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Cervical cancer (CC) remains a real public health problem in low- and middle-income countries, where technical resources and competent personnel are insufficient. Persistent cervix infection by high-risk human papillomavirus (Hr-HPV) is the main cause of CC development. In the current study, we examined the distribution of Hr-HPV in the general healthy Malian population using cervicovaginal self- sampling. A total of 354 women were recruited, with a median age of 34 ± 11.37 years, IQR (27-43). We found that 100% of participants agreed to self-sample at the health center. For result announcement 99.2% expressed their preference to be contacted by cell phone. Furthermore, 100% of study participants showed their willingness to undergo confirmatory CC test in case of Hr-HPV test proved positive, and to receive treatment in the event of the presence of cervical lesions. The overall prevalence of Hr-HPV was 21.2% (95% CI: 17-25.8). HPV31/35/33/52/58 with 11.9% (95% CI: 8.7-15.7) and HPV39/68/56/66 with 5.9% (95% CI: 3.7-8.9) were the most common Hr-HPV subtypes. We noted that Hr-HPV genotypes were more prevalent among women under 25 years, 36.1% (N = 61). In addition, the distribution of Hr-HPV was statistically associated with age, W = 12,374, p = 0.015. Our data showed that 25.3% (N = 19) of Hr-HPV-positive women were tested positive by VIA/VILI. Among the 19 VIA/VILI-positive women, histological examination showed that 4 were CIN1, 4 were CIN2, and 2 were CIN3 grades. In addition, the median age of participants with CIN2 and CIN3 was statistically higher than the median of those with CIN1 grade, 25 years IQR (21-26.75) versus 50 years, IQR (40.25-55), W = 24, p = 0.009. In sum, end-users are very satisfied with the cervicovaginal self-sampling device for identifying HR-HPV genotypes as part of CC screening. In addition, it enables hospital practitioners to take the necessary action after triaging women according to their HR-HPV genotype., Competing Interests: Declarations. Conflict of interest: The authors have not disclosed any competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Long-term exposure to high-risk human papillomavirus (Hr-HPV) is a well-known necessary condition for development of cervical cancer. The aim of this study is to screen for Hr-HPV using vaginal self-sampling, which is a more effective approach to improve women's adherence and increase screening rates., Methods: This pilot study included a total of 100 Women living with HIV (WLWHIV), recruited from the Center for Listening, Care, Animation, and Counseling of People Living with HIV in Bamako. Hr-HPV genotyping was performed on Self-collected samples using the Cepheid GeneXpert instrument., Results: The median age of WLWHIV was 44 (interquartile range [IQR], 37-50) years. Approximately 92% of the study participants preferred self-sampling at the clinic, and 90% opted to receive result notifications via mobile phone contact. The overall prevalence of Hr-HPV among study participants was 42.6%, and the most frequent Hr-HPV sub-types observed were HPV18/45 (19.1%), HPV31/35/33/52/58 (13.8%), and HPV39/68/56/66 (12.8%), followed by HPV16 (5.3%), and HPV51/59 (5.3%). WLWHIV under 35 years of age had a higher frequency of Hr-HPV compared to their older counterparts, with rates of 30% versus 11.1% (p = 0.03). The duration of antiretroviral treatment showed an inverse association with Hr-HPV negativity, with patients on treatment for 15 (IQR, 10-18) years versus 12 (IQR = 7-14) years for Hr-HPV positive patients (95% CI [1.2-5.8], t = 3.04, p = 0.003). WLWHIV with baseline CD4 T-Cell counts below 200 exhibited a higher frequency of Hr-HPV compared to those with baseline CD4 T-Cell counts above 200 (17.9% versus 1.9%, p = 0.009). However, other demographics and clinical factors, such as marital status, age of sexual debut, parity, education, history of abortion, history of preeclampsia, and cesarean delivery, did not influence the distribution of Hr-HPV genotypes., Conclusion: Our findings indicate that WLWHIV under the age of 35 years old exhibited the highest prevalence of Hr-HPV infection, with HPV18/45 being the most prevalent subtype. Additionally, WLWHIV with baseline CD4 T-Cell counts below 200 showed the highest infection rates., (© 2024. The Author(s).)

Importance: Oral tamoxifen citrate benefits women with ductal carcinoma in situ (DCIS), but concern about toxic effects has limited acceptance. Previous pilot studies have suggested transdermal 4-hydroxytamoxifen gel has equivalent antiproliferative efficacy to oral tamoxifen, with low systemic exposure., Objective: To demonstrate that 4-hydroxytamoxifen gel applied to the breast skin is noninferior to oral tamoxifen in its antiproliferative effect in DCIS lesions., Design, Setting, and Participants: This randomized, double-blind, phase 2 preoperative window trial was performed at multicenter breast surgery referral practices from May 31, 2017, to January 27, 2021. Among 408 women with estrogen receptor-positive DCIS who were approached, 120 consented and 100 initiated study treatment. The most common reasons for nonparticipation were surgical delay, disinterest in research, and concerns about toxic effects. Data were analyzed from January 26, 2021, to October 5, 2022., Intervention: Random assignment to oral tamoxifen citrate, 20 mg/d, and gel placebo or 4-hydroxytamoxifen gel, 2 mg/d per breast, and oral placebo, for 4 to 10 weeks, followed by DCIS resection., Main Outcomes and Measures: The primary end point was absolute change in DCIS Ki-67 labeling index (Ki67-LI). Secondary end points included 12-gene DCIS Score, breast tissue tamoxifen metabolite concentrations, tamoxifen-responsive plasma protein levels, and patient-reported symptoms. Noninferiority of Ki67-LI reduction by 4-hydroxytamoxifen gel was tested using analysis of covariance; within- and between-arm comparisons were performed with paired t tests for mean values or the Wilcoxon rank sum test for medians., Results: Of 90 participants completing treatment (mean [SD] age, 55 [11] years; 8 [8.9%] Asian, 16 [17.8%] Black, 8 [8.9%] Latina, and 53 [58.9%] White), 15 lacked residual DCIS in the surgical sample, leaving 75 evaluable for the primary end point analysis (40 in the oral tamoxifen group and 35 in the 4-hydroxytamoxifen gel group). Posttreatment Ki67-LI was 3.3% higher (80% CI, 2.1%-4.6%) in the 4-hydroxytamoxifen gel group compared with the oral tamoxifen group, exceeding the noninferiority margin (2.6%). The DCIS Score decreased more with oral tamoxifen treatment (-16 [95% CI, -22 to -9.4]) than with 4-hydroxytamoxifen gel (-1.8 [95% CI, -5.8 to 2.3]). The median 4-hydroxytamoxifen concentrations deep in the breast were nonsignificantly higher in the oral tamoxifen group (5.7 [IQR, 4.0-7.9] vs 3.8 [IQR, 1.3-7.9] ng/g), whereas endoxifen was abundant in the oral tamoxifen group and minimal in the 4-hydroxytamoxifen gel group (median, 13.0 [IQR, 8.9-20.6] vs 0.3 [IQR, 0-0.3] ng/g; P < .001). Oral tamoxifen caused expected adverse changes in plasma protein levels and vasomotor symptoms, with minimal changes in the transdermal group., Conclusions and Relevance: In this randomized clinical trial, antiproliferative noninferiority of 4-hydroxytamoxifen gel to oral tamoxifen was not confirmed, potentially owing to endoxifen exposure differences. New transdermal approaches must deliver higher drug quantities and/or include the most potent metabolites., Trial Registration: ClinicalTrials.gov Identifier: NCT02993159.

Introduction: Invasive cervical cancer (ICC) is an HIV-associated cancer that is preventable and precancerous stages including early ICC stages could be detected through screening offering opportunities for treatment and cure. The high incidence in women living with HIV and late presentation often at advanced stages of ICC with limited treatment facilities often result in early mortality. We sought to compare the epidemiologic characteristics and survival differences in HIV status of ICC patients in Nigeria., Methods: We conducted a cohort study at two federal academic hospital-based research sites in Jos University Teaching Hospital, and Lagos University Teaching Hospital Nigeria, between March 2018 and September 2022. We enrolled women with histologically confirmed ICC with known HIV status, and FIGO staging as part of the United States of America's National Institutes of Health/National Cancer Institute funded project titled 'Epigenomic Biomarkers of HIV-Associated Cancers in Nigeria'. The primary outcome was all-cause mortality with assessment of overall survival (OS) and time to death after ICC diagnosis. OS distribution was estimated using the method of Kaplan-Meier and compared between groups using the log-rank test., Results: A total of 239 women with confirmed ICC were enrolled and included in this analysis, of whom 192 (80.3%) were HIV-negative (HIV-/ICC +), and 47 (19.7%) were HIV-positive (HIV +/ICC +). The HIV +/ICC + patients were younger with median age 46 (IQR: 40-51) years compared to 57 (IQR: 45-66) among HIV-/ICC + (P < 0.001). Squamous cell carcinoma was the commonest histopathologic variant in 80.4% of ICC diagnosis, moderately differentiated tumor grade in 68.1% in both groups. HIV +/ICC + diagnosis was at FIGO advanced stages in 64.9% compared to 47.9% in HIV-/ICC +. The HIV-/ICC + women had better OS compared to HIV +/ICC + participants (p = 0.018), with 12-month OS 84.1% (95%CI 75-90%) and 67.6% (95%CI 42-84%) respectively., Conclusion: ICC is diagnosed at a relatively young age in women living with HIV, with a significantly lower overall survival probability compared to women without HIV. The trend of presentation and diagnosis at advanced stages in women living with HIV could partly explain the differences in overall survival., (© 2023. The Author(s).)

Inadequate pathology personnel and high cost of running a Pathology facility are factors affecting access to timely and quality pathology services in resource-constrained settings. Telepathology is a novel technology that allows Pathologists to remotely assess collected samples. Though the initial cost of setting up a telepathology facility is high, its overall benefits far outweigh the cost. Its usefulness as a quality assurance measure, as a permanent image data storage system, in reducing costs associated with repeated slide preparations, reducing turn-around time of pathology reports, in collaborative research and in teaching has been well documented. This paper highlights the experiences, gains and challenges encountered in the deployment of telepathology in two resource-constrained settings in Nigeria. Overcoming the challenges associated with setting up a telepathology service in sub-Saharan Africa is important as it has the potential to improve overall health outcomes in a medically underserved region while ensuring technology and knowledge transfer are achieved., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2022 The Author(s).)

Background: Systemic therapies for refractory meningiomas are limited with no FDA-approved therapeutics. Vascular endothelial growth factor (VEGF) is a signaling protein associated with neovascularization, peritumoral edema, and meningioma tumorigenesis., Methods: This phase II study investigates the efficacy of bevacizumab (BEV), a VEGF binding monoclonal antibody, in patients with progressive Grade I (G1M), Grade II (G2M), Grade III (G3M) meningioma, and other non-parenchymal tumors including vestibular schwannoma ( n  = 4) and hemangiopericytoma ( n  = 4) with the primary endpoint of progression-free survival rate at 6-months (PFS-6). Non-meningiomas were included with the respective meningioma grade in the analysis. Secondary endpoints include median overall survival (mOS) and response rate., Results: Fifty Patients (26 women; median age 54 years; range 23-81), 42 with progressive meningioma were treated: 10 G1M, 20 G2M, and 12 G3M. Prior treatments include surgical resection (41 patients), radiosurgery (24 patients), external beam radiotherapy (28 patients), and chemotherapy (14 patients). Median infusions administered were 16 (range, 2-68). Response was graded using the Macdonald's criteria. PFS-6, median PFS, and mOS were 87%, 22 months, 35 months for G1M; 77%, 23 months, 41 months for G2M; and 46%, 8 months, 12 months for G3M. Best radiographic responses include stable disease (G1M: 100%; G2M: 85%; G3M: 82%); partial response (G1M: 0%; G2M: 5%; G3M: 0%) and progressive disease (G1M: 0%; G2M: 10%; G3M:18%). The most common toxicities were hypertension ( n  = 19, 42.2%), proteinuria ( n  = 16, 35.6%), and fatigue ( n  = 14, 31.1%)., Conclusion: This study showed BEV is well tolerated and appears to be a promising systemic treatment option for patients with recurrent and refractory meningiomas., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Invasive cervical cancer (ICC) is a serious public health burden in Nigeria, where human immunodeficiency virus (HIV) remains highly prevalent. Previous research suggested that epigenetic age acceleration (EAA) could play a role in detection of HIV-associated ICC. However, little research has been conducted on this topic in Africa where the population is most severely affected by HIV-associated ICC. Here, we investigated the association between ICC and EAA using cervical tissues of ICC-diagnosed Nigerian women living with HIV., Methods: We included 116 cervical tissue samples from three groups of Nigerian women in this study: (1) HIV+/ICC+ ( n = 39); (2) HIV+/ICC- ( n = 53); and (3) HIV-/ICC + ( n = 24). We utilized four DNA methylation-based EAA estimators; IEAA, EEAA, GrimAA, and PhenoAA. We compared EAA measurements across the 3 HIV/ICC groups using multiple linear regression models. We also compared EAA between 26 tumor tissues and their surrounding normal tissues using paired t -tests. We additionally performed a receiver operating characteristics (ROC) curve analysis to illustrate the area under the curve (AUC) of EAA in ICC., Results: We found the most striking associations between HIV/ICC status and PhenoAge acceleration (PhenoAA). Among HIV-positive women, PhenoAA was on average 13.4 years higher in women with ICC compared to cancer-free women ( P = 0.005). PhenoAA was 20.7 and 7.1 years higher in tumor tissues compared to surrounding normal tissues among HIV-positive women ( P = 0.009) and HIV-negative women ( P = 0.284), respectively. We did not find substantial differences in PhenoAA between HIV-positive and HIV-negative women with ICC., Conclusion: PhenoAA is associated with ICC in HIV-infected women in our study. Our findings suggest that PhenoAA may serve as a potential biomarker for further risk stratification of HIV-associated ICC in Nigeria and similar resource-constrained settings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Musa, Kim, Zheng, Qu, Joyce, Wang, Nannini, Gursel, Silas, Abdulkareem, Imade, Akanmu, Wei, Kocherginsky, Kim, Wehbe, Achenbach, Anorlu, Simon, Sagay, Ogunsola, Murphy and Hou.)

Patient-derived tumor organoids (TOs) are emerging as high-fidelity models to study cancer biology and develop novel precision medicine therapeutics. However, utilizing TOs for systems-biology-based approaches has been limited by a lack of scalable and reproducible methods to develop and profile these models. We describe a robust pan-cancer TO platform with chemically defined media optimized on cultures acquired from over 1,000 patients. Crucially, we demonstrate tumor genetic and transcriptomic concordance utilizing this approach and further optimize defined minimal media for organoid initiation and propagation. Additionally, we demonstrate a neural-network-based high-throughput approach for label-free, light-microscopy-based drug assays capable of predicting patient-specific heterogeneity in drug responses with applicability across solid cancers. The pan-cancer platform, molecular data, and neural-network-based drug assay serve as resources to accelerate the broad implementation of organoid models in precision medicine research and personalized therapeutic profiling programs., Competing Interests: Declaration of interests A.A.K., A.A.S, A.B., B.D.L., B.M., B.M.L, C.-S.H., C.I., G.K., J.F.P., J.V.M., J.R.D., K.E.M., K.P.W., L.F.L, M.K., M.M.S., T.A.R, V.S.-F., J.V., and Y.Z are employees and shareholders of Tempus Labs. A.C., B.E.D., J.M.S., and M.A.S. are employees of Tempus Labs. A.A.K., A.A.S, B.M., B.M.L., M.K., M.M.S., V.S.-F., J.V., and Y.Z. are inventors on patents related to organoid technology. K.P.W. is a Senior Group Leader at A(∗)STAR. A.A.S. holds a faculty position at the University of Illinois at Chicago., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Systemic treatment of metastatic adrenocortical carcinoma (ACC) remains limited to chemotherapy and mitotane. Preliminary evidence suggesting that antitumor immune responses can be elicited in ACC has fostered interest in checkpoint inhibitors such as anti-PD-1 nivolumab., Objective: The primary endpoint was objective response rate according to the response evaluation criteria in solid tumors. Secondary endpoints were progression-free survival (PFS), overall survival, and safety., Design: Single-arm, multicenter, phase 2 clinical trial with two-stage design., Setting: Comprehensive cancer center., Patients: Ten adult patients with metastatic ACC previously treated with platinum-based chemotherapy and/or mitotane as well as patients who declined front-line chemotherapy., Intervention: Nivolumab (240 mg) IV every 2 weeks., Results: Ten patients with metastatic ACC were enrolled between March and December 2016. The median number of doses of nivolumab administered was two. Three patients only received one treatment [one died of disease progression, one discontinued due to adverse events (AEs), one withdrew after beginning treatment]. The median PFS was 1.8 months. The median follow-up was 4.5 months (range, 0.1 to 25.6 months). Two patients had stable disease for a duration of 48 and 11 weeks, respectively. One patient had an unconfirmed partial response but discontinued the study due to an AE. Most AEs were grade 1/2. The most common grade 3/4 treatment-related AEs were aspartate aminotransferase and alanine aminotransferase elevations, mucositis, and odynophagia., Conclusion: Nivolumab demonstrated modest antitumor activity in patients with advanced ACC. The nivolumab safety profile was consistent with previous clinical experience without any unexpected AEs in this population., (Copyright © 2019 Endocrine Society.)

Polycomb group proteins are important epigenetic regulators for cell proliferation and differentiation, organ development, as well as initiation and progression of lethal diseases, including cancer. Upregulated Polycomb group proteins, including Enhancer of zeste homolog 2 (EZH2), promote proliferation, migration, invasion and metastasis of cancer cells, as well as self-renewal of cancer stem cells. In our study, we report that EZH2 and embryonic ectoderm development (EED) indicate respective direct interaction with androgen receptor (AR). In the context of AR-positive prostate cancer, EZH2 and EED regulate AR expression levels and AR downstream targets. More importantly, we demonstrate that targeting EZH2 with the small-molecule inhibitor astemizole in cancer significantly represses the EZH2 and AR expression as well as the neoplastic capacities. These results collectively suggest that pharmacologically targeting EZH2 might be a promising strategy for advanced prostate cancer., (© 2019 UICC.)

Ubiquitination plays critical roles in the regulation of oncoproteins and tumor suppressors during carcinogenesis. The two ubiquitin activating enzymes (E1) in human genome, UBA1 and UBA6, initiate ubiquitination by ATP-dependent activation of ubiquitin. Recent evidence suggests that UBA1 and UBA6 play partially overlapped yet distinct roles in controlling the proteome. Here we demonstrate that ubiquitination pathways initiated specifically by UBA6 set a suppressive barrier against critical steps of mammary carcinogenesis such as loss of polarity, anoikis resistance and epithelial-mesenchymal transition (EMT). Mammary epithelial MCF-10A cells expressing shRNA against UBA6 fail in establishing cell cycle arrest in response to detachment from extracellular matrix, confluency with fully engaged cell-cell contact or growth factor deprivation. Moreover, UBA6-deficient MCF-10A cells undergo spontaneous EMT under growth factor deprivation and exhibit accelerated kinetics of TGF-β-induced EMT. The Rho-GTPase CDC42 is one of the specific targets of UBA6-initiated ubiquitination and plays a key role in the function of UBA6 in controlling epithelial homeostasis, since a CDC42 inhibitor, ML141, rescues UBA6-deficient cells from the EMT phenotype. Immunohistochemical analysis of human breast cancer tissues demonstrates that 38% of invasive carcinomas express low or undetectable expression of UBA6, suggesting that downregulation of this non-canonical E1 plays a role in breast cancer development., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing financial interests

Risk biomarkers for estrogen receptor (ER)-negative breast cancer have clear value for breast cancer prevention. We previously reported a set of lipid metabolism (LiMe) genes with high expression in the contralateral unaffected breasts (CUBs) of ER-negative cancer cases. We now further examine LiMe gene expression in both tumor and CUB, and investigate the role of Pre-B-cell leukemia homeobox-1 (PBX1) as a candidate common transcription factor for LiMe gene expression. mRNA was extracted from laser-capture microdissected epithelium from tumor and CUB of 84 subjects (28 ER-positive cases, 28 ER-negative cases, 28 healthy controls). Gene expression was quantitated by qRT-PCR. Logistic regression models were generated to predict ER status of the contralateral cancer. Protein expression of HMGCS2 and PBX1 was measured using immunohistochemistry. The effect of PBX1 on LiMe gene expression was examined by overexpressing PBX1 in MCF10A cells with or without ER, and by suppressing PBX1 in MDA-MB-453 cells. The expression of DHRS2, HMGCS2, UGT2B7, UGT2B11, ALOX15B, HPGD, UGT2B28 and GLYATL1 was significantly higher in ER-negative versus ER-positive CUBs, and predicted ER status of the tumor in test and validation sets. In contrast, LiMe gene expression was significantly lower in ER-negative than ER-positive tumors. PBX1 overexpression in MCF10A cells up-regulated most LiMe genes, but not in MCF10A cells overexpressing ER. Suppressing PBX1 in MDA-MB-453 cells resulted in decrease of LiMe gene expression. Four binding sites of PBX1 and cofactor were identified in three lipid metabolism genes using ChIP-qPCR. These data suggest a novel role for PBX1 in the regulation of lipid metabolism genes in benign breast, which may contribute to ER-negative tumorigenesis., (© 2017 UICC.)

In 2012, the College of American Pathologists and American Society for Colposcopy and Cervical Pathology published the "LAST" recommendations for histopathology reporting of human papilloma virus-related squamous lesions of the lower anogenital tract, including the use of a 2-tier nomenclature (low-grade squamous intraepithelial lesion/high-grade squamous intraepithelial lesion [LSIL/HSIL]) and expanded use of the biomarker p16 to classify equivocal lesions as either precancer (HSIL) or low-grade lesions (LSIL)/non-human papilloma virus changes. We aimed to determine (1) the frequency with which the poorly reproducible diagnosis of intermediate-grade (-IN 2) lesion in the lower anogenital tract would be downgraded on the basis of p16 results, and (2) whether p16 status was predictive of subsequent higher-grade lesions. A total of 200 specimens diagnosed as an intermediate-grade (-IN 2) lesion of the cervix (168), vagina (2), vulva (2), and anus (28) were reviewed and immunostained for p16. Slides were independently reviewed by 2 pathologists, with discrepant p16 interpretations adjudicated by a third pathologist. Of the 200 cases, 32% were negative for p16. Among the 166 patients with subsequent pathology (including 131 excisions), 26.2% of p16-positive cases versus 4.4% of p16-negative cases were associated with a subsequent diagnosis of HSIL (-IN 3) or worse (P=0.002). Reproducibility of the biopsy diagnosis was fair, with no significant difference with the addition of p16 or using 2 versus 3 tiers. In 11.5% of cases, there was discordance in p16 interpretation (κ 0.735, good agreement). The results indicate that using the Lower Anogenital Squamous Terminology recommendations would result in approximately one third of equivocal (-IN 2) diagnoses being downgraded to LSIL over 1 year in a busy academic practice. The significant association of p16 expression with a higher risk for HSIL on a subsequent specimen suggests that use of p16 to adjudicate equivocal (-IN 2) diagnoses in lower anogenital tract specimens as either LSIL or HSIL would likely predict lesion grade more accurately and avoid unnecessary excisional procedures.

Cranial irradiation is an effective treatment modality for both primary and metastatic brain tumors, yet it induces cognitive decline in a substantial number of patients. At present, there are no established methods for neuroprotection. Recent investigations have revealed a link between radiation-induced cognitive dysfunction and the loss of neural precursor cells in the hippocampus. Hence, identifying pharmacological agents, capable of protecting this cell population, is of interest. FTY720 (fingolimod), an FDA-approved oral drug for the treatment of multiple sclerosis, has been shown to promote the survival and differentiation of neural progenitors, as well as remyelination and repair after brain injury. In this study, we show that FTY720, used at nanomolar concentrations, is capable of increasing the viability and neurogenicity of irradiated neural stem cells from the hippocampus. In contrast, it does not provide radioprotection in a human breast cancer cell line and two glioma cell lines. These results suggest a potential therapeutic role for FTY720 as a neuroprotector during cranial irradiation. Further preclinical studies are warranted to evaluate this possibility., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Evidence suggests that stem-like cells are responsible for initiation, maintenance and recurrence of solid tumors, including Glioblastoma Multiforme (GBM). GBM is an intractable, highly lethal tumor of the central nervous system. Although epidermal growth factor receptor (EGFR) is highly expressed in many GBMs, anti-EGFR therapies have been unsuccessful as treatment. Few studies have examined EGFR activation in GBM stem cells (GSCs) to determine if patient-specific GSCs are amenable to anti-EGFR therapy pre-clinically. We hypothesized that EGFR activation in GSCs varied between patients and was an important determinant of responsiveness to anti-EGFR therapy. Cell cycle and apoptosis analysis was performed on tumor-spheres by immuncytochemistry in the presence and absence of the AG1478. Second messenger pathways operative in these processes were elucidated by immunoblotting. EGFR activated AKT and inactivated GSK3beta in EGFR+/PTEN+ GSCs. AG1478 and erlotinib significantly decreased the total number of tumor-spheres that EGFR+/ PTEN+ GSCs generated and the rate of sphere formation. Inhibition of EGFR signaling by AG1478 increased GSC senescence and apoptosis, likely via inhibition of AKT and activation of GSK3beta. Sphere formation by EGFR-/ PTEN- GSCs was independent of EGF stimulation, but dependant on B27 growth supplement. Our data suggest that EGFR+/PTEN+ GSCs are susceptible to anti-EGFR therapy in vitro.