Arqule (United States)

ABSTRACT Indigenous communities have taught their children to be in good relations with themselves, their land, and their people. These goals may diverge from the U.S. public education system, where teachers must meet Western-based state standards. To address this, an innovative professional development (PD) and coaching program called Pathways to Partnership (P2P) was developed for teachers to support their social-emotional learning (SEL). Five teachers received school-based virtual coaching. Thematic analysis of transcripts of the coaching sessions and post-coaching interviews revealed two primary themes highlighting their experiences: 1) Coaching fostered educators’ self-efficacy in supporting students’ positive behavior; and 2) Coaching enhanced educators’ personal agency in supporting Indigenous students. Implications for transformative SEL and school-based coaching are discussed.

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Las realidades educativas de los estudiantes dan cuenta de diferentes necesidades y vulnerabilidades a las que están expuestos y que a su vez influyen en su desarrollo físico, psicológico y social. Consciente de ello, el colectivo Territorio Teatral Okima Danza del Colegio Juan Evangelista Gómez pretende visibilizar aquellas problemáticas desde del proyecto “Voces Anónimas”, en el que a través de ejercicios narrativos, fundamentados en el teatro del oprimido de Augusto Boal y conjugados con la pedagogía del oprimido de Paulo Freire, logran que los estudiantes transformen sus realidades por medio de acciones escénicas de la danza y el teatro. Debido al impacto de este proyecto en su comunidad, se plantea la necesidad de realizar un análisis cuyo objetivo general es describir el impacto del arte como constructor de resiliencia. Para esto, se realizó una sistematización de la experiencia, con un enfoque de tipo fenomenológico hermenéutico, una población de diez estudiantes pertenecientes al proyecto mencionado anteriormente. Los resultados obtenidos demuestran que, a través de las acciones escénicas, se logran exteriorizar diversas problemáticas, promover la movilización de recursos personales y psicológicos fortaleciendo la autoestima y la seguridad, desarrollar la habilidad para tomar decisiones y solucionar problemas, fomentar la empatía, la creatividad y el humor; siendo todos estos factores característicos de la personalidad resiliente, que tiende a la transformación personal y social.

Abstract Background: Activating PI3K pathway mutations are common in endometrial and a subset of non-serous ovarian cancers and are frequently found in tumors that co-express the estrogen receptor (ER). We evaluated the safety and preliminary efficacy of miransertib, a potent pan-AKT inhibitor, in combination with the aromatase inhibitor (AI) anastrozole in pts with PIK3CA and AKT1-mutant ER+ endometrial and ovarian cancer. Methods: Eligible patients included endometrial and ovarian cancer patients (pts) with ER+ by immunohistochemistry and a PIK3CA or AKT1 mutation documented by local sequencing assays. There was no limit to prior lines of therapy including prior AIs. Miransertib dose was escalated according to a 3+3 design. TEAEs were assessed per CTCAE v. 4.03. Tumor responses were evaluated per RECIST 1.1. Results: A total of 11 pts (8 endometrial, 3 ovarian) were enrolled (median age 60 years). Pts were treated at one of 2 miransertib doses: 200 mg QD, 5 days on/9 days off (n=6) or 150 mg QD, 5 days on/9 days off (n=5). All pts received anastrozole 1 mg QD administered continuously. 2 DLTs observed (both at the miransertib 200mg): grade 3 ALT increase and grade 3 rash. Across all cycles, a total of 4 pts experienced a Grade 3 miransertib-related AE including rash (n=2), ALT increase (n=1), and hyperglycemia (n=1). There were no grade 4/5 miransertib-related AEs. Miransertib 150mg was selected as the recommended dose. 4 pts achieved a response (1 confirmed CR, 3 unconfirmed PRs - 1 pending confirmation, see Table). All responses (confirmed and unconfirmed) were in endometrial cancer (4/8 pts). In responding pts, mutations involved PIK3CA (n=3) and AKT1 (n=1). 50% (2/4) responding pts had received ≥1 prior line of endocrine therapy. Responses were ongoing in 2 of 4 patients, with the longest continuing at 60 weeks. Conclusions: The combination of miransertib and anastrozole demonstrated a manageable safety profile and preliminary efficacy. Responses were observed in endometrial pts with PIK3CA or AKT1 mutation and those who had received prior endocrine therapy. Enrollment at the recommended combination dose is ongoing and updated response data will be presented. *pt had PD at 24 weeks but continues for ongoing benefit at 56 weeks.Pt IDPrimary SiteHistologyGradeMutationLines of prior therapyBest RECIST response (confirmed)Duration on treatment (weeks)1EndometrialMixed endometriod/serous1PIK3CA H1047R3CR60+2EndometrialEndometriod2PIK3CA H1047R4uPR24*3EndometrialEndometriod1PIK3CA H1047R4SD124EndometrialSerous3PIK3CA R115L1PD85EndometrialEndometriod1PIK3CA E545K and H1047L2NE46OvarySerous3PIK3CA H1047R5PD77OvaryEndometriod1PIK3CA T1025S2PD88EndometrialSerous3PIK3CA N345K2uPR169OvarySerous3PIK3CA E542K5PD510EndometrialSerous3AKT1 E17K1uPR**12+11EndometrialSerous3PIK3CA C901F3PD9*pt had PD at 24 weeks but continues for ongoing benefit at 56 weeks**pending confirmation Citation Format: David Hyman, Michael Bonafede, Roisin O'Cearbhaill, Rachel Grisham, Dmitriy Zamarin, William Tew, Carol Aghajanian, Karen Cadoo, Claire Friedman, Ron E. Savage, Feng Chai, Brian Schwartz, Vicky Makker. A phase Ib study of miransertib (ARQ 092) in combination with anastrozole in patients with PIK3CA or AKT1-mutant ER+ endometrial or ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT035.

Postzygotic mutations of the PIK3CA [phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha] gene constitutively activate the PI3K/AKT/mTOR pathway in PIK3CA-related overgrowth spectrum (PROS) patients, causing congenital mosaic tissue overgrowth that even multiple surgeries cannot solve. mTOR inhibitors are empirically tested and given for compassionate use in these patients. PROS patients could be ideal candidates for enrolment in trials with PI3K/AKT pathway inhibitors, considering the “clean” cellular setting in which a unique driver, a PIK3CA mutation, is present. We aimed to assess the effects of blocking the upstream pathway of mTOR on PROS patient-derived cells by using ARQ 092, a potent, selective, allosteric, and experimental orally bioavailable and highly selective AKT-inhibitor with activity and long-term tolerability, currently under clinical development for treatment of cancer and Proteus syndrome. Cell samples (i.e., primary fibroblasts) were derived from cultured tissues obtained from six PROS patients [3 boys, 3 girls; aged 2 to 17 years] whose spectrum of PIK3A-related overgrowth included HHML [hemihyperplasia multiple lipomatosis; n = 1], CLOVES [congenital lipomatosis, overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies, scoliosis; n = 1], and MCAP [megalencephaly capillary malformation syndrome; n = 4]. We performed the following: (a) a deep sequencing assay of PI3K/AKT pathway genes in the six PROS patients’ derived cells to identify the causative mutations and (b) a pathway analysis to assess the phosphorylation status of AKT [Ser473 and Thr308] and its downstream targets [pAKTS1 (Thr246), pRPS6 (Ser235/236), and pRPS6Kβ1 (Ser371)]. The anti-proliferative effect of ARQ 092 was tested and compared to other PI3K/AKT/mTOR inhibitors [i.e., wortmannin, LY249002, and rapamycin] in the six PROS patient-derived cells. Using ARQ 092 to target AKT, a critical node connecting PI3K and mTOR pathways, we observed the following: (1) strong anti-proliferative activity [ARQ 092 at 0.5, 1, and 2.5 μM blunted phosphorylation of AKT and its downstream targets (in the presence or absence of serum) and inhibited proliferation after 72 h; rapamycin at 100 nM did not decrease AKT phosphorylation] and (2) less cytotoxicity as compared to rapamycin and wortmannin. We demonstrated the following: (a) that PROS cells are dependent on AKT; (b) the advantage of inhibiting the pathway immediately downstream of PI3K to circumventing problems depending on multiple classes a PI3K kinases; and (c) that PROS patients benefit from inhibition of AKT rather than mTOR. Clinical development of ARQ 092 in PROS patients is on going in these patients.