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Introduction: Despite extensive studies of the impact of COVID-19 on patients with cancer, there is a dearth of information from the Middle East and North Africa (MENA) region. Our study aimed to report pertinent MENA COVID-19 and Cancer Registry (MCCR) findingson patient management and outcomes. Methods: MCCR was adapted from the American Society of Clinical Oncology COVID-19 Registry to collect data specifically from patients with cancer and SARS-CoV-2 infection from 12 centers in eight countries including Saudi Arabia, Jordan, Lebanon, Turkey, Egypt, Algeria, United Arab Emirates, and Morocco. The Registry included data on patients and disease characteristics, treatment, and patient outcomes. Logistic regression was used to assess associations with mortality. Results: Between November 29, 2020, and June 8, 2021, data were captured on 2008 patients diagnosed with COVID-19 from the beginning of the pandemic. Median age was 56 years (16–98), 56.4% were females, and 26% were current or ex-smokers. Breast cancer (28.5%) was the leading diagnosis and 50.5% had metastatic disease. Delays of planned treatment (>14 days) occurred in 80.3% for surgery, 48.8% for radiation therapy, and 32.9% for systemic therapy. Significant reduction in the delays of all three treatment modalities occurred after June 1, 2020. All-cause mortality rates at 30 and 90 days were 17.1% and 23.4%, respectively. All-cause mortality rates at 30 days did not change significantly after June 1, 2020; however, 90-day mortality increased from 33.4% to 42.9% before and after that date (p = 0.015). Multivariable regression analysis showed the following predictors of higher 30- and 90-day mortality: age older than 70 years, having metastatic disease, disease progression, and being off chemotherapy. Conclusion: Patients with cancer in the MENA region experienced similar risks and outcome of COVID-19 as reported in other populations. Although there were fewer treatment delays after June 1, 2020, 90-day mortality increased, which may be attributed to other risk factors such as disease progression or new patients who presented with more advanced disease.

Lung transplantation has proven to be an effective treatment for end-stage lung diseases. Recognizing and acknowledging the effects of health inequities pertaining to lung transplants is important for under-resourced populations. This scoping review aims to map the extent of literature on health inequities corresponding to lung transplantation and point to knowledge gaps to direct future research. This scoping review followed guidelines from the Joanna Briggs Institute and the PRISMA extension for scoping reviews. In July 2022, we searched Ovid Embase and MEDLINE for published articles on lung transplants, published between 2011 and 2021, written in English, and examining at least one health inequity as defined by the NIH. Screening and charting were both performed in a masked, duplicate fashion. The frequency of each health inequity examined was analyzed, and findings from each included study were summarized. After screening, our sample contained 33 studies. Our findings illustrate that patients living further from lung transplant centers were less likely to be placed on the lung transplant waitlist. Further, non-white patients, women, and people who lived in low-income areas were less likely to undergo lung transplantation. Non-white patients also experienced increased mortality post-lung transplantation. Significant research gaps were found regarding the LGBTQ+ community, occupational status, income, and education level. This scoping review highlights the gaps in research regarding lung transplant inequities. To improve existing research gaps, we recommend research into the following: (1) intervention studies, (2) clinical bias, (3) donor education programs and follow-up studies, and (4) geographic information systems.

Abstract Background An ASCO taskforce comprised of representatives of oncology clinicians, the American Cancer Society National Lung Cancer Roundtable (NLCRT), LUNGevity, the GO2 Foundation for Lung Cancer, and the ROS1ders sought to: characterize U.S. oncologists’ biomarker ordering and treatment practices for advanced non‐small‐cell lung cancer (NSCLC); ascertain barriers to biomarker testing; and understand the impact of delays on treatment decisions. Methods We deployed a survey to 2374 ASCO members, targeting U.S. thoracic and general oncologists. Results We analyzed 170 eligible responses. For non‐squamous NSCLC, 97% of respondents reported ordering tests for EGFR, ALK, ROS1, and BRAF. Testing for MET, RET, and NTRK was reported to be higher among academic versus community providers and higher among thoracic oncologists than generalists. Most respondents considered 1 (46%) or 2 weeks (52%) an acceptable turnaround time, yet 37% usually waited three or more weeks to receive results. Respondents who waited ≥3 weeks were more likely to defer treatment until results were reviewed (63%). Community and generalist respondents who waited ≥3 weeks were more likely to initiate non‐targeted treatment while awaiting results. Respondents

Background: Hybrid controlled trials with real-world data (RWD), where the control arm is composed of both trial and real-world patients, could facilitate research when the feasibility of randomized controlled trials (RCTs) is challenging and single-arm trials would provide insufficient information. Methods: We propose a frequentist two-step borrowing method to construct hybrid control arms. We use parameters informed by a completed randomized trial in metastatic triple-negative breast cancer to simulate the operating characteristics of dynamic and static borrowing methods, highlighting key trade-offs and analytic decisions in the design of hybrid studies. Results: Simulated data were generated under varying residual-bias assumptions (no bias: HRRWD = 1) and experimental treatment effects (target trial scenario: HRExp = 0.78). Under the target scenario with no residual bias, all borrowing methods achieved the desired 88% power, an improvement over the reference model (74% power) that does not borrow information externally. The effective number of external events tended to decrease with higher bias between RWD and RCT (i.e. HRRWD away from 1), and with weaker experimental treatment effects (i.e. HRExp closer to 1). All dynamic borrowing methods illustrated (but not the static power prior) cap the maximum Type 1 error over the residual-bias range considered. Our two-step model achieved comparable results for power, type 1 error, and effective number of external events borrowed compared to other borrowing methodologies. Conclusion: By pairing high-quality external data with rigorous simulations, researchers have the potential to design hybrid controlled trials that better meet the needs of patients and drug development.

Objective: Racial disparities have been well characterized and African American (AA) patients have 30% lower 5-year survival rates than European Americans (EAs) for head and neck squamous carcinoma (HNSCC). This poorer survival can be attributed to a myriad of different factors. The purpose of this study was to characterize AA-EA similarities and differences in sociodemographic, lifestyle, clinical, and psychosocial characteristics in HNSCC patients near the time of surgery. Methods: Setting: Single tertiary care center. Participants: Thirty-nine newly diagnosed, untreated HNSCC patients (n = 24 EAs,n = 15 AAs) who were to undergo surgery were recruited. Study Design: Cross-sectional study Sociodemographic, lifestyle factors, and disease factors (cancer site, AJCC clinical and pathologic stage, and HPV status)were assessed. Risk factors, leisure time, quality of life and social support were also assessed using validated questionnaires. Exposures: EA and AA patients were similar in the majority of sociodemographic factors assessed. AAs had a higher trend toward pathologically later stage disease compared to EAs and significantly increased time to treatment. Results: EA and AA patients were similar in the majority of sociodemographic factors assessed. AAs had a higher trend toward pathologically later stage disease compared to EAs. AAs also had significantly increased time to treatment (P = 0.05). The majority of AA patients (62%) had later stage pathologic disease. AA were less likely to complete high school or college (P = 0.01) than their EA counterparts. Additionally, AAs were more likely to report having a gap in health insurance during the past decade (37% vs. 15%). Conclusions: This preliminary study demonstrates a similar profile of demographics, clinical and psychosocial characteristics preoperatively for AAs and EAs. Key differences were AAs tending to have later pathologic stage disease, educational status, delays in treatment initiation, and gaps in health insurance.

Summary: Oral cavity squamous cell carcinoma (OCSCC) is a prevalent surgically treated subset of head and neck cancer with frequent recurrence and poor survival. Immunotherapy has demonstrated efficacy in recurrent/metastatic head and neck cancer. However, whether antitumor responses could be fostered by neoadjuvant presurgical immunotherapy remains unclear. Using a Simon’s two-stage design, we present results of a single-arm phase-II trial where 12 patients with stage II-IVA OCSCC received 3 to 4 biweekly doses of 3 mg/kg nivolumab followed by definitive surgical resection with curative intent. Presurgical nivolumab therapy in this cohort shows an overall response rate of 33% (n = 4 patients; 95% CI: 12%–53%). With a median follow up of 2.23 years, 10 out of 12 treated patients remain alive. Neoadjuvant nivolumab is safe, well-tolerated, and is not associated with delays in definitive surgical treatment in this study. This work demonstrates feasibility and safety for incorporation of nivolumab in the neoadjuvant setting for OCSCC (ClinicalTrials.gov: NCT03021993).

Abstract Background The gene desert on human chromosomal band 8q24 harbors multiple genetic variants associated with common cancers, including breast cancer. The locus, including the gene desert and its flanking genes, MYC, PVT1 and FAM84B, is also frequently amplified in human breast cancer. We generated a megadeletion (MD) mouse model lacking 430-Kb of sequence orthologous to the breast cancer-associated region in the gene desert. The goals were to examine the effect of the deletion on mammary cancer development and on transcript level regulation of the candidate genes within the locus. Methods The MD allele was engineered using the MICER system in embryonic stem cells and bred onto 3 well-characterized transgenic models for breast cancer, namely MMTV-PyVT, MMTV-neu and C3(1)-TAg. Mammary tumor growth, latency, multiplicity and metastasis were compared between homozygous MD and wild type mice carrying the transgenes. A reciprocal mammary gland transplantation assay was conducted to distinguish mammary cell-autonomous from non-mammary cell-autonomous anti-cancer effects. Gene expression analysis was done using quantitative real-time PCR. Chromatin interactions were evaluated by 3C. Gene-specific patient outcome data were analysed using the METABRIC and TCGA data sets through the cBioPortal website. Results Mice homozygous for the MD allele are viable, fertile, lactate sufficiently to nourish their pups, but maintain a 10% lower body weight mainly due to decreased adiposity. The deletion interferes with mammary tumorigenesis in mouse models for luminal and basal breast cancer. In the MMTV-PyVT model the mammary cancer-reducing effects of the allele are mammary cell-autonomous. We found organ-specific effects on transcript level regulation, with Myc and Fam84b being downregulated in mammary gland, prostate and mammary tumor samples. Through analysis using the METABRIC and TCGA datasets, we provide evidence that MYC and FAM84B are frequently co-amplified in breast cancer, but in contrast with MYC, FAM84B is frequently overexpressed in the luminal subtype, whereas MYC activity affect basal breast cancer outcomes. Conclusion Deletion of a breast cancer-associated non-protein coding region affects mammary cancer development in 3 transgenic mouse models. We propose Myc as a candidate susceptibility gene, regulated by the gene desert locus, and a potential role for Fam84b in modifying breast cancer development.

Background: Primary management of advanced head/neck cancers involves concurrent chemoradiotherapy . Subsequently, regional and local failures are managed with resection but there have been few reports that describe the morbidity and disease control outcomes of surgical salvage in this setting. Methods: Retrospective analysis describes complications, survival, and patterns of failure after salvage resection of isolated local and/or regional failures of head/neck cancer following definitive concurrent chemoradiotherapy. Results: Sixteen patients were identified for inclusion: laryngectomy in 11 patients, oral cavity/oropharynx resection in 2 patients, and neck dissection alone in 4 patients. Ten patients required graft tissue reconstruction (6 pedicle and 4 free flap). Median post-operative hospitalization was 7 days (range 3-19), and 4 patients required hospital re-admission. At a median survivor follow-up of 15.8 months (range 4.3-34.9), 10 patients were alive (6 without evidence of disease). Seven patients experienced disease recurrence at a median 6.7 months (range 0-12.6) following salvage resection (2 with isolated distant failures). Estimated 2-year local/regional control, freedom from failure, and overall survival were 58%, 39%, and 58%, respectively. Conclusions: Surgical salvage after primary definitive concurrent chemoradiotherapy is feasible with toxicity and outcomes similar to prior radiotherapy alone or sequential chemotherapy and radiation. Local andregional recurrence remains the predominant pattern of failure.

T cell receptor (TCR)-gene-modified T cells for adoptive cell transfer can mediate objective clinical responses in melanoma and other malignancies. When introducing a second TCR, mispairing between the endogenous and introduced α and β TCR chains limits expression of the introduced TCR, which can result in impaired efficacy or off-target reactivity and autoimmunity. One approach to promote proper TCR chain pairing involves modifications of the introduced TCR genes: introducing a disulfide bridge, substituting murine for human constant regions, codon optimization, TCR chain leucine zipper fusions, and a single-chain TCR. We have introduced these modifications into our hepatitis C virus (HCV) reactive TCR and utilize a marker gene, CD34t, which allows us to directly compare transduction efficiency with TCR expression and T cell function. Our results reveal that of the TCRs tested, T cells expressing the murine Cβ2 TCR or leucine zipper TCR have the highest levels of expression and the highest percentage of lytic and interferon-γ (IFN-γ)-producing T cells. Our studies give us a better understanding of how TCR modifications impact TCR expression and T cell function that may allow for optimization of TCR-modified T cells for adoptive cell transfer to treat patients with malignancies.

Abstract Background Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC). Methods We generated autologous DCs from the peripheral blood of HLA-A2+ patients with PC. DCs were pulsed with three distinct A2-restricted peptides: 1) human telomerase reverse transcriptase (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin (SRV.A2). Patients received four intradermal injections of 1 × 107 peptide-pulsed DC vaccines every 2 weeks (Day 0, 14, 28, and 42). Concurrently, patients received intramuscular administration of Poly-ICLC at 30 μg/Kg on vaccination days (i.e., day 0, 14, 28, and 42), as well as on days 3, 17, 21, 31, 37, and 45. Our key objective was to assess safety and feasibility. The effect of DC vaccination on immune response was measured at each DC injection time point by enumerating the phenotype and function of patient T cells. Results Twelve patients underwent apheresis: nine patients with metastatic disease, and three patients with locally advanced unresectable disease. Vaccines were successfully manufactured from all individuals. We found that this treatment was well-tolerated, with the most common symptoms being fatigue and/or self-limiting flu-like symptoms. Among the eight patients who underwent imaging on day 56, four patients experienced stable disease while four patients had disease progression. The median overall survival was 7.7 months. One patient survived for 28 months post leukapheresis. MHC class I –tetramer analysis before and after vaccination revealed effective generation of antigen-specific T cells in three patients with stable disease. Conclusion Vaccination with peptide-pulsed DCs in combination with poly-ICLC is safe and induces a measurable tumor specific T cell population in patients with advanced PC. Trial registration NCT01410968 ; Name of registry: clinicaltrials.gov; Date of registration: 08/04/2011).

The chromosome 8p11-p12 amplicon is present in 12% to 15% of breast cancers, resulting in an increase in copy number and expression of several chromatin modifiers in these tumors, including KAT6A. Previous analyses in SUM-52 breast cancer cells showed amplification and overexpression of KAT6A, and subsequent RNAi screening identified KAT6A as a potential driving oncogene. KAT6A is a histone acetyltransferase previously identified as a fusion partner with CREB binding protein in acute myeloid leukemia. Knockdown of KAT6A in SUM-52 cells, a luminal breast cancer cell line harboring the amplicon, resulted in reduced growth rate compared to non-silencing controls and profound loss of clonogenic capacity both in mono-layer and in soft agar. The normal cell line MCF10A, however, did not exhibit slower growth with knockdown of KAT6A. SUM-52 cells with KAT6A knockdown formed fewer mammospheres in culture compared to controls, suggesting a possible role for KAT6A in self-renewal. Previous data from our laboratory identified FGFR2 as a driving oncogene in SUM-52 cells. The colony forming efficiency of SUM-52 KAT6A knockdown cells in the presence of FGFR inhibition was significantly reduced compared to cells with KAT6A knockdown only. These data suggest that KAT6A may be a novel oncogene in breast cancers bearing the 8p11-p12 amplicon. While there are other putative oncogenes in the amplicon, the identification of KAT6A as a driving oncogene suggests that chromatin-modifying enzymes are a key class of oncogenes in these cancers, and play an important role in the selection of this amplicon in luminal B breast cancers.

PURPOSE: The factors preventing the translation of preclinical findings supporting the clinical development mTOR-targeted therapy in pancreatic cancer therapy remain undetermined. Stromal cell.derived factor 1α (SDF-1α)-CXCR4 signaling was examined as a representative microenvironmental factor able to promote mTOR-targeted therapy resistance in pancreatic cancer. EXPERIMENTAL DESIGN: Primary pancreas explant xenografts and in vitro experiments were used to perform pharmacodynamic analyses of SDF-1α-CXCR4 regulation of the mTOR pathway. Combinatorial effects of CXCR4, EGFR, and mTOR pharmacologic inhibition were evaluated in temsirolimus-resistant and -sensitive xenografts. Intratumoral gene and protein expressions of mTOR pathway effectors cyclin D1, c-Myc, and VEGF were evaluated. RESULTS: Baseline intratumoral SDF-1α gene expression correlated with temsirolimus resistance in explant models. SDF-1α stimulation of pancreatic cells resulted in CXCR4-mediated PI3-kinase-dependent S6-RP phosphorylation (pS6-RP) on exposure to temsirolimus. Combinatorial therapy with AMD3465 (CXCR4 small-molecule inhibitor) and temsirolimus resulted in effective tumor growth inhibition to overcome temsirolimus resistance. In contrast, SDF-1α exposure induced a temsirolimus-resistant phenotype in temsirolimus-sensitive explants. AMD3465 inhibited CXCR4-mediated intratumoral S6-RP phosphorylation and cyclin D and c-myc gene expression. Next, CXCR4 promoted intratumoral EGFR expression in association with temsirolimus resistance. Treatment with AMD3465, temsirolimus- and erlotinib-mediated tumor growth inhibition to overcome temsirolimus resistance in the explant model. Lastly, SDF-1α-CXCR4 signaling increased intratumoral VEGF gene and protein expression. CONCLUSIONS: SDF-1α-CXCR4 signaling represents a microenvironmental factor that can maintain mTOR pathway fidelity to promote resistance to mTOR-targeted therapy in pancreatic cancer by a variety of mechanisms such as recruitment of EGFR signaling and angiogenesis.

Abstract Introduction At the University of Missouri-Columbia School of Medicine, providing effective patient-centered care is core to our mission. We believe this requires the values of generosity, self-reflection, humility, gratitude, and treating the patient as a complete person. We expect our students to share these values. The Legacy Teachers program was designed and implemented to encourage students to focus on the physician-patient relationship, to reflect on a particular patient who taught them lessons they would carry with them through their professional careers, to honor and thank our patients as teachers, to highlight for patients and their families the positive aspects of having medical students involved in their care, and to help with transitions in the students' emerging professional roles. Methods Legacy Teachers is a voluntary program where third-year students are invited to participate by writing a two− to three-page essay or a poem or creating artwork about a patient they cared for during their third year. Poems and artwork are accompanied by a one-page summary describing what their Legacy Teacher taught them. The Legacy Teachers are invited to a celebratory luncheon that occurs every spring. On the first day of the third year of medical school, each clerkship director encourages students to participate in Legacy Teachers by including a brief discussion of the program in clerkship orientation. Results Legacy Teachers started with a focus on the third-year medical school class. In the early years, the number of students participating was small. Since we began including the second-year students at the luncheon, third-year submission rates have significantly increased. Thirty to forty percent of each third-year class now participates. The growing participation in this voluntary experience is evidence of strong student endorsement of the program. The number of participating faculty has also grown over the years, steadily rising from approximately 10 in the first year to 30 at the most recent luncheon. A wide variety of Legacy Teachers are recognized each year. They come from both rural and urban areas covering 49% of Missouri counties. Discussion The overall objective of Legacy Teachers is to contribute to an institutional climate that promotes patient-centered care. At the outset, we also believed this program could offer a great deal to the Legacy Teachers and their families. They repeatedly tell us that they had no idea that they could have taught a young physician something that made a difference in their professional lives.

The transcription factor FOXO3 is a well-established tumor suppressor whose activity, stability, and localization are regulated by phosphorylation and acetylation. Previous data by our laboratory demonstrated amplified thromboxane-A2 signaling was associated with poor prognoses in bladder cancer patients and overexpression of the thromboxane-A2 isoform-β receptor (TPβ), but not TPα, induced malignant transformation of immortalized bladder cells in vivo. Here, we describe a mechanism of TP mediated modulation of FOXO3 activity and localization by phosphorylation and deacetylation in a bladder cancer cell model. In vitro gain and loss of function studies performed in non-transformed cell lines, UROsta and SV-HUC, revealed knockdown of FOXO3 expression by shRNA increased cell migration and invasion, while exogenously overexpressing TPβ raised basal phosphorylated (p)FOXO3-S294 levels. Conversely, overexpression of ERK-resistant, mutant FOXO3 reduced increases in UMUC3 cell migration and invasion, including that mediated by TP agonist (U46619). Additionally, stimulation of UMUC3 cells with U46619 increased pFOXO3-S294 expression, which could be attenuated by treatment with a TP antagonist (PTXA2) or ERK inhibitor (U0126). Initially U46619 caused nuclear accumulation of pFOXO3-S294; however, prolonged stimulation increased FOXO3 cytoplasmic localization. U46619 stimulation decreased overall FOXO3 transcriptional activity, but was associated with increased expression of its pro-survival target, manganese superoxide dismutase. The data also shows that TP stimulation increased the expression of the histone deacetylase, SIRT1, and corresponded with decreased acetylated-FOXO3. Collectively, the data suggest a role for TP signaling in the regulation of FOXO3 activity, mediated in part through phosphorylation and deacetylation.

Background Flavopiridol is a protein-bound, cytotoxic, cyclin dependent kinase inhibitor. A phase II trial of flavopiridol followed by ara-C and mitoxantrone with flavopiridol given by 1-h bolus for adults with newly-diagnosed, poor-risk acute myelogenous leukemia yielded 67% complete remission with median disease-free survival of 13.6 months.Design and Methods We compared bolus flavopiridol (50 mg/m2/day, Arm A) versus 'hybrid' flavopiridol (30 mg/m2 over 30 min followed by 40 mg/m2 over 4 h, Arm B) followed by ara-C and mitoxantrone in 78 patients (39 per arm) with newly diagnosed, poor-risk acute myelogenous leukemia. To mitigate imbalance, patients were stratified by presence or absence of secondary leukemia and therapy for antecedent disorder.Results Death at or before Day 60 occurred in 8% of patients per arm. Complete remission plus complete remission with incomplete recovery was 68% (Arm A, 62%; Arm B, 74%) overall, and 65% or over in both arms for patients with secondary leukemia and leukemia with adverse genetics. In Arm A 91% and in Arm B 86% of patients received chemotherapy and/or allogeneic transplantation in complete remission. Median overall survival for all remission patients has not been reached for either arm, with median disease free survival of 13.6 months for Arm A and of 12.0 months for Arm B.Conclusions Both flavopiridol schedules produce comparably encouraging results in adults with poor-risk acute myelogenous leukemia. Given the greater ease of bolus administration, we are conducting a randomized phase II study of bolus flavopiridol followed by ara-c and mitoxantrone versus conventional induction therapy for patients aged 70 years and under with intermediate or poor-risk acute myelogenous leukemia. This study is registered at www.clinicaltrials.gov as #NCT 00407966.

Extracellular Hsp90 protein (eHsp90) potentiates cancer cell motility and invasion through a poorly understood mechanism involving ligand mediated function with its cognate receptor LRP1. Glioblastoma multiforme (GBM) represents one of the most aggressive and lethal brain cancers. The receptor tyrosine kinase EphA2 is overexpressed in the majority of GBM specimens and is a critical mediator of GBM invasiveness through its AKT dependent activation of EphA2 at S897 (P-EphA2(S897)). We explored whether eHsp90 may confer invasive properties to GBM via regulation of EphA2 mediated signaling.We find that eHsp90 signaling is essential for sustaining AKT activation, P-EphA2(S897), lamellipodia formation, and concomitant GBM cell motility and invasion. Furthermore, eHsp90 promotes the recruitment of LRP1 to EphA2 in an AKT dependent manner. A finding supported by biochemical methodology and the dual expression of LRP1 and P-EphA2(S897) in primary and recurrent GBM tumor specimens. Moreover, hypoxia mediated facilitation of GBM motility and invasion is dependent upon eHsp90-LRP1 signaling. Hypoxia dramatically elevated surface expression of both eHsp90 and LRP1, concomitant with eHsp90 dependent activation of src, AKT, and EphA2.We herein demonstrate a novel crosstalk mechanism involving eHsp90-LRP1 dependent regulation of EphA2 function. We highlight a dual role for eHsp90 in transducing signaling via LRP1, and in facilitating LRP1 co-receptor function for EphA2. Taken together, our results demonstrate activation of the eHsp90-LRP1 signaling axis as an obligate step in the initiation and maintenance of AKT signaling and EphA2 activation, thereby implicating this pathway as an integral component contributing to the aggressive nature of GBM.