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Supplementary Data from Enhanced Vulnerability of LKB1-Deficient NSCLC to Disruption of ATP Pools and Redox Homeostasis by 8-Cl-Ado

PURPOSE To provide evidence-based recommendations for practicing physicians and other health care providers on immunotherapy and biomarker testing for head and neck cancers. METHODS ASCO convened an Expert Panel of medical oncology, surgical oncology, radiation oncology, radiology, pathology, and patient advocacy experts to conduct a literature search, including systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2022. Outcomes of interest included survival, overall response, and locoregional control. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 28 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS When possible, evidence-based recommendations were developed to address biomarker testing, first-line treatment regimens based on programmed death ligand-1 scores, immunotherapy in platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma, immunotherapy in nasopharyngeal carcinoma, and radiation therapy in combination with immunotherapy for treatment of local recurrence. Additional information is available at www.asco.org/head-neck-cancer-guidelines .

Loss-of-function somatic mutations of STK11, a tumor suppressor gene encoding LKB1 that contributes to the altered metabolic phenotype of cancer cells, is the second most common event in lung adenocarcinomas and often co-occurs with activating KRAS mutations. Tumor cells lacking LKB1 display an aggressive phenotype, with uncontrolled cell growth and higher energetic and redox stress due to its failure to balance ATP and NADPH levels in response to cellular stimulus. The identification of effective therapeutic regimens for patients with LKB1-deficient non–small cell lung cancer (NSCLC) remains a major clinical need. Here, we report that LKB1-deficient NSCLC tumor cells displayed reduced basal levels of ATP and to a lesser extent other nucleotides, and markedly enhanced sensitivity to 8-Cl-adenosine (8-Cl-Ado), an energy-depleting nucleoside analog. Treatment with 8-Cl-Ado depleted intracellular ATP levels, raised redox stress, and induced cell death leading to a compensatory suppression of mTOR signaling in LKB1-intact, but not LKB1-deficient, cells. Proteomic analysis revealed that the MAPK/MEK/ERK and PI3K/AKT pathways were activated in response to 8-Cl-Ado treatment and targeting these pathways enhanced the antitumor efficacy of 8-Cl-Ado. Implications: Together, our findings demonstrate that LKB1-deficient tumor cells are selectively sensitive to 8-Cl-Ado and suggest that therapeutic approaches targeting vulnerable energy stores combined with signaling pathway inhibitors merit further investigation for this patient population.

Yetki, yeterlik ve güvenirliğin onaylandığı sertifikalı bir kalite güvence sistemi ve süreci olarak görülen akreditasyon, kalite güvencesi ile iç içe girmiş bir kavramdır. Akreditasyon, kurum ve programların markalaşmasında ve sürdürülebilir biçimde kalmasına katkı sağlamaktadır. Akreditasyon, birçok ülkede ve sektörde topluma sunulan program ve hizmetlerin niteliğinin sistematik bir yaklaşımla güvence altına alınması için geliştirilen bir yöntemdir. Yükseköğretim sisteminde de akreditasyon, kalite ve niteliğin önemli göstergelerinden biri olarak kabul edilebilir. Akreditasyona inanan, bu çerçevede niteliğin artırılmasına yönelik görev ve sorumluluk üstlenen öğretim elemanları ise kurumun kurumsallaşmasına ve sürdürülebilir iyileşmesine daha fazla katkıda bulunabilir. Bu bağlamda araştırmanın amacı, Bartın Üniversitesi akademik birimlerinde görev yapan öğretim elemanlarının akreditasyon algılarının belirlenmesidir. Tarama modeli ile gerçekleştirilen araştırmada kolay ulaşılabilir örneklem yöntemiyle toplam 181 öğretim elemanına ulaşılmıştır. Akreditasyon Algısı Ölçeği ile toplanan veriler SPSS programı kullanılarak analiz edilmiştir. Araştırma sonucunda öğretim elemanlarının akreditasyon algısının yüksek düzeyde olduğu görülmüştür. Öğretim elemanlarının akreditasyon algısının yükseltilmesi ve bu algının somut olarak niteliğe dönüşmesine ilişkin çalışmalar yapılmalıdır.

ImportanceSurvival outcomes for anaplastic thyroid cancer (ATC), the most aggressive subtype of thyroid cancers, have remained poor. However, targeted therapies and immunotherapies present new opportunities for treatment of this disease. Evaluations of survival outcomes over time with new multimodal therapies are needed for optimizing treatment plans.ObjectiveTo evaluate the association of treatment strategies and tumor characteristics with overall survival (OS) among patients with ATC.Design, Setting, and ParticipantsThis retrospective case series study evaluated the survival outcomes stratified by treatment strategies and tumor characteristics among patients with ATC treated at a tertiary level academic institution from January 1, 2000, to December 31, 2021. Demographic, tumor, treatment, and outcome characteristics were analyzed. Kaplan-Meier method and log rank test modeled OS by treatment type and tumor characteristics. Data were analyzed in May 2022.Main Outcomes and MeasuresOverall survival (OS).ResultsThe study cohort comprised 97 patients with biopsy-proven ATC (median [range] age at diagnosis, 70 [38-93] years; 60 (62%) female and 85 [88%] White individuals; 59 [61%] never smokers). At ATC diagnosis, 18 (19%) patients had stage IVA, 19 (20%) had stage IVB, and 53 (55%) had stage IVC disease. BRAF status was assessed in 38 patients; 18 (47%) had BRAF-V600E variations and 20 (53%), BRAF wild type. Treatment during clinical course included surgery for 44 (45%) patients; chemotherapy, 41 (43%); definitive or adjuvant radiation therapy, 34 (RT; 35%); and targeted therapy, 28 (29%). Median OS for the total cohort was 6.5 (95% CI, 4.3-10.0) months. Inferior OS was found in patients who did not receive surgery (hazard ratio [HR], 2.12; 95% CI, 1.35-3.34; reference, received surgery), chemotherapy (HR, 3.28; 95% CI, 1.99-5.39; reference, received chemotherapy), and definitive or adjuvant RT (HR, 2.47; 95% CI, 1.52-4.02; reference, received definitive/adjuvant RT). On multivariable analysis, age at diagnosis (HR, 1.03; 95% CI, 1.01-1.06), tumor stage IVC (HR, 2.65; 95% CI, 1.35-5.18), and absence of definitive or adjuvant RT (HR, 1.90; 95% CI, 1.01-3.59) were associated with worse OS.Conclusions and RelevanceThis retrospective single-institution study found that lower tumor stage, younger age, and the ability to receive definitive or adjuvant RT were associated with improved OS in patients with ATC.

The purpose of this study is to examine the effect of Strengths Based Approach (SBA) on attendance, academic achievement and student motivation in English class. For this purpose, an experimental study was carried out with freshman students at a state university in Turkey in the spring term of 2011-2012 academic year. The sampling of the study consisted of 66 students in total, 33 students in experimental group and 33 students in control group. Pretest posttest quasi-experimental design with a control group was used in the study. Clifton StrengthsfinderTM was used to determine the talent themes of students. The data on the motivation levels of students were obtained through the motivation scale, which was adapted from Attitude/Motivation Test Battery developed by Gardner (1985). The data regarding the attendance percentages of students in English class were obtained from attendance sheets taken by the researcher weekly. Students’ exam scores in mid-term and final exams administered by the researcher in both terms were taken into consideration for the academic achievement of students. The study indicated that the most frequently encountered talent themes were restorative (f=16), responsibility (f=11), deliberative (f=9), ideation (f=9) and learner (f=9) respectively. Also, SBA affected the attendance rates of students positively in favour of experimental group; however, it didn’t have a significant effect on students’ academic achievement and motivation levels. It is considered important to study SBA, which is a fairly new area of study for both the world and Turkey.

93 Background: Chemotherapy Induced Peripheral Neuropathy (CIPN) is a debilitating side effect associated with many chemotherapeutic agents. It significantly impacts quality of life during treatment, causes lasting neuropathy, and may also shorten the treatment regimen, potentially impacting clinical benefit. The pathology of CIPN is still not completely understood, however, increasing evidence suggests sphingosine-1-phosphate (S1P) may be an important signaling molecule. Altered neuronal sphingolipid metabolism has been linked to neuropathic pain, evidenced by elevated plasma levels of S1P in patients receiving chemotherapy. Methods: BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that lowers systemic S1P. BXQ-350 was investigated in an adult Phase 1 dose-escalation safety study in heavily pretreated all-comer cancer patients with advanced solid malignancies ( NCT02859857 ). The primary objective was to determine the safety profile and potential clinical activity of BXQ-350 as monotherapy. Samples were collected to explore potential biomarkers. Results: BXQ-350 was safe and well tolerated. Clinical signs of activity were observed in 13 patients (~17.8% of evaluable patients) experiencing a clinical benefit (PR, SD) up to cycle 6 and beyond including: 4 CRC, 1 pancreatic, and 1 GIST patient. Two patients are still on study six years after enrollment, including 1 CRC. Interestingly, a pancreatic cancer patient with chronic CIPN at time of enrollment spontaneously reported a significant improvement of her neuropathic symptoms shortly after receiving BXQ-350. Investigation of potential improvements in patients with chronic CIPN at time of enrollment revealed that 4 out of 10 patients experienced an improvement of their symptoms that seemed to be associated with a decrease in S1P systemic levels following BXQ-350 administration. BXQ-350 was subsequently investigated in a murine oxaliplatin-CIPN preclinical model with results showing a dose-dependent prevention/resolution of CIPN correlating with decreasing systemic S1P levels. Conclusions: Results of this Phase 1 study in heavily pretreated patients shows that BXQ-350 was well tolerated and seems to generate a clinical benefit via modulation of S1P. There were preliminary signs that BXQ-350 may alleviate symptoms of CIPN in relation to decreasing S1P concentration. Additional studies are underway to better understand this novel mechanism of action. Clinical trial information: 02859857 .

154 Background: Sphingolipids are a class of bioactive signaling molecules implicated in multiple cellular processes and molecular pathways. Many publications have demonstrated that ceramides are proapoptotic, synergize with cancer treatments, and mitigate chemoresistance. Findings also demonstrated that sphingosine-1-phosphate (S1P) is a key sphingolipid that promotes cancer cell proliferation, activates multiple oncogenic pathways, and stimulates immuno-suppressor cell populations promoting a pro-tumoral microenvironment. Several studies of colorectal cancer patients have shown high levels of ceramides being associated with improved survival, while high S1P levels are associated with a poor prognosis. Hence, modulation of sphingolipid metabolism continues to be a promising treatment approach. Methods: BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that lowers systemic S1P and increases C18 ceramide. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in an all-comer cancer patients with advanced solid malignancies ( NCT02859857 ) to determine its safety profile and potential clinical activity as monotherapy. Samples were collected to explore potential biomarkers. Results: 13 patients (~17.8% of evaluable patients) had a clinical benefit up to cycle 6 (PR, SD), with the majority experiencing a decrease in systemic S1P levels and an increase in C18 levels. 8 patients (~11% of evaluable patients) had PFS > 6 months, with 2 patients still on study six years after enrollment. Analysis of plasma samples also revealed an increase in anti-tumoral cytokines (IFNg, TNFa, IL-2) and a decrease in pro-tumoral ones (IL-6, 8, 10). Among patients with PFS > 6 months, there were 4 recurrent CRC patients (1PR, 3SD): 1 patient had a PFS of ~12 months, 2 of ~18 months, and 1 is still on study after 6 years. Conclusions: Results of this Phase 1 study in heavily pretreated patients show BXQ-350 was well tolerated and seem to generate a clinical benefit in CRC patients via modulation of S1P and ceramides. A phase 2 trial of BXQ-350 in combination with FOLFOX/Bevacizumab in newly diagnosed mCRC is on-going with plans to further investigate this novel mechanism of action. Clinical trial information: 02859857 .

Simple Summary The anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma. Patients with locoregional, pathologically high-risk disease recur frequently despite adjuvant cisplatin–radiation therapy. Targeting PD1 may reverse immunosuppression induced by cancer, chemotherapy, or radiation therapy. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule for adding fixed-dose pembrolizumab to standard adjuvant cisplatin–radiation therapy. Eligible patients had resected, human papillomavirus-negative, stage III–IV oral cavity, pharynx, or larynx cancer with extracapsular nodal extension or positive margin. A total of four dose-limiting toxicities were observed in 34 patients (fever, wound infection, diverticulitis, nausea). Three of four were successfully rechallenged with pembrolizumab. The recommended phase II schedule was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before adjuvant CRT. The regimen was safe and feasible in the cooperative group setting. Further development is warranted. Abstract The anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Patients with locoregional, pathologically high-risk HNSCC recur frequently despite adjuvant cisplatin–radiation therapy (CRT). Targeting PD1 may reverse immunosuppression induced by HNSCC and CRT. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to standard adjuvant CRT. Eligible patients had resected HPV-negative, stage III–IV oral cavity, pharynx, or larynx HNSCC with extracapsular nodal extension or positive margin. RP2S was declared if three or fewer dose-limiting toxicities (DLT) occurred in a cohort of 12. DLT was defined as grade 3 or higher non-hematologic adverse event (AE) related to pembrolizumab, immune-related AE requiring over 2 weeks of systemic steroids, or unacceptable RT delay. A total of 34 patients enrolled at 23 NRG institutions. During the first cohort, only one DLT was observed (fever), thus RP2S was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before CRT. During expansion, three additional DLTs were observed (wound infection, diverticulitis, nausea). Of the 34 patients, 28 (82%) received five or more doses of pembrolizumab. This regimen was safe and feasible in a cooperative group setting. Further development is warranted.

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], pINTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.FUNDING: Merck Sharp & Dohme.

e15045 Background: Chemical Induced Peripheral Neuropathy (CIPN) is a debilitating and serious side-effect associated with many chemotherapeutic treatments. Often, CIPN is a dose-limiting toxicity, and its effects can be long-lasting in some patients. The pathology of CIPN is thought to involve not only cytotoxicity of neuronal cells, but also inflammation and immune responses. Hence, it is not surprising that the sphingolipid sphingosine-1-phosphate (S1P) is thought to be a key contributor to CIPN. Methods: BXQ-350, a nanovesicle comprised of recombinantly expressed Saposin C and dioleoylphosphatidylserine, has broad anticancer activity. It modulates sphingolipid metabolism and signaling, lowers S1P and increases pro-apoptotic ceramides, and induces an anti-tumoral immune response. BXQ-350 was investigated in a Phase 1 dose-escalation safety study of all-comer cancer patients with advanced solid malignancies, including high grade gliomas ( NCT02859857 )*. Multiple secondary parameters were included to characterize BXQ-350’s pharmacokinetics, efficacy profile and to elucidate potential biomarkers. Results: Interestingly, several patients with established CIPN spontaneously reported improvement of their neuropathy-related symptoms following BXQ-350 administration. Plasma samples from those patients revealed changes in circulating levels of sphingolipids and cytokines, including reduction of circulating levels of S1P and of IL-6, IL-8, cytokines, following BXQ-350 dosing. These properties of BXQ-350 were subsequently investigated in a murine oxaliplatin-CIPN preclinical model; results showed a dose-dependent prevention/resolution of CIPN, which also correlated with decreasing systemic S1P levels. Additional plasma based CIPN specific biomarkers were investigated, and preclinical results suggest that BXQ-350 may also favorably inhibit specific immune cells that favor CPIN. Conclusions: These preclinical and clinical observations related to CIPN, coupled with the fact that BXQ-350 acts synergistically with many chemotherapies and radiation, warrant further its investigation into preventing or improving CIPN related symptoms in cancer patients. Clinical trial information: 02859857.

e15007 Background: BXQ-350 was investigated in a Phase 1 dose-escalation safety study of all-comer cancer patients with advanced solid malignancies, including high grade gliomas ( NCT02859857 ) (safety/efficacy results reported in a separate abstract). The primary objective of this single agent study was to describe the safety profile and to determine the maximum tolerated dose. Multiple secondary parameters were included to characterize BXQ-350’s pharmacokinetic parameters, efficacy profile and elucidation of potential biomarkers. BXQ-350 is a nanovesicle of recombinantly expressed Saposin C (SapC) and dioleoylphosphatidylserine. In nature, SapC is a protein encoded by the Psap gene, and serves as an allosteric activator of several enzymes involved in sphingolipid/ceramide metabolism, enzymes which are being investigated as novel therapeutic targets in cancers. Indeed, sphingolipids are a class of bioactive signaling molecules implicated in multiple cellular processes and molecular pathways. Amongst these sphingolipids, Sphingosine-1-Phosphate (S1P) induces cancer cell survival and proliferation, activates multiple oncogenic pathways, and promotes a pro-tumoral microenvironment. SapC has broad anticancer activity, lowering S1P and increasing ceramides, also inducing an anti-tumoral immune response. Methods: Lipodomic analysis (sphingolipids) and cytokines were analyzed in plasma samples of a subset of patients enrolled in this study. Results: Analysis of plasma biomarker samples, collected throughout the period patients were on study, reveals notable changes of circulating sphingolipids and cytokines. A subset of patients exhibited clinical benefits following BXQ-350 administration (see other presentation for details; ̃17% of the evaluable patients remained on study up to Cycle 6; and 8 patients (̃11%) with PFS> 6 months). Concomitant circulating changes in S1P and other ceramides may be indicative of treatment effect. Also, concurrent changes in circulating levels of pro/antitumoral cytokines were noted. Conclusions: While these results are exploratory and preliminary in nature, these initial results warrant further investigation. These observations will be further explored in specific cancer and non-cancer indications. Clinical trial information: 02859857.

e15059 Background: Bexion recently completed an all-comer Phase 1 clinical study of BXQ-350 in patients with advanced solid tumors including high grade gliomas to evaluate the safety profile and to determine the maximum tolerated- or biologically effective dose. BXQ-350 is a nanovesicle comprised of recombinantly expressed Saposin C (SapC) and dioleoylphosphatidylserine. SapC, a human protein encoded by the Psap gene, is an allosteric activator of several enzymes involved sphingolipid metabolism. Sphingolipids are bioactive signaling molecules implicated in multiple cellular processes including apoptosis and immune stimulation/inhibition. In nonclinical studies, BXQ-350 evidences broad anticancer activity, selectively inducing apoptosis of cancer cells by modulating sphingolipids (ceramides/S1P), and BXQ-350 acts synergistically with multiple classes of anticancer agents and treatments. Methods: In the trial (NTC02859857), performed at four US sites, BXQ-350 was administered intravenously for a minimum of 6 cycles over 28 weeks at escalating doses from 0.7 mg/kg up to 2.4 mg/kg. Multiple secondary parameters were included to characterize its pharmacokinetics, efficacy profile and identify potential biomarkers. Results: Results indicate that: i) BXQ-350 was safe and well-tolerated as no DLT was observed and an MTD was not reached; ii) treatment related adverse events leading to discontinuation were typical for this patient population and disease related; iii)* biomarker analyses suggest positive modulation of sphingolipid metabolism and stimulation of the immune system; iv)* surprisingly, some patients noted improvement of existing peripheral neuropathies. RANO or RECIST ver 1.1 criteria were used to evaluate tumor response: 13 patients reached Cycle 6 restaging (17% ORR); 8 patients (11.0% of evaluable patients) demonstrated progression free survival over more than 6 months; and 2 patients (a GBM and CRC patient) are still on study after 5 years. * subject of separate abstracts. Conclusions: In conclusion, BXQ-350 is a first-in-human and first-in-class novel biologic whose Phase 1 results suggest that it may have clinical utility either as a monotherapy or when combined with other targeted agents. Clinical trial information: 028559857.

The significance of a dysregulated sphingolipid metabolism in cancer, including brain tumors, has been demonstrated and several enzymes involved in sphingolipid metabolism are being investigated as novel therapeutic targets for adult and pediatric brain cancers. Saposin C (Sphingolipid Activator PrO[S]etIN) is a human protein encoded by the Psap gene and is an allosteric activator of several enzymes involved in sphingolipid/ceramide metabolism. BXQ-350 is a nanovesicle of Saposin C that has broad anticancer activity, selectively inducing apoptosis of cancer cells by lowering Sphingosine-1-Phosphate and increasing ceramides concentrations and inducing an anti-tumoral immune response. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in cancer patients with advanced solid malignancies including brain tumors (NCT02859857). The primary objective of this single agent study was to describe the safety profile and to determine the maximum tolerated dose, or the biological effective dose, of BXQ-350 administered intravenously at escalating doses from 0.7 mg/kg up to 2.4 mg/kg. Multiple secondary parameters were included to characterize BXQ-350’s pharmacokinetic parameters, efficacy profile and potential biomarkers. This trial was performed at four US sites. Results indicate that BXQ-350 was safe and well-tolerated as no DLT was observed and an MTD was not reached. RANO or RECIST 1.1 criteria were used to evaluate tumor response. Analysis of plasma samples suggests that BXQ-350 modulates sphingolipid metabolism and impacts the immune system positively. Furthermore, potential signs of single agent activity were observed across tumor types, including in two ependymomas for which results will be presented.

2586 Background: PD-1/PD-L1 immune checkpoint inhibitors (ICIs) are widely used in the treatment of metastatic malignancies. Judiciously balancing disease control (DC) against development of immune-related adverse events (irAE) remains a crucial aspect of treatment. The effect of treatment discontinuation after sustained disease control (SDC) is unknown. The purpose of this analysis was to evaluate outcomes of responders to ICI who discontinue treatment after a minimum of 12 months (SDC). Methods: We retrospectively reviewed the database of the University of New Mexico Comprehensive Cancer Center between 2014 and 2021 and identified patients who had received ICI. Patients with metastatic solid tumors who had stopped ICI therapy after achieving SDC [stable disease, partial response, complete response (SD,PR,CR)] were selected and outcomes reviewed from their electronic health records. Results: We identified 204 patients who were treated with ICI for various solid cancers. Forty-four patients (21.6%) met the criteria, of whom 35 with follow-up data were included in the final analysis; including 11 melanoma, 5 non-small cell lung, 4 head & neck, 8 renal, 4 urothelial, 1 anal, 1 Merkel cell carcinoma, and 1 liposarcoma. Patients were divided into two groups: those who stopped ICI due to an irAE [irAE group, n=14, median treatment time (MTT), 16.6 mo] and those who stopped due to other reasons (eg completion of 2 years of therapy, n=20, non-cancer related surgery, n=1) (non-irAE group, n=21, MTT, 23.7 mo). Among the irAE group, the most common irAE included pneumonitis, rash, transaminitis, and fatigue. As of data cutoff date, 10 of 14 (71%) patients continued to show SDC. Only 4 of 14 (28.6%) patients in this group experienced progression of disease (PD), one of whom was re-challenged with nivolumab and achieved DC (median follow-up of 19.2 mo after last dose of treatment, range 3-50.2 mo). Among the non-irAE group, 13 of 21 (62%) continued to have SDC. Eight of 21 (38%) experienced PD after stopping treatment, 7 of whom received ICI rechallenge, with 2 of 7 achieving DC (median follow-up of 22.2 mo, range 3.6-54.8 mo). At a median follow-up of 21.3 mo from stopping ICI therapy (range, 3-54.8 mo), 10 patients (71%) from the irAE group and 13 (61.9%) from the non-irAE group are in DC and have not experienced PD. Conclusions: We demonstrate that 23 (66%) patients experienced SDC, regardless of cancer type or development of irAE. After including patients who were re-challenged with ICI due to PD, 26 (74%) remain in DC. Future prospective malignancy-specific trials such as NCT04637594 are warranted to evaluate optimal treatment duration. [Table: see text]

Anaplastic thyroid cancer (ATC) is among the most lethal malignancies. The mitotic kinase PLK1 is overexpressed in the majority of ATCs and PLK1 inhibitors have shown preclinical efficacy. However, they also cause mitotic slippage and endoreduplication, leading to the generation of tetraploid, genetically unstable cell populations. We hypothesized that PI3K activity may facilitate mitotic slippage upon PLK1 inhibition, and thus tested the effect of combining PLK1 and PI3K inhibitors in ATC models, in vitro and in vivo. Treatment with BI6727 and BKM120 resulted in a significant synergistic effect in ATC cells, independent of the levels of AKT activity. Combination of the two drugs enhanced growth suppression at doses for which the single drugs showed no effect, and led to a massive reduction of the tetraploid cells population. Furthermore, combined treatment in PI3K(high) cell lines showed a significant induction of apoptosis. Finally, combined inhibition of PI3K and PLK1 was extremely effective in vivo, in an immunocompetent allograft model of ATC. Our results demonstrate a clear therapeutic potential of combining PLK1 and PI3K inhibitors in anaplastic thyroid tumors.

Intracellular pathogens have evolved to utilize normal cellular processes to complete their replicative cycles. Pathogens that interface with proliferative cell signaling pathways risk infections that can lead to cancers, but the factors that influence malignant outcomes are incompletely understood. Human papillomaviruses (HPVs) predominantly cause benign hyperplasia in stratifying epithelial tissues. However, a subset of carcinogenic or “high-risk” HPV (hr-HPV) genotypes are etiologically linked to nearly 5% of all human cancers. Progression of hr-HPV-induced lesions to malignancies is characterized by increased expression of the E6 and E7 oncogenes and the oncogenic functions of these viral proteins have been widely studied. Yet, the mechanisms that regulate hr-HPV oncogene transcription and suppress their expression in benign lesions remain poorly understood. Here, we demonstrate that EGFR/MEK/ERK signaling, influenced by epithelial contact inhibition and tissue differentiation cues, regulates hr-HPV oncogene expression. Using monolayer cells, epithelial organotypic tissue models, and neoplastic tissue biopsy materials, we show that cell-extrinsic activation of ERK overrides cellular control to promote HPV oncogene expression and the neoplastic phenotype. Our data suggest that HPVs are adapted to use the EGFR/MEK/ERK signaling pathway to regulate their productive replicative cycles. Mechanistic studies show that EGFR/MEK/ERK signaling influences AP-1 transcription factor activity and AP-1 factor knockdown reduces oncogene transcription. Furthermore, pharmacological inhibitors of EGFR, MEK, and ERK signaling quash HPV oncogene expression and the neoplastic phenotype, revealing a potential clinical strategy to suppress uncontrolled cell proliferation, reduce oncogene expression and treat HPV neoplasia., Author summary Human papillomavirus (HPV) infections occur in differentiating squamous epithelium and induce hyperplasia during the viral replicative cycle. Although HPV oncogene expression is necessary to promote cellular proliferation for viral genome amplification in the middle epithelial layers, oncogene levels are thereafter suppressed to permit differentiation-induced late gene expression in the uppermost epithelial cells. Yet, the mechanisms responsible for controlling HPV oncogene expression are not well understood. Here, we demonstrate that EGFR/MEK/ERK signaling, which is subject to the normal cellular cues of contact inhibition and epithelial tissue differentiation, is a critical regulator of hr-HPV oncogene expression. We found that extrinsic activation of ERK overrides cellular control to promote oncogene expression and the neoplastic phenotype. Many epidemiologically defined risk factors activate the EGFR/MEK/ERK pathway, suggesting a common mechanism whereby they may promote HPV persistence and disease progression. Lastly, we show that HPV oncogene transcription and protein expression remain susceptible to MEK/ERK control in early neoplastic tissues and tumor cells and that targeted inhibition of MEK/ERK signaling might be exploited therapeutically for HPV-induced infections and tumors.

Background Locally advanced head and neck squamous cell carcinomas (HNSCC) are treated with multidisciplinary approach which includes radiation therapy. Immunotherapy with nivolumab or pembrolizumab is used for platinum refractory disease. We analyzed the association of radiation treatment patterns and immunotherapy responses HNSCC. Methods We performed a retrospective analysis at University of New Mexico Comprehensive Cancer Center for patients with diagnosis of HNSCC treated at our institution between 2011 and 2020 with immunotherapy agent’s nivolumab and pembrolizumab. Our cohort included 21 patients with previous history of definitive radiation therapy for HNSCC who received immunotherapy for recurrent disease, as part of adjuvant treatment as either front-line or second line therapy. In terms of response, patients were divided into responders (R) and non-responders (NR). Responders were defined as the presence of partial remission in initial imaging or stable disease for a period of six months or longer. Results Of our 21 patients, 10 patients were R and 11 patients were NR. p16 positivity was 6 (60%) in R vs 3 (27%) in NR. 8 patients in R group (80%) and 10 patients in NR group (91%) had prior platinum based chemotherapy concurrent with radiation or for recurrence as salvage chemotherapy.All patients had radiation therapy prior to immunotherapy for adjuvant or for definitive treatment. Time from last day of radiation treatment to start of immunotherapy was 47 months in R group while it was 9 months in NR group (P Conclusions Immunotherapy with single agent PD-L1 inhibitor is used for platinum refractory disease in HNSCC, however response rates are low. Our study shows that the patients who had early recurrence and received immunotherapy closer to definitive radiation therapy had lower response rate. Therefore we need further studies to investigate changes in immune micorenvironment with radiation therapy for better immune targeting of patients with early recurrence after radiation treatment.

Background Melanoma has high response rate to immune checkpoint inhibitors. KIT, a driver mutation in melanoma seen in ~10% of the patients.1 However, the role of the KIT mutation in immune microenvironment of melanoma is not well established yet. Here we report a case with KIT mutation and a likely impaired B cell activity with poor response to Immune-checkpoint inhibitor therapy (ICI). We also describe the overall survival of melanoma depending on KIT mutation and MS4A1/CD20 expression, which encodes CD20, B-lymphocyte-specific membrane protein that plays a role in the development, differentiation, and activation of B-lymphocytes.2 Methods A case with poor response to ICI with KIT mutation and monoclonal B cell lymphocytosis was identified. Clinical and molecular characteristics of melanoma in TCGA was analyzed using cBioPortal web page. TCGA data were analyzed to determine KIT mutation status and MS4A1/CD20 expression in melanoma cohort. Samples in the upper 33 percentile of MS4A1 expression were identified as high expression, and the lower 33 percentile were identified as low expression. Mantel-Cox method was used for overall survival (OS) comparison between the cohorts. Results 69-year-old male with initial diagnosis of stage III-B melanoma of the left thumb with local recurrence in the resection site and then lung metastases. Patient was then started on nivolumab/ipilimumab with rapid progression on immunotherapy. He was found to have KIT mutation (exon 13K642EMT), and started on imatinib, but he continued to have progression. He was switched to temozolomide with no response. He also had history of leukopenia, pre-dating the metastatic melanoma and was diagnosed with monoclonal B cell lymphocytosis. With the hypothesis that the patient‘s dysfunctional B cells may have impaired ability of ICI and poor prognosis; we analyzed TCGA database for KIT mutation and MS4A1/CD20 expression- which was used as marker for B cell activity. KIT mutation was seen in 10 of 147 patients with high MS4A1/CD20 expression, and 10 of 135 patients with low MS4A1/CD20 expression. Overall survival was 15 months for the patients with KIT mutation and low MS4A1/CD20 expression, and significantly lower when compared with other groups despite low number of patients. (P Conclusions B cells have significant role in immune response to tumor. Lower expression of MS4A1/CD20 is known to be associated with poor prognosis in melanoma and other solid tumors.3 We demonstrated that a concurrent KIT mutation in melanoma with lower expression of MS4A1/CD20 contributes to poor prognosis in melanoma. Therefore, this small subset of aggressive tumors may need combination strategies involving targeting driver pathways with a kinase and immune checkpoint inhibitor. References de Mendonca UB, Cernea CR, Matos LL, de Araujo Lima RR. Analysis of KIT gene mutations in patients with melanoma of the head and neck mucosa: a retrospective clinical report. Oncotarget 2018 May 1;9(33):22886. Tedder TF, Boyd AW, Freedman AS, Nadler LM, Schlossman S. The B cell surface molecule B1 is functionally linked with B cell activation and differentiation. The Journal of Immunology 1985 Aug 1;135(2):973–9. Liu Y, Wang L, Lo KW, Lui VW. Omics-wide quantitative B-cell infiltration analyses identify GPR18 for human cancer prognosis with superiority over CD20. Communications biology 2020 May 12;3(1):1–1.

Primary squamous cell carcinoma of thyroid (SCC-T) is an extremely rare, aggressive neoplasm with median survival of 9 months. Pure squamous morphology with absence of other cell types is required for diagnosis of SCC-T. Clinically, SCC-T behaves like anaplastic thyroid carcinoma (ATC) showing rapid growth, and extra thyroidal extension. We report a 91-year-old woman presenting with an enlarging thyroid mass and accompanying dysphagia and hoarseness. Fine needle aspiration revealed hypercellular specimen with large, pleomorphic, malignant cells. Intraoperative assessment revealed an inoperable tumor involving both thyroid lobes and extensively infiltrating surrounding soft tissues. A subtotal thyroidectomy was performed. Histology revealed squamous cell carcinoma replacing native thyroid tissue and infiltrating adjacent skeletal muscle. Lymphovascular and perineural invasion were present. Immunohistochemistry showed tumor cells positive for CK5-p40, Pax-8, TTF-1 and negative for thyroglobulin. P53 expression by IHC was high and Ki-67 proliferation index was > 90 %. (Next generation sequencing revealed a novel BRAF mutation (BRAF c.1799 T > A; 1801_1812del) along with TP53 and TERT mutations. PDL-1 immunohistochemistry showed positive expression in tumor cells (>80%), making patient also amenable to anti-PDL-1 immunotherapy. Patient was treated with BRAF inhibitor therapy with initial relief but eventually was put on hospice care due to increasing intolerance to therapy. This case represents a rare thyroid malignancy with a unique molecular signature consisting of a novel BRAF mutation [previously not described in SCC-T or ATC], associated with TERT-TP53 mutations. Further, importance of PDL-1 testing as a prognostic marker and as a guide to immunotherapy in refractory tumors is discussed.

This study aims to reveal the relationship between lifelong learning and philosophies of education. The sampling of the study consisted of 570 prospective teachers attending a pedagogical formation course at Bartin University and Bulent Ecevit University in 2016. Relational screening model was used in the study and the data were collected through Educational-Instructional Philosophies Determination Scale and Lifelong Learning Tendency Scale. The collected data were analysed using regression analysis via SPSS 22. According to the data obtained, there is a weak, positive correlation (r=0.286) between prospective teachers' lifelong learning tendency and the philosophies of education they favour at 99% confidence interval. As the standardised regression coefficient (β) indicates, the relative order of importance of predictor values on lifelong learning tendency is as follows; essentialism, perennialism, reconstructionism and progressivism. It is observed that essentialism and perennialism are important predictors for lifelong learning tendency.

Bu çalışmanın amacı öğretmen adaylarınınbenimsedikleri eğitim felsefeleri ile sahip oldukları başarı motivasyonlarıarasındaki ilişkinin araştırılmasıdır. Bu amaçla, 2016 yılında Türkiye’de ikiüniversite tarafından verilen pedagojik formasyon kursuna devam eden 570 deneğeeğitim-öğretim felsefesini belirleme ölçeği ve başarı odaklı motivasyonbelirleme ölçeği uygulanmıştır. SPSS 22 istatistik programı kullanılarakyapılan analizlere göre başarı motivasyonu genel değişkeni ile en yüksekilişkiye sahip olan eğitim felsefesi ilerlemecilik iken, ilerlemeciliği yenidenkurmacılık, daimicilik ve esasicilik takip etmektedir. Standartlaştırılmışkatsayılara göre başarı odaklı motivasyon üzerinde en yüksek etkiye sahip olandeğişkenler sırasıyla ilerlemecilik, daimicilik, yeniden kurmacılık veesasicilik şeklinde sıralanmıştır. Modern eğitim felsefelerinin klasik olanlarakıyasla başarı motivasyonu ile daha yakından ilişkili olduklarıgözlenmiştir., The aim of this study is to examine therelationship between educational philosophies favoured by prospective teachersand their achievement motivation. To this end, educational philosophiesdetermination scale and achievement focused motivation scale were applied to570 subjects attending pedagogical formation courses provided by twouniversities in Turkey in 2016. In the light of the analyses carried out inSPSS 22 statistical package programme, a medium level, positive, significantcorrelation was found between prospective teachers’ achievement motivation andphilosophies of education they favour. The educational philosophy having thehighest correlation with achievement motivation was progressivism followed byreconstructionism, perennialism and essentialism, respectively. As thestandardised coefficients suggest, the variable with the highest effect onachievement motivation was progressivism followed by perennialism,reconstructionism and essentialism, respectively. It was observed thatcontemporary philosophies of education more closely correlated with achievementmotivation compared to the classical ones.

The aim of this study is to carryout the validity and reliability studies of critical thinking barriers (CTB)scale. The ideas of a sum of 19 experts were taken for 86 items, which wereformed as a result of literature survey. The number of the items in the draftscale was reduced to 54 following the ideas of experts and it was implementedon 11 undergraduate students and their ideas were also taken. The draft scalewas applied to 566 undergraduate students. The scale was applied at a stateuniversity in Turkey. %59.7 (338) of the subjects consisted of female studentsand %40.3 (228) of them was male students. The factor loads of the items in thescale ranged between 0.388-0.677. It is observed that 40.454% of the totalvariance was accounted for as a result of the factor analysis. The KMO value ofthe CTB scale was 0.892, Bartlett’s test value3.783E3 (Sd= 378, p=0.000). Thesub factors of the scale were; inability to reason, egocentrism, reliance onauthority and self-confidence. The eventual scale, after removing the itemswith relatively low factor loads, consisted of a sum of 26 items; 10 itemsunder the sub factor inability to reason, 6 items under egocentrism, 6 itemsunder reliance on authority and 4 items under self-confidence. Equivalent testand test-retest implementations were performed for the scale. The split-halfreliability coefficient was found 0.74. The Cronbach’s alpha reliabilitycoefficient of the scale was 0.87. According to the confirmatory factoranalysis made on AMOS, the RMSEA, SRMR, GFI and AGFI values demonstrated thatthe model had a strong consistency. Departing from these results, it can beclaimed that CTB scale meets the criteria of a valid scale., Bu çalışmanın amacı eleştirel düşünme engelleri ölçeğinin geçerlik ve güvenirlik çalışmalarının yapılmasıdır. Alanyazın taraması sonucunda oluşturulan 86 madde için toplam 19 uzmanın görüşüne başvurulmuştur. Uzman görüşleri sonucunda 54 maddeye düşen ölçek 11 öğrenci üzerinde uygulanmış ve onların da görüşleri alınmıştır. Taslak ölçek, geliştirilmek üzere 566 lisans öğrencisine uygulanmıştır. Uygulama, Türkiye'de bir devlet üniversitesinde yapılmıştır. Öğrencilerin %59.7’si (338) kadın ve %40.3’ü (228) erkektir. Ölçekteki maddelerin faktör yükleri 0.388-0.677 arasında değişmektedir. Faktör analizi sonucunda varyansın % 40.454’ünün karşılandığı söylenebilir. ELDEN ölçeğinin KMO değeri 0.892, Bartlett testi değeri 3.783E3’dür (Sd=378, p=0.000). Ölçeğin alt temaları; mantık yürütememe, ben merkezlilik, otoriteye inanç ve kendine güven olarak tespit edilmiştir. Mantık yürütememe temasında 10 madde, ben merkezlilik temasında 6 madde, otoriteye inanç temasında 6 madde ve kendine güven temasında 4 madde olmak üzere ölçekte toplam 26 madde yer almıştır. Ölçeğe eşdeğer test ve test-tekrar test uygulamaları yapılmıştır. İki yarı korelasyon katsayısı 0.74 olarak hesaplanmıştır. 566 öğrencinin vermiş olduğu cevaplar üzerinde ölçeğin bütünü için Cronbach Alpha katsayısı hesaplanmış olup sonuç 0.87 bulunmuştur. AMOS programı üzerinde yapılan doğrulayıcı faktör analizine göre, RMSEA, SRMR, GFI ve AGFI’nın sonuçları modelin güçlü bir uyum içinde olduğunu göstermektedir. Bu sonuçlardan hareketle, ELDEN ölçeğinin geçerli bir ölçek olma kriterlerini karşıladığı söylenebilir.

Bu çalışmanın amacı eleştirel düşünme engelleri ölçeğinin geçerlik ve güvenirlik çalışmalarının yapılmasıdır. Literatür taraması sonucunda oluşturulan 86 madde için toplam 19 uzmanın görüşüne başvurulmuştur. Uzman görüşleri sonucunda 54 maddeye düşen ölçek 11 öğrenci üzerinde uygulanmış ve onların da görüşleri alınmıştır. Taslak ölçek, geliştirilmek üzere 566 lisans öğrencisine uygulanmıştır. Öğrencilerin %59.7’si (338) kadın ve %40.3’ü (228) erkektir. Ölçekteki maddelerin faktör yükleri 0.388-0.677 arasında değişmektedir. Faktör analizi sonucunda varyansın %40.454’ünün karşılandığı söylenebilir. ELDEN ölçeğinin KMO değeri 0.892, Bartlett testi değeri 3.783E3’dür (Sd378, p0.000). Ölçeğin alt temaları; mantık yürütememe, ben merkezlilik, otoriteye inanç ve aşırı güven olarak tespit edilmiştir. Mantık yürütememe temasında 10 madde, ben merkezlilik temasında 6 madde, otoriteye inanç temasında 6 madde ve aşırı güven temasında 4 madde olmak üzere ölçekte toplam 26 madde yer almıştır. Ölçeğe eşdeğer test ve test-tekrar test uygulamaları yapılmıştır. İki yarı korelasyon katsayısı 0.74 olarak hesaplanmıştır. 566 öğrencinin vermiş olduğu cevaplar üzerinde ölçeğin bütünü için Cronbach Alpha katsayısı hesaplanmış olup sonuç 0.87 bulunmuştur. AMOS programı üzerinde yapılan doğrulayıcı faktör analizine göre, RMSEA, SRMR, GFI ve AGFI’nın sonuçları modelin güçlü bir uyum içinde olduğunu göstermektedir. Bu sonuçlardan hareketle, ELDEN ölçeğinin geçerli bir ölçek olma kriterlerini karşıladığı söylenebilir. The aim of this study is to carry out the validity and reliability studies of critical thinking barriers (CTB) scale. The opinions of a sum of 19 experts were taken for 86 items, which were formed as a result of literature survey. The number of the items in the draft scale was reduced to 54, following the expert opinions and it was implemented on 11 undergraduate students and their opinions were also taken. The draft scale was applied to 566 undergraduate students. %59.7 (338) of the subjects consisted of female students and %40.3 (228) of them was male students. The factor loads of the items in the scale ranged between 0.388-0.677. It was observed that 40.454% of the total variance was accounted for as a result of the factor analysis. The KMO value of the CTB scale was 0.892, Bartlett’s test value3.783E3 (Sd 378, p0.000). The sub factors of the scale were; inability to reason, egocentrism, reliance on authority and overconfidence. The final version of the scale, after removing the items with relatively low factor loads, consisted of a sum of 26 items; 10 items under the sub factor inability to reason, 6 items under egocentrism, 6 items under reliance on authority and 4 items under overconfidence. Equivalent test and test-retest implementations were performed for the scale. The split-half reliability coefficient was found 0.74. The Cronbach’s alpha reliability coefficient of the scale was 0.87. According to the confirmatory factor analysis made on AMOS, the RMSEA, SRMR, GFI and AGFI values demonstrated that the model had a strong consistency. Taking these results into consideration, it can be claimed that CTB scale meets the criteria of a valid scale.

3084 Background: The G protein-coupled estrogen receptor (GPER) is a broadly expressed G protein-coupled receptor that is tumor suppressive. LNS8801 is an oral, highly selective small molecule agonist of GPER. GPER activation results in c-Myc depletion, inhibition of tumor proliferation, and enhancement of tumor immune recognition. Preclinically, LNS8801 demonstrates potent single-agent and combinatorial anti-cancer activity and can overcome established resistance to standard-of-care anti-cancer therapies including immune checkpoint inhibitors. Methods: The primary objective of this phase 1/1B first-in-human, open-label, multicenter study (NCT04130516) was to determine the safety and tolerability and recommended phase 2 dose (RP2D) of LNS8801 in patients (pts) with locally advanced or metastatic solid tumor malignancies, both as monotherapy and in combination with the anti-PD-1 antibody, pembrolizumab. Dose levels were escalated in a 3+3 fashion and included 10, 40 and 125 mg dosed 3/7, 125 mg daily, and 125 and 250 mg twice daily. Dose limiting toxicity (DLT) was defined via NCI CTCAE v5.0 during the first 21 days of treatment. An increase in prolactin over the initial 12 hrs of dosing was measured to assess systemic GPER signaling. Tumor c-Myc expression was measured as a surrogate of treatment-related biologic response. Radiographic response (RECIST v1.1) was evaluated every 8 weeks until progression. Results: 33 pts (19 M/14 F) with median age 58.8 y and 4 (1-9) prior therapies enrolled. Median duration of treatment was 66 d (1–367+). With monotherapy (n = 28), no DLTs, treatment-related SAEs, or treatment-related study discontinuations were observed up through the maximum administered dose (250 mg bid). Possibly related AEs were grade 1 or 2 and did not correlate with dose level. Exposure was above that predicted for efficacy and t1/2 was ̃10 hr at all doses. Of 26 evaluable monotherapy pts, 8 (27%) experienced stable disease (SD) for up to a year. All SD pts had a prolactin response. Among tumors expressing GPER, c-Myc depletion was observed in 100% (5/5) of paired pre and on-treatment biopsies. In the combination cohort (n = 5), 2/2 evaluable pts demonstrated net tumor reductions on initial f/up scans, including one RECIST partial response. Based on PK/PD data, 125 mg daily has provisionally been identified as the monotherapy and combination RP2D. Conclusions: LNS8801 is well tolerated and demonstrates signals of anti-tumor activity when administered both as monotherapy and in combination with pembrolizumab. Confirmation of RP2Ds and updated efficacy data will be presented in June. A phase 2A expansion study to evaluate these RP2Ds in clinical settings of high unmet need is now in development. Clinical trial information: NCT04130516.

INTRODUCTION: FAT1 alterations with somatic mutations or deletions are observed in head and neck squamous cell carcinomas (HNSCC). These alterations lead to loss of function of FAT1. FAT1 loss of function was known to be associated with aberrant Wnt activation, cell migration and invasion. In this study, we present analysis and outcomes of co-mutations seen in FAT1-mutation positive HNSCC. METHODS: TCGA data were analyzed for mutation, gene expression data and overall survival. We examined mutation data in 415 HPV negative samples and 72 HPV positive samples. The Fisher's Exact test was used to determine if differences in mutation frequency existed between the different cohorts. Mantel-Cox method was used for overall survival (OS) comparison between the cohorts. RESULTS: FAT1 somatic mutation was the third most commonly mutated gene in HPV-negative HNSCC while it was not common in HPV-positive HNSCC. FAT1 mutation was seen in 25.8% of HPV negative HNSCC (107/415), while 4.2% (3/72) HPV positive HNSCC had FAT1 mutation. We then analyzed the frequency of co-mutations in FAT1-mutated HPV-negative HNSCC. CDKN2A, NOTCH1, CASP8, FBXW7, ZFHX4, HRAS, DCC, ATR mutations were more common in FAT1-mutated cancers. CASP8 mutation was seen in 24.30% (26 out of 107 samples) of FAT1-mutations positive HPV negative HNSCC, while it was less common in FAT1-mutation negative HNSCC (9.08% 28/308) (P=0.002). The patients with FAT1 and CASP8 co-mutation were associated with shorter overall survival when compared with patients with FAT1-mutation (19.8 months vs 52.3 months P=0.02). FAT1 only or CASP8 only mutation without co-mutation did not affect survival. To determine the mutation impact of the FAT1 and CASP8 mutations in HNSCC, differentially expressed genes between mutated and non-mutated genes were analyzed in HNSCC. CASP8 mutation was the top gene among the genes with somatic mutation in HNSCC and associated with gene expression changes in more than 6000 genes. FAT1 was ranked 11th resulting in differential gene expression in more than 1000 genes. DISCUSSION: FAT1 somatic mutations are commonly seen in HPV negative HNSCC. We have demonstrated for the first time that CASP8 and FAT1 co-mutations are associated with poor prognosis with decreased overall survival in HPV negative HNSCC. Both CASP8 and FAT1 mutations are among the top genes with mutation impact on differential gene expression in HNSCC suggesting significance of these mutations in HNSCC. Citation Format: Emrullah Yilmaz, David Lee, Andrew Cowan, Gregory Gan, Michelle Ozbun, Yan Guo. FAT1 and CASP8 co-mutations are associated with poor prognosis in HPV negative head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6474.

3505 Background: BXQ-350 is a first-in-class agent comprised of Saposin C (SapC) and dioleoyl phosphatidylserine (DOPS). SapC, a multifunctional lysosomal-activator glycoprotein that preferentially interacts with tumor cell phospholipids, has demonstrated anti-tumor effects in both in vitro and in vivo preclinical models. The tolerability and preliminary efficacy of BXQ-350 in the first-in-human study are summarized here. Methods: Eighty-six refractory solid tumor (ST) or high-grade glioma (HGG) patients age ≥18 (36F:50M, age 24-81) were enrolled in a 3-part first-in-human trial (NCT02859857) from 2016-2019 and received at least one dose of BXQ-350. Doses were administered via intravenous infusion during 28-day cycles until disease progression occurred. The previously reported part 1 dose escalation portion of the study (9 HGG, 9 ST patients) established the highest planned dose of 2.4mg/kg as safe but did not identify a maximum tolerated dose. The part 2 expansion cohort treated 37 patients (18 HGG and 19 ST) and an additional part 3 cohort treated 31 ST gastrointestinal (GI) patients, both at the 2.4 mg/kg dose level. Preliminary antitumor activity was evaluated (RECISTv1.1 or RANO). Results: There were no BXQ-350-related serious adverse events, dose limiting toxicities or withdrawals with the exception of 1 allergic type reaction. Three patients (Glioblastoma, Ependymoma, Appendiceal) demonstrated a partial response per RECIST/RANO. Two HGG patients with progressive radiologic enhancement were seen to have treatment effect at surgery, and hence considered to have stable disease. Seven patients (2 HGG, 3 GI, 2 other ST) remain on study and have received treatment for 9+ to 41+ months, with 5 patients treated for > 1 year. A continuing treatment protocol is planned in order to allow these patients to remain on BXQ-350 treatment. Conclusions: BXQ-350 was well tolerated with no significant dose-limiting toxicities at the highest planed dose level. Preliminary results indicate this novel agent demonstrated possible anti-tumor activity in refractory solid tumors and HGG. Clinical trial information: NCT03967093) .

TPS4671 Background: SEA-CD40 is an investigational non-fucosylated, humanized IgG1 monoclonal antibody directed against CD40, a co-stimulatory receptor expressed on antigen-presenting cells (APCs). Activation of CD40 on APCs upregulates cytokine production and co-stimulatory receptors, enhancing tumor antigen presentation to T cells. Preclinical data indicate that treatment of PDAC with chemotherapy in conjunction with a CD40 agonist could enhance antigen presentation and initiate an antitumor immune response (Byrne KT and Vonderheide RH, Cell Rep 2016;15, 2719–32). An ongoing Phase 1 study (SGNS40-001) is evaluating SEA-CD40 as monotherapy and in combination with pembrolizumab in patients with advanced solid or hematologic malignancies. A new cohort is enrolling to evaluate the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in PDAC. Methods: The cohort consists of patients with metastatic PDAC who have had no prior therapy for metastatic disease. Patients must be ≥18 years old, with (neo)adjuvant therapy completed >4 months prior to enrollment, ECOG status ≤1, adequate renal, hepatic, and hematologic function, and measurable disease per RECIST v 1.1 criteria. A standard regimen of gemcitabine and nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle is administered with SEA-CD40 IV on Day 3. Pembrolizumab is administered every 42 days starting on Day 8. The primary objective is antitumor activity; secondary objectives are safety and tolerability and SEA-CD40 and pembrolizumab pharmacokinetics. Efficacy endpoints are confirmed RECIST ORR per investigator (primary), disease control rate (response or stable disease ≥16 weeks), duration of response, PFS, and OS. Disease is assessed every 8 weeks using RECIST and immune-based RECIST (iRECIST). Treatment continues until occurrence of unacceptable toxicity, progressive disease per iRECIST, consent withdrawal, or study closure. Assessment of dose-limiting toxicity will occur initially in groups of 6 patients to identify the recommended phase 2 dose of SEA-CD40 for the cohort. Enrollment to this cohort began in November 2019. Clinical trial information: NCT02376699 .

The aim of this study is to analyse the errors of higher education students in English writing tasks. In the study, the paragraphs in the exam papers of 57 preparatory class students, studying at a state university in Turkey in 2017-2018 academic year, were analysed. The study was conducted using qualitative research method. Case study was used in the research. Document analysis was used to collect data. The collected data were analysed in line with Surface Strategy Taxonomy and errors were identified and classified. As a result of the error analysis process, it was observed that the students made a total of 381 errors on 57 exam papers; 192 of them were misformation errors, 113 were omission errors, 65 were addition errors and only 11 were misordering errors. Misformation was the most frequent error among the students with a percentage of 50.39. In addition, the percentage of omission errors was 29.66%, that of addition errors was 17.06% and misordering errors was 2.89%. The professionals teaching English as a foreign language should focus more on prepositions, verb “to be”, spelling, articles, singular/plural forms of nouns, word formation, tenses, word choice and subject-verb agreement, which were the most problematic areas of language listed under the four main categories by developing efficient instructional techniques and materials. They should also respect learners’ errors and set up a positive atmosphere where learners can easily express themselves in the target language without the fear of committing errors.INTRODUCTIONThere are lots of languages in the world and some of them have come to the fore due to the fact that they are spoken by millions and even billions of people. People generally learn the language spoken where they are born, however; the developments in the fields such as communication, transportation, tourism and trade forced people to learn the languages that they didn’t need to learn in the past. English is the most popular one of those languages and for some it is the lingua franca (Modiano, 2004; Becker and Kluge, 2014) of our age.Millions of people in the world speak English as their mother tongue while others must learn it as a second (ESL) or foreign language (EFL). Learning English as second or foreign language differs with respect to learners’ attitudes towards English and the people who speak it as their native language, exposure to English, their sources of motivation and so on. The main focus of this study is learning English as a foreign language as English is not the primary language in the country where the study was carried out.A considerable