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

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.

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

Neuro-Oncology ◽

10.1093/neuonc/noaa215.838 ◽

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.

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Anterior gradient protein 2 expression in high grade head and neck squamous cell carcinoma correlated with cancer stem cell and epithelial mesenchymal transition

Oncotarget ◽

10.18632/oncotarget.3556 ◽

2015 ◽

Vol 6 (11) ◽

pp. 8807-8821 ◽

Cited By ~ 29

Author(s):

Si-Rui Ma ◽

Wei-Ming Wang ◽

Cong-Fa Huang ◽

Wen-Feng Zhang ◽

Zhi-Jun Sun

Keyword(s):

Squamous Cell Carcinoma ◽

Stem Cell ◽

Cancer Stem Cell ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Epithelial Mesenchymal Transition ◽

Neck Squamous Cell Carcinoma ◽

High Grade ◽

Mesenchymal Transition

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KS02.4.A Olaparib in Recurrent IDH-mutant High-Grade Glioma (OLAGLI)

Neuro-Oncology ◽

10.1093/neuonc/noab180.011 ◽

2021 ◽

Vol 23 (Supplement_2) ◽

pp. ii4-ii4

Author(s):

F Ducray ◽

M Sanson ◽

O Chinot ◽

M Fontanilles ◽

R Rivoirard ◽

...

Keyword(s):

Median Time ◽

High Grade Glioma ◽

Median Number ◽

Parp Inhibition ◽

Low Grade ◽

Type I ◽

High Grade ◽

Rano Criteria ◽

Anaplastic Gliomas ◽

New Treatments

Abstract BACKGROUND There is a need to develop new treatments in IDH-mutant high-grade gliomas recurring after radiotherapy and chemotherapy. Based on preclinical studies showing that IDH-mutant tumors could be vulnerable to PARP inhibition we launched a phase II study to test the efficacy of olaparib (Lynparza) monotherapy in this population. METHODS Adults with recurrent high-grade IDH-mutant gliomas after radiotherapy and at least one line of alkylating chemotherapy (PCV or TMZ), KPS > 60, normal organ function were enrolled. The primary endpoint was 6 months PFS according to RANO criteria. Patients were treated with olaparib 300 mg twice daily. We used a single-stage Fleming design with p0 = 30%, p1 = 50%, a type I unilateral error rate of 5% and a power of 80%. RESULTS 35 patients with recurrent IDH-mutant gliomas (IDH1R132H-mutant n = 32, other IDH mutation n = 3, 1p/19 codeleted n = 16, 1p/19q non-codeleted n = 14) were enrolled (malignantly transformed low-grade gliomas n = 21, anaplastic gliomas n = 8, glioblastomas n = 6). Median time since diagnosis was 7.4 years (1–22 years), median time since radiotherapy was 2.8 years (0.6–18 years), median number of previous chemotherapy lines was 2 (1–5). With a median follow-up of 11 months, 30 patients had stopped treatment due to tumor progression and 2 patients were still on treatment 16 to 18 months after treatment start. At 6 months, 11/35 patients were progression-free (31 %). According to RANO criteria, based on local investigator analysis, 2 patients (5%) had a partial response and 14 patients a stable disease (37%) with a median duration of response of 9 months (4–18+). Median PFS and OS were 2.3 and 15.9 months and were similar in 1p/19q codeleted and non-codeleted patients. A grade 3 olaparib-related adverse event was observed in 5 patients (14%, lymphopenia n = 3, fatigue n = 2, diarrhea n = 1) and a grade 2 in 15 patients (43%), most frequently consisting in fatigue (23%), gastrointestinal disorders (20%) and lymphopenia (20%). No patient definitively stopped olaparib due to side effects. CONCLUSIONS In this heavily pre-treated population of recurrent IDH-mutant gliomas, olaparib monotherapy was well tolerated and resulted in some activity supporting its evaluation in association with alkylating chemotherapy in recurrent IDH-mutant gliomas in future studies.

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Expression of the cancer stem cell marker SSEA1 is associated with poor survival in metastatic high-grade serous carcinoma

Virchows Archiv ◽

10.1007/s00428-020-02850-4 ◽

2020 ◽

Vol 477 (5) ◽

pp. 677-685

Author(s):

Ben Davidson ◽

Arild Holth ◽

Hiep Phuc Dong

Keyword(s):

Stem Cell ◽

Survival Analysis ◽

Cancer Stem Cell ◽

Ovarian Carcinoma ◽

Progression Free Survival ◽

Stem Cell Marker ◽

Serous Carcinoma ◽

High Grade ◽

Poor Survival ◽

Free Survival

Abstract The objective of the present study was to perform a quantitative analysis of cancer stem cell (CSC) marker expression in ovarian carcinoma effusions. The clinical role of SSEA1 in metastatic high-grade serous carcinoma (HGSC) was additionally analyzed. CD133, Nanog, SOX2, Oct3/4, SSEA1, and SSEA4 protein expressions were quantitatively analyzed using flow cytometry (FCM) in 24 effusions. SSEA1 expression by immunohistochemistry was analyzed in 384 HGSC effusions. Highly variable expression of CSC markers by FCM was observed, ranging from 0 to 78% of Ber-EP4-positive cells in the case of CD133, with the largest number of negative specimens seen for SSEA4. SSEA1 expression by immunohistochemistry was found in HGSC cells in 336/384 (89%) effusions, most commonly focally (< 5% of cells). SSEA1 was overexpressed in post-chemotherapy disease recurrence specimens compared with chemo-naïve HGSC effusions tapped at diagnosis (p = 0.029). In univariate survival analysis, higher SSEA1 expression was significantly associated with poor overall survival (p = 0.047) and progression-free survival (p = 0.018), though it failed to retain its prognostic role in Cox multivariate survival analysis in which it was analyzed with clinical parameters (p = 0.059 and p = 0.111 for overall and progression-free survival, respectively). In conclusion, CSC markers are variably expressed in ovarian carcinoma effusions. SSEA1 expression is associated with disease progression and poor survival in metastatic HGSC. Silencing this molecule may have therapeutic relevance in this cancer.

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Coping with a newly diagnosed high-grade glioma: patient-caregiver dyad effects on quality of life

Journal of Neuro-Oncology ◽

10.1007/s11060-016-2161-6 ◽

2016 ◽

Vol 129 (1) ◽

pp. 155-164 ◽

Cited By ~ 10

Author(s):

K. Baumstarck ◽

T. Leroy ◽

Z. Hamidou ◽

E. Tabouret ◽

P. Farina ◽

...

Keyword(s):

Quality Of Life ◽

High Grade Glioma ◽

High Grade ◽

Newly Diagnosed ◽

Glioma Patient

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Current Concepts in Brain Tumor Imaging

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2012.32.119 ◽

2012 ◽

pp. 119-124

Author(s):

Andrew D. Norden ◽

Whitney B. Pope ◽

Susan M. Chang

Keyword(s):

Standard Treatment ◽

Tumor Imaging ◽

High Grade Glioma ◽

Response Assessment ◽

Recurrent Glioblastoma ◽

High Grade ◽

Resonance Imaging ◽

Imaging Tool ◽

Magnetic Resonance Imaging Mri ◽

New Criteria

Overview: Magnetic resonance imaging (MRI) is the most useful imaging tool in the evaluation of patients with brain tumors. Most information is supplied by standard anatomic images that were developed in the 1980s and 1990s. More recently, functional imaging including diffusion and perfusion MRI has been investigated as a way to generate predictive and prognostic biomarkers for high-grade glioma evaluation, but additional research is needed to establish the added benefits of these indices to standard MRI. Response critieria for high-grade gliomas have recently been updated by the Response Assessment in Neuro-Oncology (RANO) working group. The new criteria account for nonenhancing tumor in addition to the contrast-enhancing abnormalities on which older criteria relied. This issue has recently come to the fore with the introduction of the antiangiogenic agent bevacizumab into standard treatment for recurrent glioblastoma. Because of its potent antipermeability effect, contrast enhancement is markedly reduced in patients who receive bevacizumab. The RANO criteria also address the phenomenon of pseudoprogression, in which there may be transient MRI worsening of a glioblastoma following concurrent radiotherapy and temozolomide.

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A Pilot Study of Vaccine Therapy with Multiple Glioma Oncoantigen/Glioma Angiogenesis-Associated Antigen Peptides for Patients with Recurrent/Progressive High-Grade Glioma

Journal of Clinical Medicine ◽

10.3390/jcm8020263 ◽

2019 ◽

Vol 8 (2) ◽

pp. 263 ◽

Cited By ~ 5

Author(s):

Ryogo Kikuchi ◽

Ryo Ueda ◽

Katsuya Saito ◽

Shunsuke Shibao ◽

Hideaki Nagashima ◽

...

Keyword(s):

T Lymphocyte ◽

High Grade Glioma ◽

Complete Response ◽

Recurrent Glioblastoma ◽

Vaccine Therapy ◽

High Grade ◽

Peptide Epitopes ◽

Dismal Prognosis ◽

Multiple Glioma ◽

Lymphocyte Responses

High-grade gliomas (HGGs) carry a dismal prognosis despite current treatments. We previously confirmed the safety and immunogenicity of a vaccine treatment targeting tumor angiogenesis with synthetic peptides, for vascular endothelial growth factor receptor (VEGFR) epitopes in recurrent HGG patients. In this study, we evaluated a novel vaccine therapy targeting not only tumor vasculature but also tumor cells, using multiple glioma oncoantigen (GOA)/glioma angiogenesis-associated antigen (GAAA) peptides in HLA-A2402+ recurrent/progressive HGG patients. The vaccine included peptide epitopes from four GOAs (LY6K, DEPDC1, KIF20A, and FOXM1) and two GAAAs (VEGFR1 and VEGFR2). Ten patients received subcutaneous vaccinations. The primary endpoint was the safety of the treatment. T-lymphocyte responses against GOA/GAAA epitopes and treatment response were evaluated secondarily. The treatment was well tolerated without any severe systemic adverse events. The vaccinations induced immunoreactivity to at least three vaccine-targeted GOA/GAAA in all six evaluable patients. The median overall survival time in all patients was 9.2 months. Five achieved progression-free status lasting at least six months. Two recurrent glioblastoma patients demonstrated stable disease. One patient with anaplastic oligoastrocytoma achieved complete response nine months after the vaccination. Taken together, this regimen was well tolerated and induced robust GOA/GAAA-specific T-lymphocyte responses in recurrent/progressive HGG patients.

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Bevacizumab in recurrent high-grade glioma: a single institution retrospective analysis on 92 patients

La radiologia medica ◽

10.1007/s11547-021-01381-5 ◽

2021 ◽

Author(s):

Beatrice Detti ◽

Silvia Scoccianti ◽

Maria Ausilia Teriaca ◽

Virginia Maragna ◽

Victoria Lorenzetti ◽

...

Keyword(s):

Recurrent Disease ◽

Performance Status ◽

High Grade Glioma ◽

Recurrent Glioblastoma ◽

High Grade ◽

Two Phase ◽

Primary Tumors ◽

Entire Cohort ◽

Bevacizumab Treatment ◽

High Grade Gliomas

Abstract Background High-grade gliomas are among the most aggressive central nervous system primary tumors, with a high risk of recurrence and a poor prognosis. Re-operation, re-irradiation, chemotherapy are options in this setting. No-best therapy has been established. Bevacizumab was approved on the basis of two Phase 2 trials that evaluated its efficacy in patients with recurrent glioblastoma. Materials and methods We have retrospectively review data of patients with high-grade glioma treated at our institution that undergone radiological or histological progression after at least one systemic treatment for recurrent disease. Bevacizumab was administered alone or in combination with chemotherapy until disease progression or unacceptable toxicity. Bevacizumab regimen was analyzed to assess PFS and OS. Histological, molecular and clinical features of the entire cohort were collected. Results We reviewed data from 92 patients, treated from April 2009 to November 2019, with histologically confirmed diagnosis of high-grade gliomas and recurrent disease. A PFS of 55.2%, 22.9% and 9.6% was observed at 6, 12 and 24 months, respectively. Performance status, age at diagnosis (< 65 or > 65 ys.) and use of corticosteroids during bevacizumab therapy were strongly associated with PFS. The OS was 74.9% at 6 months, 31.7% at 12 months, 10.1% at 24 months. In our cohort, 51.1% were long-term responders (PFS > 6 months). Globally, bevacizumab treatment was well tolerated. Conclusion Our analysis confirms the efficacy of bevacizumab in recurrent high-grade glioma patients with an acceptable toxicity profile, in keeping with its known safety in the literature.

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