CSCs) that contribute to tumor initiation, maintenance, and therapy resistance. For these reasons, its is extremely important to determine the sensitivity of CSCs to chemotherapeutic agents, with the intent of identifying more effective treatment protocols which would then translate into improved clinical survival. METHODS. We have used a novel CLIA and CAP-accredited Cancer Stem Cell Cytotoxicity Assay (ChemoID) to guide treatment for 55 Grade III and Grade IV glioma patients with the most efficacious chemotherapy treatments from a panel of FDA approved drugs or their combinations. Patients were evaluated by MRI scans and response was assessed according to RANO criteria. RESULTS: We report here a prospective clinical investigation using the ChemoID assay to measure the sensitivity and resistance of CSCs and bulk of tumor cells cultured from 55 GBM clinical specimens challenged with several chemotherapy agents, which were also correlated to the clinical response of the treated patients, independently of other biomarkers. The median recurrence time was 15 months for patients with a sensitive (>40% cell kill) CSCs test versus only 6 months for patients with a resistant CSCs test. CONCLUSIONS. The data suggests that GBM patients treated with CSC Cytotoxicity Assay-guided responsive drugs have delayed time to recurrence and the assay has the potential to help tailor chemotherapy choices to improve clinical outcomes.

scholarly journals STEM-13. CANCER STEM CELL CYTOTOXICITY ASSAY-GUIDED TREATMENT IN RECURRENT GLIOBLASTOMA AND PROGRESSIVE ANAPLASTIC GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi236-vi236
Author(s):  
Tulika Ranjan ◽  
Candace Howard ◽  
Alexander Yu ◽  
Linda Xu ◽  
Khaled Aziz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
High Grade Glioma ◽  
Recurrent Glioblastoma ◽  
Cytotoxicity Assay ◽  
High Grade ◽  
Cell Cytotoxicity ◽  
Glioma Patient ◽  
Patient Cohort ◽  
Anaplastic Gliomas

Abstract BACKGROUND The presence of chemotherapy-resistant cancer stem cells (CSC) leading to tumor recurrence is postulated to be one of the major factors in the poor response to the current standard of care treatments in progressive high-grade gliomas. Unfortunately, in spite of several new drug discoveries for other tumor types, not many advances have been reported for this disease and therefore recurrent and progressive high-grade glioma survival remains dismal. METHODS We have used a CLIA and CAP accredited Cancer Stem Cell Cytotoxicity Assay(ChemoID) to guide most effective chemotherapy treatments from a panel of FDA approved drugs or their combinations for 12 recurrent glioblastoma (GBM) patients and 2 progressive anaplastic gliomas, all eligible to receive a stereotactic biopsy. Patients were evaluated by MRI scans and response was assessed according to RANO criteria. RESULTS The median age of our patient cohort was 49 years (21–63), with 11 males (79%) and 3 females (21%). We observed 6 complete responses (CR) 43%, 6 partial responses (PR) 43%, and 2 progressive diseases (PD) 14%. Of note, the two PD were observed in patients that could not be treated with assay recommended therapy due to their health status. Patients treated with ChemoID assay-directed therapy had a longer median overall survival (OS) of 13.3 months (5.4-NA) compared to the historical median OS of 9.0 months (8.0–10.8 months) previously reported (1). Notably, our recurrent and progressive high-grade glioma patient cohort treated with assay-guided therapy had a 57% probability to survive at 12 months, compared to the 27% historical probability of survival at 12 months observed in previous studies (1). CONCLUSIONS The data suggests that the ChemoID Cancer Stem Cell Cytotoxicity Assay has the potential to help guide individualized chemotherapy choices to improve recurrent and progressive high-grade glioma patient outcome. 1) Friedman, H.S. et. al. JCO2009 27:28, 4733–4740.

Integrin β3 links therapy resistance and cancer stem cell properties

2014 ◽  
Vol 16 (5) ◽  
pp. 397-399 ◽  
Author(s):  
Nagarajan Kannan ◽  
Long V. Nguyen ◽  
Connie J. Eaves
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Therapy Resistance ◽  
Integrin Β3

scholarly journals Dual Knockdown of Musashi RNA-Binding Proteins MSI-1 and MSI-2 Attenuates Putative Cancer Stem Cell Characteristics and Therapy Resistance in Ovarian Cancer Cells

2021 ◽  
Vol 22 (21) ◽  
pp. 11502
Author(s):  
Maria T. Löblein ◽  
Isabel Falke ◽  
Hans Theodor Eich ◽  
Burkhard Greve ◽  
Martin Götte ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cancer Cells ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Therapy Resistance ◽  
Ovarian Cancer Cells

In ovarian cancer, therapy resistance mechanisms complicate cancer cell eradication. Targeting Musashi RNA-binding proteins (MSI) may increase therapeutic efficacy. Database analyses were performed to identify gene expression associations between MSI proteins and key therapy resistance and cancer stem cell (CSC) genes. Then, ovarian cancer cells were subjected to siRNA-based dual knockdown of MSI-1 and MSI-2. CSC and cell cycle gene expression was investigated using quantitative polymerase chain reaction (qPCR), western blots, and flow cytometry. Metabolic activity and chemoresistance were assessed by MTT assay. Clonogenic assays were used to quantify cell survival post-irradiation. Database analyses demonstrated positive associations between MSI proteins and putative CSC markers NOTCH, MYC, and ALDH4A1 and negative associations with NOTCH inhibitor NUMB. MSI-2 expression was negatively associated with the apoptosis regulator p21. MSI-1 and MSI-2 were positively correlated, informing subsequent dual knockdown experiments. After MSI silencing, CSC genes were downregulated, while cell cycle progression was reduced. Metabolic activity was decreased in some cancer cells. Both chemo- and radioresistance were reduced after dual knockdown, suggesting therapeutic potential. Dual knockdown of MSI proteins is a promising venue to impede tumor growth and sensitize ovarian cancer cells to irradiation and chemotherapy.

scholarly journals NOTCH1 inhibition enhances the efficacy of conventional chemotherapeutic agents by targeting head neck cancer stem cell

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Zhi-Li Zhao ◽  
Lu Zhang ◽  
Cong-Fa Huang ◽  
Si-Rui Ma ◽  
Lin-Lin Bu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Neck Cancer ◽  
Chemotherapeutic Agents ◽  
Head Neck Cancer ◽  
Head Neck

Abstract 1123: The role of proto-oncogene PELP1 in breast cancer stem cell maintenance and therapy resistance

2016 ◽  
Author(s):  
Suryavathi Viswanadhapalli ◽  
Monica Mann ◽  
Gangadhara Reddy Sareddy ◽  
Xaionan Lix ◽  
Hariprasad Vankayalapati ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Therapy Resistance ◽  
Breast Cancer Stem Cell ◽  
Stem Cell Maintenance ◽  
Cell Maintenance

scholarly journals Plasticity of Cancer Stem Cell: Origin and Role in Disease Progression and Therapy Resistance

2020 ◽  
Vol 16 (2) ◽  
pp. 397-412 ◽  
Author(s):  
Plabon Kumar Das ◽  
Suja Pillai ◽  
Md. Abdur Rakib ◽  
Jahan Ara Khanam ◽  
Vinod Gopalan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Disease Progression ◽  
Therapy Resistance

scholarly journals Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Martina Lepore Signorile ◽  
Valentina Grossi ◽  
Simone Di Franco ◽  
Giovanna Forte ◽  
Vittoria Disciglio ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Kinase Inhibitor ◽  
Synthetic Lethality ◽  
Locally Advanced ◽  
Treatment Strategies ◽  
Chemotherapeutic Agents ◽  
Model Systems ◽  
Metastatic Dissemination

AbstractThe prognosis of locally advanced colorectal cancer (CRC) is currently unsatisfactory. This is mainly due to drug resistance, recurrence, and subsequent metastatic dissemination, which are sustained by the cancer stem cell (CSC) population. The main driver of the CSC gene expression program is Wnt signaling, and previous reports indicate that Wnt3a can activate p38 MAPK. Besides, p38 was shown to feed into the canonical Wnt/β-catenin pathway. Here we show that patient-derived locally advanced CRC stem cells (CRC-SCs) are characterized by increased expression of p38α and are “addicted” to its kinase activity. Of note, we found that stage III CRC patients with high p38α levels display reduced disease-free and progression-free survival. Extensive molecular analysis in patient-derived CRC-SC tumorspheres and APCMin/+ mice intestinal organoids revealed that p38α acts as a β-catenin chromatin-associated kinase required for the regulation of a signaling platform involved in tumor proliferation, metastatic dissemination, and chemoresistance in these CRC model systems. In particular, the p38α kinase inhibitor ralimetinib, which has already entered clinical trials, promoted sensitization of patient-derived CRC-SCs to chemotherapeutic agents commonly used for CRC treatment and showed a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Taken together, these results suggest that p38α may be targeted in CSCs to devise new personalized CRC treatment strategies.

scholarly journals Clinical Impact of Intratumoral EpCAM-Positive Cancer Stem Cell Heterogeneity in Patients with Hepatocellular Carcinoma

2020 ◽  
Author(s):  
Jenny Krause ◽  
Johann von Felden ◽  
Christian Casar ◽  
Thorben W. Fründt ◽  
Johanna Galaski ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Spatial Heterogeneity ◽  
Adjuvant Treatment ◽  
Early Recurrence ◽  
Epcam Expression ◽  
Clinical Endpoints ◽  
Time To Recurrence ◽  
Dismal Prognosis

Abstract Backgrounds & Aims: Intratumoural heterogeneity of hepatocellular carcinoma (HCC) is of increasing translational interest. Dismal prognosis is frequently linked to HCC harbouring cancer stem cell (CSC)-features, represented by EpCAM-expression. However, to what extent intratumoural distribution of CSC-features impacts on recurrence after curative resection remains unknown. Hence, we aimed to investigate the spatial heterogeneity of CSC-features and its impact on clinical outcome, identifying high-risk patients amenable to adjuvant treatment.Methods: We designed a tissue microarray (TMA) from patients, who received liver resection between 2011 and 2017. Tumour specimens were sampled at multiple locations (n=3-8). EpCAM-positivity was assessed for intensity and proportion by applying a score dividing three groups: negative (E-/-), heterogeneous-positive (E-/+), homogeneous-positive (E+/+). The groups were further analysed with respect to time-to-recurrence (TTR) and recurrence-free-survival (RFS).Results: We included 341 tumour spots from 75 patients (77% male, median age 66 years, liver cirrhosis/fibrosis 74.6%). Risk factors were alcohol abuse in 23.9%, NASH 16.3%, HBV 14.1%, HCV 17.4% and others 28.3%, representing a typical Western cohort. E+/+ patients experienced a significantly shorter TTR and RFS compared to E+/- (and E-/-) patients (TTR 5 vs. 19 months, p=0.017; RFS 5 vs. 14 vs. 18 months, p=0.016). Only homogeneous EpCAM-positivity correlated with higher AFP levels (>400 ng/ml, p=0.024).Conclusions: Spatial heterogeneity of EpCAM-expression was markedly present. Only homogeneously positive EpCAM-expression correlated significantly with early recurrence, whereas heterogeneous EpCAM-expression was associated with clinical endpoints comparable to EpCAM-negativity. Similar to colorectal cancer, high or low risk features for recurrence could be decisive for adjuvant treatment.

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