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Objectives Paid care provided in the home includes important support services for older adults with dementia such as cleaning and personal care assistance. By reducing unmet needs, these services could delay the transition to residential long-term care, but access may differ across racial groups. This study examined the relationship between paid care and transitioning out of the community among Black and White older adults with dementia. Methods Using data from 303 participants (29.4% Black) with probable dementia in the 2011 National Health and Aging Trends Study, competing risk hazards models estimated the association between receiving paid care at baseline and the probability of transitioning out of the community over 8 years (through 2019). Covariate selection was guided by the Andersen model of health care utilization. Results Paid care was associated with lower risk of transitioning out of the community (subhazard ratios [SHR] = 0.70, 95% CI [0.50, 0.98]). This effect was similar after controlling for predisposing factors and most prominent after controlling for enabling and need for services factors (SHR = 0.65, 95% CI [0.44, 0.95]). There was no racial difference in the use of paid care despite evidence of greater care needs in Blacks. Furthermore, Black participants were less likely to transition out of the community than Whites. Discussion Paid care services may help delay transitions out of the community. Future research should seek to explain racial differences in access to and/or preferences for home-based, community-based, and residential care.

The SWI/SNF complex is a major regulator of gene expression and is increasingly thought to play an important role in human cancer, as evidenced by the high frequency of subunit mutations across virtually all cancer types. We previously reported that in preclinical models, malignant rhabdoid tumors, which are deficient in the SWI/SNF core component INI1 (SMARCB1), are selectively killed by inhibitors of the H3K27 histone methyltransferase EZH2. Given the demonstrated antagonistic activities of the SWI/SNF complex and the EZH2-containing PRC2 complex, we investigated whether additional cancers with SWI/SNF mutations are sensitive to selective EZH2 inhibition. It has been recently reported that ovarian cancers with dual loss of the redundant SWI/SNF components SMARCA4 and SMARCA2 are characteristic of a rare rhabdoid-like subtype known as small-cell carcinoma of the ovary hypercalcemic type (SCCOHT). Here, we provide evidence that a subset of commonly used ovarian carcinoma cell lines were misdiagnosed and instead were derived from a SCCOHT tumor. We also demonstrate that tazemetostat, a potent and selective EZH2 inhibitor currently in phase II clinical trials, induces potent antiproliferative and antitumor effects in SCCOHT cell lines and xenografts deficient in both SMARCA2 and SMARCA4. These results exemplify an additional class of rhabdoid-like tumors that are dependent on EZH2 activity for survival. Mol Cancer Ther; 16(5); 850–60. ©2017 AACR.

PDF File -1 MB, Supplemental data is to further support the statements made it the main text. Captions: Supplemental Table 1: Cell Lines used in the CRISPR pooled screen. Supplemental Table 2: Table of ovarian lines screened for tazemetostat sensitivity along with mutational and protein status for SMARCA2, SMARCA4, and ARID1A. Supplemental Table 3: p-values of COV434 SCCOHT cell line treated with tazemetostat. Supplemental Table 4: p-values of JHOC-5 clear cell ovarian cell line treated with tazemetostat. Supplemental Table 5: p-values of cell cycle analysis after tazemetostat treatment. Supplemental Table 6: p-values of apoptosis analysis after tazemetostat treatment. Supplemental Table 7: LogP scores for SWI/SNF components in ovarian lines +/- tazemetostat treatment. Supplemental Figure 1: Baseline measurement of histone 3 lysine 27 trimethyl mark and EZH2. Supplemental Figure 2a: Growth curves of SCCOHT and ovarian cancer cell lines treated with tazemetostat. Supplemental Figure 2b: Growth curves of SCCOHT and ovarian cancer cell lines treated with EPZ-007210. Supplemental Figure 3: Reduction in H3K27me3 mark after treatment. Supplemental Figure 4a: Sensitivity to PLK1 knockout as pan-essential in CRISPR pooled screen. Supplemental Figure 4b: Control sgRNAs from CRISPR pooled screen. Supplemental Figure 5: TOV112D xenograft tumor growth inhibition, tumor volume, and methyl mark. Supplemental Figure 6: body weights of mice treated with tazemetostat. Supplemental Figure 7: measured blood plasma levels of tazemetostat from xenograft mice.

Education being the crux of National development, the curriculum has to be revised and revamped to suit the needs of the society. Presently, the National Education Policy 2020 is striving on the revision of all aspects of the education. The policy regards Education; in every sense is one of the fundamental factors of development as it raises people’s productivity and creativity. The National Education Policy 2020putsteachersat the centre of the fundamental reforms in theEducationsystem. Its main objective is to encourage, train and support the teachers with continuous professionaldevelopment. The policy emphasises on the teacher effectiveness and also personal attributes like empathy, altruism, passion towards profession and service mind on the part of the teachers. Thus the present study aims to find out the teacher Effectiveness and Emotional Intelligence of Secondary school teachers.120 Secondary school teachers have been selected using Random sampling method from Mandya city, Karnataka State. The major findings of the study revealed that there was no significant difference between the teacher Effectiveness of Male and Female secondary school teachers. No significant difference was found between the Emotional Intelligence of male and female secondary school teachers and a positive co-relation was found between Teacher Effectiveness and Emotional Intelligence of secondary school teachers.

We assess the heterogeneous impact of economic downturns on individuals’ decisions to bring high-technology ideas to the market in the form of new ventures. We thereby examine how worsening labor market conditions influence individuals’ opportunity costs of starting new ventures, the resulting composition of the entrepreneurial pool, and start-up performance outcomes. Using a rich data set of start-up founders in the biotechnology and medical device sectors, we find that an increase in the unemployment rate is associated with a substantial rise in the share of entrepreneurs who are most sensitive to worsening labor market conditions. Additionally, we find that start-ups founded by these entrepreneurs display lower financial and innovative performance than start-ups founded by entrepreneurs who are relatively insensitive to business cycles. Finally, we provide suggestive evidence that individuals’ heterogeneous response to worsening labor market conditions is a relevant factor in explaining the negative relationship between unemployment and start-up performance outcomes.

In this paper, we analyze how the physical layout of cities affects innovation by influencing the organization of knowledge exchange. We exploit a novel data set covering all census block groups in the contiguous United States with information on innovation outcomes, street infrastructure, as well as population and workforce characteristics. To deal with concerns of omitted variable bias, we apply commuting zone fixed effects and construct instruments based on historic city planning. The results suggest that variation in street network density may explain regional innovation differentials beyond the traditional location externalities found in the literature.

Summary Background Targeting of KIT and PDGFRA with imatinib revolutionised treatment in gastrointestinal stromal tumour; however, PDGFRA Asp842Val (D842V)-mutated gastrointestinal stromal tumour is highly resistant to tyrosine kinase inhibitors. We aimed to assess the safety, tolerability, and antitumour activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D842V, in patients with advanced gastrointestinal stromal tumours, including patients with KIT and PDGFRA D842V-mutant gastrointestinal stromal tumours (NAVIGATOR). Methods NAVIGATOR is a two-part, open-label, dose-escalation and dose-expansion, phase 1 study done at 17 sites across nine countries (Belgium, France, Germany, Poland, Netherlands, South Korea, Spain, the UK, and the USA). Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 2 or less, and with adequate end-organ function were eligible to participate. The dose-escalation part of the study included patients with unresectable gastrointestinal stromal tumours. The dose-expansion part of the study included patients with an unresectable PDGFRA D842V-mutant gastrointestinal stromal tumour regardless of previous therapy or gastrointestinal stromal tumour with other mutations that either progressed on imatinib and one or more tyrosine kinase inhibitor, or only received imatinib previously. On the basis of enrolment trends, ongoing review of study data, and evolving knowledge regarding the gastrointestinal stromal tumour treatment paradigm, it was decided by the sponsor's medical director together with the investigators that patients with PDGFRA D842V mutations would be analysed separately; the results from this group of patients is reported in this Article. Oral avapritinib was administered once daily in the dose-escalation part (starting dose of 30 mg, with increasing dose levels once daily in continuous 28-day cycles until the maximum tolerated dose or recommended phase 2 dose was determined; in the dose-expansion part, the starting dose was the maximum tolerated dose from the dose-escalation part). Primary endpoints were maximum tolerated dose, recommended phase 2 dose, and safety in the dose-escalation part, and overall response and safety in the dose-expansion part. Safety was assessed in all patients from the dose-escalation part and all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour in the dose-expansion part, and activity was assessed in all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour who received avapritinib and who had at least one target lesion and at least one post-baseline disease assessment by central radiology. This study is registered with ClinicalTrials.gov , NCT02508532 . Findings Between Oct 26, 2015, and Nov 16, 2018 (data cutoff), 46 patients were enrolled in the dose-escalation part, including 20 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour, and 36 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour were enrolled in the dose-expansion part. At data cutoff (Nov 16, 2018), 38 (46%) of 82 patients in the safety population (median follow-up of 19·1 months [IQR 9·2–25·5]) and 37 (66%) of the 56 patients in the PDGFRA D842V population (median follow-up of 15·9 months [IQR 9·2–24·9]) remained on treatment. The maximum tolerated dose was 400 mg, and the recommended phase 2 dose was 300 mg. In the safety population (patients with PDGFRA D842V-mutant gastrointestinal stromal tumour from the dose-escalation and dose-expansion parts, all doses), treatment-related grade 3–4 events occurred in 47 (57%) of 82 patients, the most common being anaemia (14 [17%]); there were no treatment-related deaths. In the PDGFRA D842V-mutant population, 49 (88%; 95% CI 76–95) of 56 patients had an overall response, with five (9%) complete responses and 44 (79%) partial responses. No dose-limiting toxicities were observed at doses of 30–400 mg per day. At 600 mg, two patients had dose-limiting toxicities (grade 2 hypertension, dermatitis acneiform, and memory impairment in patient 1, and grade 2 hyperbilirubinaemia in patient 2). Interpretation Avapritinib has a manageable safety profile and has preliminary antitumour activity in patients with advanced PDGFRA D842V-mutant gastrointestinal stromal tumours. Funding Blueprint Medicines.

Avapritinib; Tumors de l'estroma gastrointestinal; PDGFRA Avapritinib; Tumores del estroma gastrointestinal; PDGFRA Avapritinib; Gastrointestinal stromal tumours; PDGFRA Background PDGFRA D842V mutations occur in 5–10% of gastrointestinal stromal tumours (GISTs), and previously approved tyrosine kinase inhibitors (TKIs) are inactive against this mutation. Consequently, patients have a poor prognosis. We present an updated analysis of avapritinib efficacy and long-term safety in this patient population. Methods NAVIGATOR (NCT02508532), a two-part, open-label, dose-escalation/dose-expansion phase I study, enrolled adult patients with unresectable GISTs. Patients with PDGFRA D842V-mutant GIST were a prespecified subgroup within the overall safety population, which included patients who received ≥1 avapritinib dose. Primary end-points were overall response rate (ORR) and avapritinib safety profile. Secondary end-points were clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS). Overall survival (OS) was an exploratory end-point. Results Between 7 October 2015 and 9 March 2020, 250 patients enrolled in the safety population; 56 patients were included in the PDGFRA D842V population, 11 were TKI-naïve. At data cut-off, median follow-up was 27.5 months. Safety profile was comparable between the overall safety and PDGFRA D842V populations. In the PDGFRA D842V population, the most frequent adverse events were nausea (38 [68%] patients) and diarrhoea (37 [66%]), and cognitive effects occurred in 32 (57%) patients. The ORR was 91% (51/56 patients). The CBR was 98% (55/56 patients). The median DOR was 27.6 months (95% confidence interval [CI]: 17.6–not reached [NR]); median PFS was 34.0 months (95% CI: 22.9–NR). Median OS was not reached. Conclusion Targeting PDGFRA D842V-mutant GIST with avapritinib resulted in an unprecedented, durable clinical benefit, with a manageable safety profile. Avapritinib should be considered as first-line therapy for these patients. The NAVIGATOR study (NCT02508532) was supported by Blueprint Medicines Corporation, Cambridge, Massachusetts, USA.

Background Most gastrointestinal stromal tumors (GIST) driven by KIT or platelet‐derived growth factor receptor A (PDGFRA) mutations develop resistance to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two‐part, single‐arm, dose escalation and expansion study designed to evaluate safety and antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and PDGFRA, in patients with unresectable or metastatic GIST. Materials and Methods Eligible patients were 18 years or older with histologically or cytologically confirmed unresectable GIST and Eastern Cooperative Oncology Group performance status ≤2 and initiated avapritinib at 300 mg or 400 mg once daily. Primary endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg once daily and overall response rate (ORR) in patients in the safety population with three or more previous lines of TKI therapy. Results As of November 16, 2018, in the safety population (n = 204), the most common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients discontinued due to treatment‐related AEs, most frequently confusion, encephalopathy, and fatigue. ORR in response‐evaluable patients with GIST harboring KIT or non‐D842V PDGFRA mutations and with at least three prior therapies (n = 103) was 17% (95% confidence interval [CI], 10–25). Median duration of response was 10.2 months (95% CI, 7.2–10.2), and median progression‐free survival was 3.7 months (95% CI, 2.8–4.6). Conclusion Avapritinib has manageable toxicity with meaningful clinical activity as fourth‐line or later treatment in some patients with GIST with KIT or PDGFRA mutations. Implications for Practice In the NAVIGATOR trial, avapritinib, an inhibitor of KIT and platelet‐derived growth factor receptor A tyrosine kinases, provided durable responses in a proportion of patients with advanced gastrointestinal stromal tumors (GIST) who had received three or more prior therapies. Avapritinib had a tolerable safety profile, with cognitive adverse events manageable with dose interruptions and modification in most cases. These findings indicate that avapritinib can elicit durable treatment responses in some patients with heavily pretreated GIST, for whom limited treatment options exist., This article presents safety and efficacy findings of the phase I NAVIGATOR trial of avapritinib in patients with metastatic or unresectable KIT‐ or PDGFRA‐ mutant gastrointestinal stromal tumors with the efficacy analysis focused on patients who had previously received a minimum of three prior lines of therapy.

We study the participation of nascent firms in open-source communities and its implications for attracting funding. To do so, we exploit unique data on 160,065 US startups linking information from Crunchbase to firms’ GitHub accounts. Estimating a within-startup model saturated with fixed effects, we show that startups accelerate their activities on the platform in the twelve months prior to raising their first financing round. The intensity of their involvement on GitHub declines in the twelve months after. Startups intensify those activities that rely on external technology sources above and beyond the technologies they themselves control. Exploiting a shock that reduced the relative cost of internal collaborations we provide evidence that startups' decision to integrate external sources of knowledge in their production function hinges on the relative cost vis-a-vis internal collaboration. Applying machine learning to classify GitHub projects, we further unveil that the most prevalent among these external activities are related to software development, data analytics, and integration. Our results indicate that VCs and renowned investors are the most responsive to these activities.

PURPOSE Primary or secondary mutations in KIT or platelet-derived growth factor receptor alpha ( PDGFRA) underlie tyrosine kinase inhibitor resistance in most GI stromal tumors (GISTs). Avapritinib selectively and potently inhibits KIT- and PDGFRA-mutant kinases. In the phase I NAVIGATOR study ( NCT02508532 ), avapritinib showed clinical activity against PDGFRA D842V–mutant and later-line KIT-mutant GIST. VOYAGER ( NCT03465722 ), a phase III study, evaluated efficacy and safety of avapritinib versus regorafenib as third-line or later treatment in patients with unresectable or metastatic GIST. PATIENTS AND METHODS VOYAGER randomly assigned patients 1:1 to avapritinib 300 mg once daily (4 weeks continuously) or regorafenib 160 mg once daily (3 weeks on and 1 week off). Primary end point was progression-free survival (PFS) by central radiology per RECIST version 1.1 modified for GIST. Secondary end points included objective response rate, overall survival, safety, disease control rate, and duration of response. Regorafenib to avapritinib crossover was permitted upon centrally confirmed disease progression. RESULTS Four hundred seventy-six patients were randomly assigned (avapritinib, n = 240; regorafenib, n = 236). Median PFS was not statistically different between avapritinib and regorafenib (hazard ratio, 1.25; 95% CI, 0.99 to 1.57; 4.2 v 5.6 months; P = .055). Overall survival data were immature at cutoff. Objective response rates were 17.1% and 7.2%, with durations of responses of 7.6 and 9.4 months for avapritinib and regorafenib; disease control rates were 41.7% (95% CI, 35.4 to 48.2) and 46.2% (95% CI, 39.7 to 52.8). Treatment-related adverse events (any grade, grade ≥ 3) were similar for avapritinib (92.5% and 55.2%) and regorafenib (96.2% and 57.7%). CONCLUSION Primary end point was not met. There was no significant difference in median PFS between avapritinib and regorafenib in patients with molecularly unselected, late-line GIST.

Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma, with approximately 5,000 patients diagnosed per year in the US. Approximately 80% of patients with GIST present with mutations in the c-KIT oncogene at exon 9 or 11, which leads to constitutive, ligand-independent activation of the KIT receptor tyrosine kinase. For patients with metastatic GIST, frontline therapy with imatinib is effective, with a response rate of approximately 51-54% and median progression-free survival (PFS) of 19-23 months, in a molecularly unselected population. Other agents are approved for advanced GIST, without molecular selection, after progression on imatinib, including sunitinib, regorafenib, and ripretinib; however, response rates are less than 10% with PFS of approximately 5-6 months. Notably, patients who progress on imatinib and other tyrosine kinase inhibitors may develop a variety of on-target resistance mutations in the KIT oncogene, such as those in exon 17 (including at amino acids D816 and D820, activation loop mutation), exon 13 (V654A, ATP-binding region mutation), and less frequently in exon 14 (T670I, gatekeeper mutation). Several KIT inhibitors have been developed to potently target the exon 17 resistance mutations (avapritinib and ripretinib); however, there remains an important medical need in 2nd- and 3rd-line therapy in a molecularly unselected population of imatinib-resistant GIST. This suggests more broad-spectrum KIT inhibition is likely required, a hypothesis supported by the observation of large inter- and intra-patient heterogeneity of KIT secondary mutations across hundreds of samples obtained from patients with GIST treated with avapritinib. Sequencing data from the NAVIGATOR phase 1 trial (NCT02508532) revealed that patients with KIT mutant GIST and with the KIT V654A secondary resistance mutation had a poor response to treatment with avapritinib. To address this, we developed a highly potent and selective inhibitor of KIT V654A. This inhibitor showed dose-dependent modulation of downstream pharmacodynamic markers and induced tumor regression in a mastocytoma xenograft model driven by an exon 11 plus 13 V654A resistance mutation. Importantly, this inhibitor was generally well-tolerated and showed high selectivity over wild-type KIT. These findings suggest this novel KIT inhibitor has the potential to be used as a single agent or combination therapy for patients with imatinib-resistant GIST harboring the KIT V654A mutation. Citation Format: Alexandra R. Grassian, Joseph Kim, Omar Ahmad, Kevin Barvian, Alison Davis, Tom Dineen, Wei Hu, Ebby Job, Ludivine Moine, Kate Newberry, Maria Roche, Doug Shorten, Yeon Sook Choi, Francis Wolenski, Sebastian Bauer, Cesar Serrano, Jonathan Trent, Suzanne George. Efficacy of a highly potent and selective KIT V654A inhibitor for treatment of imatinib resistant GIST [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB565.

Objectives: Paid care provided in the home or through community organizations includes important support services for older adults with dementia such as cleaning and personal care assistance. These services could delay the transition to long-term care, but access may differ across sociodemographic groups. This study examined the relationship between paid care and transitioning out of the community among diverse older adults with dementia. Methods: Using data from 303 participants (29.4% Black) with probable dementia in the National Health and Aging Trends Study (2011-2019), subdistribution hazard models estimated the association between receiving paid care at baseline and the probability of transitioning out of the community over the next eight years. Covariate selection was guided by the Andersen model of healthcare utilization. Results: Paid care was associated with lower risk of transitioning out of the community (SHR = 0.70, 95% CI [0.50, 0.98]). This effect was similar after controlling for predisposing factors and most prominent after controlling for enabling and need for services factors (SHR = 0.63, 95% CI [0.42, 0.94]) and was only evident among Whites. There were no racial differences in the use of paid care, but Black participants were less likely to transition out of the community than Whites despite evidencing greater care needs. Discussion: Paid care services may help delay transitions out of the community. Future research should seek to explain racial differences in access to and/or preferences for home-based, community-based, and residential care.

Purpose: The selective tyrosine kinase inhibitor avapritinib has been shown to improve skin lesions in pts with ISM (Hartmann K et al. EACCI 2020. Abstract 1832). We assessed numbers and immunophenotypic changes of MCs in bone marrow (BM) and skin biopsies from lesional tissue (LT) and non-lesional tissue (NLT) in 39 pts with ISM from Part 1 of the placebo-controlled PIONEER (NCT03731260) study. Methods: BM biopsies and aspirates were obtained at Screening; skin biopsies from LT and NLT were obtained at Screening and end of Week 12 (W12). Immunohistochemistry was performed on formalin-fixed sections using the Ventana Benchmark assay with CD117, tryptase, CD25, CD30, and CD34 antibodies. Samples were centrally reviewed by three pathologists. Statistical significance of MC numbers and immunophenotypic changes were assessed. Data cut-off was December 4, 2020. Results: Screening BM biopsies had median 10% (range, 1-60%) MCs, of which 90% (10-100%) were spindled. BM aspirates had median 1% (0-10%) MCs, of which 5% (2-6%) were immature. Median number of MCs/mm2 was 355 (53-4300) in LT and 90 (10-540) in NLT. At W12, avapritinib reduced median number of MCs/mm2 in LT (143 [33-837]) but not NLT (102 [32-207]). BM biopsies had higher median rates of CD25+ and CD30+ MCs (90% CD25+/50% CD30+) compared with skin LT (2% CD25+/10% CD30+) and NLT (1% CD25+/1% CD30+) (Table). Avapritinib produced significant reductions in the proportion of CD30+ MCs in LT at W12 versus placebo (P=0.0053) and non-significant reductions in CD30+ MCs in NLT (P=0.0988). Conclusions: CD25+ and CD30+ MCs were observed in both LT and NLT skin biopsies; however, at markedly lower levels than seen in BM. Treatment with avapritinib decreased the total number of MCs as well as the number of CD30+ and CD25+ MC in both LT and NLT with statistically significant decreases in the CD30+ MC fraction in LT. This is the first study to examine changes in MCs in LT and NLT or ISM during precision therapy of ISM. Table. Immunophenotypic changes of MCs in BM and skin biopsies at screening and W12MC PhenotypeBone MarrowSkin Lesional TissueSkin Non-Lesional TissueAvapritinibPlaceboAvapritinibPlaceboScreening (n=39)Screening (n=25)W12 (n=17)Screening (n=8)W12 (n=7)Screening (n=25)W12 (n=21)Screening (n=8)W12 (n=7)CD25+, median % (range)90 (0-100)2 (1-40)2 (1-10)3 (1-50)5 (2-5)1 (1-5)2 (1-10)2 (1-5)5 (2-5)CD30+, median % (range)50 (0-100)10 (1-100)1 (1-5)13 (1-80)5 (1-30)1 (1-20)1 (1-2)2 (1-30)1 (1-10)Abbreviations: BM, bone marrow; MC, mast cell; W12, Week 12. Citation Format: Tracy George, Sigurd Broesby-Olsen, David Wada, Scott Florell, Karin Hartman, Frank Siebenhaar, Cem Akin, Kate Newberry, Hongliang Shi, Maria Roche, Marcus Maurer, Hanneke Oude Elberink. Changes in mast cell (MC) numbers and phenotype in patients (pts) with indolent systemic mastocytosis (ISM) treated with avapritinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT168.

The SWI/SNF complex is a major regulator of gene expression and is increasingly thought to play an important role in human cancer, as evidenced by the high frequency of subunit mutations across virtually all cancer types. We previously reported that in preclinical models, malignant rhabdoid tumors, which are deficient in the SWI/SNF core component INI1 (SMARCB1), are selectively killed by inhibitors of the H3K27 histone methyltransferase EZH2. Given the demonstrated antagonistic activities of the SWI/SNF complex and the EZH2-containing PRC2 complex, we investigated whether additional cancers with SWI/SNF mutations are sensitive to selective EZH2 inhibition. It has been recently reported that ovarian cancers with dual loss of the redundant SWI/SNF components SMARCA4 and SMARCA2 are characteristic of a rare rhabdoid-like subtype known as small-cell carcinoma of the ovary hypercalcemic type (SCCOHT). Here, we provide evidence that a subset of commonly used ovarian carcinoma cell lines were misdiagnosed and instead were derived from a SCCOHT tumor. We also demonstrate that tazemetostat, a potent and selective EZH2 inhibitor currently in phase II clinical trials, induces potent antiproliferative and antitumor effects in SCCOHT cell lines and xenografts deficient in both SMARCA2 and SMARCA4. These results exemplify an additional class of rhabdoid-like tumors that are dependent on EZH2 activity for survival. Mol Cancer Ther; 16(5); 850–60. ©2017 AACR.

Introduction: Systemic mastocytosis (SM) is a rare clonal mast cell (MC) neoplasm characterized by MC accumulation and is primarily driven by the KIT D816V mutation. The D816V mutation is located in the activation loop of the KIT receptor tyrosine kinase resulting in constitutive activation of the receptor, causing aberrant MC proliferation and hyperactivation. MC mediator release can lead to severe clinical manifestations including skin, gastrointestinal, neurocognitive, skeletal, and systemic symptoms. Indolent SM is the most common subtype of SM; abnormal activation of mast cells leads to debilitating symptoms, poor quality of life, and has life-threatening consequences such as anaphylaxis. Although symptomatic treatments are used to control symptom severity (eg, cromolyn sodium, antihistamines, leukotriene inhibitors, omalizumab), there are no approved disease-modifying therapies to reduce MC burden and activation. Avapritinib is a potent, selective tyrosine kinase inhibitor that targets the KIT D816V mutant. Avapritinib has shown good tolerability in toxicology and safety pharmacology studies when assessed at active doses. PIONEER (NCT03731260) is an international, multicenter, randomized, double-blind, placebo-controlled, phase 2 study investigating the safety and efficacy of avapritinib in patients with indolent SM and symptoms inadequately controlled by best supportive care (BSC). PIONEER Part 1 assessed the safety and pharmacokinetics of avapritinib and identified the recommended phase 2 dose of 25 mg once daily in 4-weekly cycles. PIONEER Part 2 will assess the safety and efficacy of 25 mg avapritinib once daily versus placebo with BSC in patients with indolent SM whose symptoms are not adequately controlled by BSC. Study design and methods: PIONEER Part 2 will enroll approximately 204 patients with indolent SM who will be randomized 2:1 to avapritinib plus BSC (25 mg once daily; n=136) or matched placebo plus BSC (n=68), stratified by baseline serum tryptase level (97% power to detect superiority of avapritinib compared with placebo using a 2-sample Fisher Exact test, with a 1-sided type I error rate of 0.025, for the primary endpoint at Week 24. PIONEER Part 2 will enroll patients at sites in the USA, Canada, and Europe. Patients who complete PIONEER Part 1 or Part 2 will be eligible to enter an open-label extension to evaluate long-term safety and efficacy of avapritinib 25 mg once daily. Disclosures Akin: Novartis: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding. Elberink:Novartis: Research Funding; Blueprint Medicines Corporation: Membership on an entity's Board of Directors or advisory committees. Gotlib:Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding. Sabato:Blueprint Medicines Corporation: Other: My institution received research funding. Hartmann:Allergopharma: Consultancy, Honoraria, Other: reimbursement of travel expenses , Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Other: reimbursement of travel expenses , Research Funding; Deciphera: Consultancy, Honoraria, Other: reimbursement of travel expenses , Research Funding; Menarini: Honoraria, Other: reimbursement of travel expenses , Research Funding; Novartis: Consultancy, Honoraria, Other: reimbursement of travel expenses , Research Funding; Takeda: Consultancy, Honoraria, Other: reimbursement of travel expenses , Research Funding; Euroimmun: Honoraria, Other: reimbursement of travel expenses , Research Funding; Thermofisher: Other: reimbursement of travel expenses , Research Funding; ALK-ABello: Consultancy, Honoraria, Other: reimbursement of travel expenses , Research Funding. Broesby-Olsen:Thermo Fisher: Honoraria; Novartis: Honoraria; Blueprint Medicines Corporation: Honoraria, Other: study steering committee member. Castells:Annals of Allergy, Asthma & Immunology: Other: Editorial Board; Blueprint Medicines Corporation: Consultancy, Other: Clinical trials: Principle Investigator; UpToDate: Other: Author fee. Heaney:Partner Therapeutics: Consultancy; AbbVie: Consultancy; Sierra Oncology: Research Funding; Novartis: Consultancy, Research Funding; Incyte: Research Funding; Deciphera: Research Funding; CTI Biopharma: Consultancy, Research Funding; BMS: Research Funding; Blueprint Medicines Corporation: Research Funding. George:Celgene: Consultancy; Deciphera: Other: consultancy, but has received no financial compensation for the past 12 months; Blueprint Medicines Corporation: Consultancy, Other: I have received no funding for this research. ARUP Laboratories, owned by the University of Utah, has received funding; Allakos: Consultancy. Siebenhaar:Hyphens: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Pediapharm: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Aralez: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; SunPharma: Other; Moxie: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Allakos: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Novartis: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Sanofi: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Glenmark: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Uriach: Other; Biocryst: Other: received honoraria (advisory board, speaker) and/or institutional grant/research support ; Blueprint Medicines Corporation: Honoraria, Research Funding. Radia:Blueprint Medicines Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Education events. Triggiani:Deciphera: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines Corporation: Membership on an entity's Board of Directors or advisory committees. DeAngelo:Abbvie: Research Funding; Jazz: Consultancy; Incyte Corporation: Consultancy; Forty-Seven: Consultancy; Pfizer: Consultancy; Shire: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Glycomimetics: Research Funding; Novartis: Consultancy, Research Funding; Autolos: Consultancy; Agios: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding. Reiter:Gilead: Other: travel support ; Incyte: Consultancy, Other: travel support ; AOP: Consultancy, Other: travel support ; Celgene,: Consultancy, Other: travel support ; Abbvie: Consultancy, Other: travel support ; Deciphera: Consultancy, Other: travel support ; Blueprint: Consultancy, Other: travel support ; Novartis: Consultancy, Honoraria, Other: travel support , Research Funding. Hew:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Lin:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Roche:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company; Epizyme: Other: outside the submitted work. Maurer:Novartis: Honoraria, Other; Regeneron: Honoraria, Other; UCB: Honoraria, Other; ThirdHarmonicBio: Honoraria, Other; Sanofi: Honoraria, Other; Roche: Honoraria, Other; FAES: Honoraria, Other: institutional grant/research support; Dr. Pfleger: Honoraria, Other: institutional grant/research support; Blueprint Medicines Corporation: Honoraria, Other: institutional grant/research support; Bayer: Honoraria, Other: institutional grant/research support; AstraZeneca: Honoraria, Other: institutional grant/research support; Amgen: Honoraria, Other: institutional grant/research support; Allakos: Honoraria, Other: institutional grant/research support; Moxie: Honoraria, Other; Merckle Recordati: Honoraria, Other; Uriach: Honoraria, Other; CellDex: Honoraria, Other; GIInnovation: Honoraria, Other; Lilly: Honoraria, Other; Kyowa Kirin: Honoraria, Other; Innate Pharma: Honoraria, Other: institutional grant/research support; GSK: Honoraria, Other: institutional grant/research support; Genentech: Honoraria, Other: institutional grant/research support.

Poster-Abstract

Review papers provide a foundation for knowledge development in information systems (IS) as well as in any other scientific discipline. While some of the prominent reviews in information systems are cited more than twice a day on average, others take years to accumulate single digit citations. The magnitude of these differences and the proliferation of review papers in recent years prompt us to empirically analyze what distinguishes those reviews that have proven to be integral to scientific progress from those that might not be considered impactful. Our results demonstrate that the attributes explaining scientific impact are unique for the different types of reviews: reviews for describing, understanding, explaining, and theory testing. Transparency of the applied methodology is important for reviews that target theory testing, understanding, or explaining; similarly, reviews for describing, understanding or explaining achieve a higher impact when they develop a research agenda. By providing nuanced insights into the attributes of review papers that are valued by subsequent research, our study contributes to the vibrant discourse on literature reviews in IS. We thereby inform the different stakeholders involved in the development and publication of review papers in the IS field.

What role do differences in founders' occupational backgrounds play in new venture performance? Analyzing a novel dataset of 2998 founders creating 1723 innovative startups in biomedicine, we find that the likelihood and hazard of achieving a liquidity event are lower for academic than for non-academic startups. However, academic startups produce as many patents and receive as much funding as non-academic startups, suggesting that the observed differences in achieving a liquidity event are not driven by differential invention performance. Exploiting heterogeneity among academic startups, we also find that differences between professor and student startups do not explain academic startups' comparatively low performance on the exit market vis-a-vis non-academic startups. Yet, startups founded by superstar professors perform similarly to non-academic startups on the exit market for new ventures, and better than startups founded by highly productive professors but without external certification.

This paper examines the impact of exposure to an advisor engaged in entrepreneurship on the innovative output of their advisees. Using a unique sample of advisors and advisees in computer sciences ...

826 Background: Targeting oncogenic KIT and PDGFRA mutations revolutionized treatment of patients (pts) with advanced GIST; however, nearly all pts succumb to resistant disease. Avapritinib is a potent and selective kinase inhibitor with broad activity against oncogenic KIT/PDGFRA mutants, including PDGFRA D842V and other primary or secondary resistance mutations. Results from the phase 1 NAVIGATOR (NCT02508532) study of avapritinib in pts with advanced GIST are presented. Methods: Adult pts with unresectable PDGFRA D842V or other mutant GIST who progressed on imatinib and ≥1 other tyrosine kinase inhibitor (TKI) were treated with oral, daily, continuous avapritinib. Adverse events (AE) and response by mRECIST 1.1 per central radiology were assessed. Overall population safety (30-600 mg starting doses) and efficacy in the response-evaluable 4L+ and PDGFRA Exon 18 (Ex 18) populations treated at the MTD (400 mg)/RP2D (300 mg) were analyzed. Results: As of 16 Nov 2018, 237 pts [172 KIT, 62 PDGFRA Ex 18 [56 D842V, 6 non-D842V), 2 PDGFRA N659K, 1 missing] were enrolled including 111 in the 4L+ population (primarily KIT, median 4 prior TKI) and 43 in the Ex 18 population (median 1 prior TKI). The 4L+ ORR was 22% [1 CR, 23 PR (1 pending)], and 52 SD with mDOR of 10.2 months (95% CI: 7.2–NE). The Ex 18 ORR was 86% [3 CR, 34 PR (1 pending)] and 5 SD; mDOR was not reached (95% CI: 11.3–NE). Most AEs were grade 1–2, most commonly nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (most common cognitive AE, 29%). 10% of pts discontinued due to a related AE. Grade 3–4 related AE ≥ 2% were anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia, and diarrhea. Conclusions: Avapritinib has important clinical activity in pts with advanced GIST who have no effective therapies. The ORR and DOR of avapritinib in 4L+ exceeds that of approved 2nd and 3rd line therapies and shows impressive activity in D842V and other Ex 18 mutant PDGFRA GIST. Results suggest avapritinib has the potential to change the treatment paradigm of pts with advanced GIST. Clinical trial information: NCT02508532.

Background Intraperitoneal (IP) chemotherapy can improve outcomes for women with optimally cytoreduced epithelial ovarian cancer but toxicities are a concern. We conducted 2 phase 2 trials of an IV/IP regimen using carboplatin and paclitaxel without (Trial A) and with bevacizumab (Trial B). Methods Both trials consisted of carboplatin AUC 6 day 1, and paclitaxel 60 mg/m2 on days 1,8, 15 of a 21-day cycle; in Trial B, patients received IV bevacizumab 15 mg/kg every cycle starting cycle 2. Chemotherapy was administered IV for cycle 1 and then IP for all subsequent cycles. Primary objectives included safety and tolerability, pathologic CR rate (Trial A), and the rate of completion of IP cycles of therapy (Trial B). Progression-free (PFS), overall survival (OS), and pharmacokinetic analysis were secondary endpoints. Results 81 patients were treated on both trials (n = 40 and 41 in trials A and B, respectively). Median age for trials A and B was 59 (range, 36–76) and 55 (range, 19–69) years, respectively. 68% and 85% of patients, respectively for A and B, completed at least 4 cycles of treatment in both trials. Treatment with bevacizumab resulted in higher rates of grade 3 fatigue (37 versus 33%) and grade 3–4 diarrhea (22 versus 8%). Median PFS was 23.5 (95%CI 16.2–35.3) and 25 (95%CI 16.4–42.7) months, respectively; median OS was 68 (95%CI 49.5-NR) and 79.7 (95%CI 59.0–79.7) months, respectively for Trial A and B. Conclusions Weekly administered IP carboplatin and IP paclitaxel is tolerable and safe with similar activity with and without concommittant bevacizumab in these 2 trials.

We assess the heterogeneous impact of economic downturns on individuals’ decisions to bring high-technology ideas to the market in the form of new ventures. We thereby examine how worsening labor market conditions influence individuals’ opportunity costs of starting new ventures, the resulting composition of the entrepreneurial pool, and startup performance outcomes. Using a rich dataset of startup founders in the biotechnology and medical device sectors, we find that an increase in the unemployment rate is associated with a substantial rise in the share of entrepreneurs who are most sensitive to worsening labor market conditions. Additionally, we find that startups founded by these entrepreneurs display lower financial and innovative performance than startups founded by entrepreneurs who are relatively insensitive to business cycles. Finally, we provide suggestive evidence that individuals’ heterogeneous response to worsening labor market conditions is a relevant factor in explaining the negative relationship between unemployment and startup performance outcomes. Previously circulated as: When Push Comes to Shove: External Conditions, Opportunity Costs, and Startup Outcomes

Rho-associated kinase 2 (ROCK2) regulates the secretion of proinflammatory cytokines and the development of autoimmunity in mice. Data from a phase 1 clinical trial demonstrate that oral administration of KD025, a selective ROCK2 inhibitor, to healthy human subjects down-regulates the ability of T cells to secrete IL-21 and IL-17 by 90% and 60%, respectively, but not IFN-γ in response to T-cell receptor stimulation in vitro. Pharmacological inhibition with KD025 or siRNA-mediated inhibition of ROCK2, but not ROCK1, significantly diminished STAT3 phosphorylation and binding to IL-17 and IL-21 promoters and reduced IFN regulatory factor 4 and nuclear hormone RAR-related orphan receptor γt protein levels in T cells derived from healthy subjects or rheumatoid arthritis patients. Simultaneously, treatment with KD025 also promotes the suppressive function of regulatory T cells through up-regulation of STAT5 phosphorylation and positive regulation of forkhead box p3 expression. The administration of KD025 in vivo down-regulates the progression of collagen-induced arthritis in mice via targeting of the Th17-mediated pathway. Thus, ROCK2 signaling appears to be instrumental in regulating the balance between proinflammatory and regulatory T-cell subsets. Targeting of ROCK2 in man may therefore restore disrupted immune homeostasis and have a role in the treatment of autoimmunity.

11022 Background: Targeting oncogenic KIT and PDGFRA mutations revolutionized treatment of patients (pts) with advanced GIST; however, nearly all pts succumb to resistant disease. Avapritinib is a potent and selective kinase inhibitor with broad activity against oncogenic KIT/PDGFRA mutants, including PDGFRA D842V and other primary or secondary resistance mutations. Updated results from the phase 1 NAVIGATOR (NCT02508532) study of avapritinib in pts with advanced GIST are presented. Methods: Adult pts with unresectable PDGFRA D842V or other mutant GIST who progressed on imatinib and ≥ 1 other tyrosine kinase inhibitor (TKI) were treated with oral, daily, continuous avapritinib. Adverse events (AE) and response by mRECIST 1.1 per central radiology were assessed. Safety from the overall population (30-600 mg doses) and efficacy in the response evaluable 4L+ and PDGFRA Exon 18 (Ex 18) populations treated at the MTD (400 mg)/RP2D (300 mg) were analyzed. Results: As of 16 Nov 2018, 237 pts [172 KIT, 62 PDGFRA Ex 18 (56 D842V, 6 non-D842V), 2 PDGFRA N659K, 1 missing] were enrolled including 111 in the 4L+ population (primarily KIT, median 4 prior TKI) and 43 in the Ex 18 population (median 1 prior TKI). The 4L+ ORR was 22% [1 CR, 23 PR (1 pending)], and 52 SD with median duration of response (mDOR) of 10.2 months (95% CI: 7.2-NE). The Ex 18 ORR was 86% [3 CR, 34 PR (1 pending)] and 5 SD; mDOR was not reached (95% CI: 11.3-NE). Most AE were grade 1-2, most commonly nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (most common cognitive AE, 29%). 10% of pts discontinued due to a related AE. Grade 3-4 related AE ≥ 2% were anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia, and diarrhea. Conclusions: Avapritinib has important clinical activity in pts with advanced GIST who have no effective therapies. The ORR and DOR of avapritinib in 4L+ exceeds that of approved 2nd and 3rd line therapies and shows unprecedented activity in D842V and other Ex 18 mutant PDGFRA GIST. Results suggest avapritinib has the potential to change the treatment paradigm of pts with advanced GIST. Clinical trial information: NCT02508532.

Objective Ovarian cancer is a highly angiogenic tumor and a model for antiangiogenic research. The tyrosine kinase receptor inhibitors target several receptors allowing for the pharmacological disruption of several independent pathways. Sunitinib malate® is a multitargeted tyrosine kinase inhibitor. A phase II study utilizing a modified dosing schedule was conducted to assess the efficacy and safety of Sunitinib® in recurrent ovarian, fallopian tube and peritoneal carcinoma. Methods A nonrandomized phase II study was modeled as a two-stage Simon design initially enrolling 17 evaluable participants in stage one and 18 patients in stage two. Patients received the study drug at 37.5mg every day over a 28day treatment cycle until clinical or radiological evidence of progressive disease. Disease was evaluated radiographically and best overall response was defined using the RECIST 1.0 criteria. The primary objective of this study was to define the response rate (defined as complete response and partial response) while the secondary objectives included both the progression free rate as well as the safety of this agent in this patient population. Results The response rate (PR+CR) was 8.3% (95% confidence interval: 1.8%, 22.5%). The 16-week and 24week progression-free survival estimate was 36% (95% confidence interval and 19.2%), respectively. The median progression-free survival estimate was 9.9weeks. Hypertension and gastrointestional events were the most common toxicities noted. Conclusions A modest response rate of 8.3% was achieved with Sunitinib malate®. This phase II study adds to the body of literature of VEGFR inhibitors and further underscores the need of defining a genetic angiogenic signature.

The SWI/SNF complex is a major regulator of gene expression and is increasingly thought to play an important role in human cancer, as evidenced by the high frequency of subunit mutations across virtually all cancer types. We previously reported that in preclinical models, malignant rhabdoid tumors, which are deficient in the SWI/SNF core component INI1 (SMARCB1), are selectively killed by inhibitors of the H3K27 histone methyltransferase EZH2. Given the demonstrated antagonistic activities of the SWI/SNF complex and the EZH2-containing PRC2 complex, we investigated whether additional cancers with SWI/SNF mutations are sensitive to selective EZH2 inhibition. It has been recently reported that ovarian cancers with dual loss of the redundant SWI/SNF components SMARCA4 and SMARCA2 are characteristic of a rare rhabdoid-like subtype known as small-cell carcinoma of the ovary hypercalcemic type (SCCOHT). Here, we provide evidence that a subset of commonly used ovarian carcinoma cell lines were misdiagnosed and instead were derived from a SCCOHT tumor. We also demonstrate that tazemetostat, a potent and selective EZH2 inhibitor currently in phase II clinical trials, induces potent antiproliferative and antitumor effects in SCCOHT cell lines and xenografts deficient in both SMARCA2 and SMARCA4. These results exemplify an additional class of rhabdoid-like tumors that are dependent on EZH2 activity for survival.