Citations

Abstract Background: Aurora-A (AURKA) belongs to the family of serine-threonine kinases that are crucial for cell cycle control. In particular, AURKA controls centrosome function, mitotic spindle formation, and proper chromosome segregation. In contrast to the well-defined function of AURKA in normal cells, the role of AURKA in malignant transformation and cancer progression is still under investigation. Here, we report that AURKA directly interacts with MEK1/2 kinase and induces chemotaxis of breast cancer cells. Results: We demonstrated that overexpression of AURKA in luminal ER+ MCF-7 cells (MCF-7AURKA) resulted in over 10-fold increase in the number of cells displaying chemotactic response upon stimulation with growth factors when compared to parental MCF-7 cells. Both AURKA inhibitor MLN8237 and MEK1/2 inhibitor PD0325901 reduced migratory properties of MCF-7AURKA cells. In contrast, treatment with the pan RAF inhibitor TAK-632 did not affect chemotactic response of MCF-7AURKA cells. We demonstrated colocalization of AURKA and MEK1/2 immunofluorescence signals in MCF-7AURKA and triple-negative BT549 cells. In situ proximity ligation assay (PLA) revealed the presence of AURKA-MEK1/2 complexes in MCF-7AURKA and BT549 cells, and the notion that AURKA and MEK1/2 formed cellular complexes was confirmed with co-immunoprecipitation experiments. In vitro kinase assays with recombinant AURKA and MEK1 proteins showed that AURKA kinase could directly phosphorylate MEK1. Incubation of MCF-7AURKA and BT549 cells with the AURKA-specific inhibitors MLN8237 or MK8745 resulted in over a 2-fold increase in the level of pERK1/2 compared to the untreated controls. Treatment with the pan RAF inhibitor TAK-632 did not diminish MLN8237-induced pERK1/2, whereas treatment with the MEK1/2 specific inhibitor PD0325901 completely abrogated MLN8237-induced activation of ERK1/2. Conclusions: Our data present a novel AURKA-MEK1/2 interaction that contributes to the increased chemotaxis of breast cancer cells. The results suggest that AURKA negatively regulates MEK1 through a novel, direct phosphorylation event, possibly leading to constitutive activation of MEK2 and increased chemotaxis. The combined treatment of AURKA and MEK1/2 inhibitors represents a new therapeutic approach to decrease metastatic potential of breast cancer cells and delay tumor progression. The in-depth analysis of the AURKA-MEK1/2 complexes as well as in vivo studies testing the efficacy of combining AURKA and MEK1/2 inhibitors on patient-derived xenografts are currently in progress. Citation Format: Malgorzata Gil, Archana Chidambaram, Thaer Khoury, Kazuaki Takabe, Igor Puzanov, Irwin H. Gelman, Antonino B. D’Assoro, Evanthia Galanis, Mateusz Opyrchal. AURKA interaction with MEK1/2 complex and its role in promoting breast cancer cell metastasis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A60.

Abstract Background Sexual dysfunction is often complex and biopsychosocial. Traditional sexual health care management involves individual providers not in a multi-disciplinary setting. A multi-disciplinary team may consist of a medical provider, pelvic floor physical therapist, and sex therapist. Aim The aim was to explore the patient perceptions of benefit from management of their sexual dysfunction by a biopsychosocial multi-disciplinary team. Methods A survey was e-mailed to women patients seen by multi-disciplinary teams at 2 different settings: San Diego Sexual Medicine or Mayo Clinic Women's Health Clinic during a 27-month period. Data are reported using summary statistics for age and count for remaining survey responses. Cochran-Armitage tests for trend were used to compare pre- and post-comfort levels. Outcomes Main outcome measures included perceived benefit of being managed in a team-based model of care, level of benefit and satisfaction from each provider, and difference from pre-conceived level of comfort to actual comfort after each provider visit. Results 89 of 270 e-mailed surveys were analyzed. Patient populations (mean age 47.6, range 23–77 years) were similar between sites. Overall, 82% of respondents reported moderate/great benefit from the team-based model; 72.1% reported management by all 3 providers valuable/extremely valuable; and 84.3% were somewhat/very satisfied with the model. Women endorsed specific ways in which they benefitted from the team-based model including: improved sexual function (58.1%), feeling validated (72.1%) and listened to (62.8%), that they better understood their health concerns (65.1%), that their partner better understood their health concerns (46.5%), and feeling normal (46.5%). There were no significant differences between the 2 clinics in terms of patient-perceived benefit, value, or satisfaction. Conclusions The team-based model of care for management of sexual dysfunction in women including a medical provider, physical therapist, and sex therapist is associated with patient-perceived benefit, satisfaction, and value.

AbstractBackgroundVorinostat combined with retinoids produces additive antitumor effects in preclinical studies of neuroblastoma. Higher systemic exposures of vorinostat than achieved in pediatric phase I trials with continuous daily dosing are necessary for in vivo increased histone acetylation and cytotoxic activity. We conducted a phase I trial in children with relapsed/refractory neuroblastoma to determine the maximum tolerated dose (MTD) of vorinostat on an interrupted schedule, escalating beyond the previously identified pediatric MTD.MethodsIsotretinoin (cis‐13‐retinoic acid) 80 mg/m2/dose was administered by mouth twice daily on days 1–14 in combination with escalating doses of daily vorinostat up to 430 mg/m2/dose (days 1–4; 8–11) in each 28‐day cycle using the standard 3 + 3 design. Vorinostat pharmacokinetic testing and histone acetylation assays were performed.ResultsTwenty‐nine patients with refractory or relapsed neuroblastoma were enrolled and 28 were evaluable for dose escalation decisions. Median number of cycles completed was two (range 1–15); 11 patients received four or more cycles. Three patients experienced cycle 1 dose‐limiting toxicities. A total of 18 patients experienced grade 3/4 toxicities related to study therapy. The maximum intended dose of vorinostat (430 mg/m2/day, days 1–4; 8–11) was tolerable and led to increased histone acetylation in surrogate tissues when compared to lower doses of vorinostat (P = 0.009). No objective responses were seen.ConclusionsIncreased dose vorinostat (430 mg/m2/day) on an interrupted schedule is tolerable in combination with isotretinoin. This dose led to increased vorinostat exposures and demonstrated increased histone acetylation. Prolonged stable disease in patients with minimal residual disease warrants further investigation.

In studies on dogs, blood was sampled as for the recording of dye-dilution curves through monochromatic densitometers. Injection of hypertonic media into the superior vena cava caused transient increases in the optical density of blood in the pulmonary and femoral arteries so as to produce apparent “dye” curves. The injection of hypotonic and hemolyzing media produced negative deflections, representing decreases in the optical density of blood, as did brief ventilation with 5% and 50% carbon dioxide in oxygen. Similar changes were demonstrated in vitro. They were compensated for in vivo by the use of a dichromatic densitometer. The changes observed are attributed to altered physical properties of the erythrocytes, which consequently change their light-transmitting and light-reflecting characteristics. Such nonspecific changes in the optical density of blood may constitute an important source of error in monochromatic densitometry done on whole blood. Submitted on January 11, 1961