A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results.

BACKGROUND: SERENA-1 (NCT03616587) is a phase I, multi-part, open-label study of camizestrant in pre- and post-menopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. PATIENTS AND METHODS: Women aged ≥18 years with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy, were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, antitumor efficacy, pharmacokinetics, and impact on mutations in the estrogen receptor gene (ESR1m) circulating tumor (ct)DNA levels were assessed. RESULTS: By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events at doses ≤150 mg. Median tmax was achieved ∼2-4 h post-dose at all doses investigated, with an estimated half-life of 20-23 h. Efficacy was observed at all doses investigated, including in patients with prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. CONCLUSIONS: Camizestrant is a next-generation oral selective ER antagonist and degrader (SERD) and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75-, 150-, and 300-mg QD doses for phase II testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).

Converse magneto-electric effects in a core-shell multiferroic nanofiber by electric field tuning of ferromagnetic resonance.

This report is on studies directed at the nature of magneto-electric (ME) coupling by ferromagnetic resonance (FMR) under an electric field in a coaxial nanofiber of nickel ferrite (NFO) and lead zirconate titanate (PZT). Fibers with ferrite cores and PZT shells were prepared by electrospinning. The core-shell structure of annealed fibers was confirmed by electron- and scanning probe microscopy. For studies on converse ME effects, i.e., the magnetic response of the fibers to an applied electric field, FMR measurements were done on a single fiber with a near-field scanning microwave microscope (NSMM) at 5-10 GHz by obtaining profiles of both amplitude and phase of the complex scattering parameter S11 as a function of bias magnetic field. The strength of the voltage-ME coupling Av was determined from the shift in the resonance field Hr for bias voltage of V = 0-7 V applied to the fiber. The coefficient Av for the NFO core/PZT shell structure was estimated to be - 1.92 kA/Vm (- 24 Oe/V). A model was developed for the converse ME effects in the fibers and the theoretical estimates are in good agreement with the data.

Disentangling topographic contributions to near-field scanning microwave microscopy images.

We develop empirical models to predict the contribution of topographic variations in a sample to near-field scanning probe microwave microscopy (NSMM) images. In particular, we focus on |S11| images of a thin Perovskite photovoltaic material and a GaN nanowire. The difference between the measured NSMM image and this prediction is our estimate of the contribution of material property variations to the measured image. Prediction model parameters are determined from either a reference sample that is nearly free of material property variations or directly from the sample of interest. The parameters of the prediction model are determined by robust linear regression so as to minimize the effect of material property variations on results. For the case where the parameters are determined from the reference sample, the prediction is adjusted to account for instrument drift effects. Our statistical approach black is fully empirical black and thus complementary to current approaches based on physical models that are often overly simplistic.

CXCR4 expression mediates glioma cell invasiveness.

Glioblastoma multiforme is a highly invasive tumor bearing a dismal prognosis. Experimental strategies that focus on the specific biological cues governing the invasive capacity of these tumors may hold significant therapeutic promise. In this context, we describe the in vitro and in vivo association of the cell surface chemokine receptor, CXCR4, with the development of an invasive phenotype in malignant glioblastoma. We demonstrate that invasive populations of glioma cells overexpress CXCR4 at the message and protein levels, and that this expression ranges from 25- to 89-fold higher than that found in noninvasive tumor cells. Furthermore, neutralization of CXCR4 significantly impairs the in vitro invasive capacity of malignant glial cells. In addition, glioma cells secrete CXCL12 and demonstrate robust invasive capacity toward a CXCL12 gradient in vitro. These findings underscore the importance of CXCR4 as a potential therapeutic target for the treatment of invasive glioblastoma.

Estrogen promotes the brain metastatic colonization of triple negative breast cancer cells via an astrocyte-mediated paracrine mechanism.

Brain metastases (BM) are a devastating consequence of breast cancer. BM occur more frequently in patients with estrogen receptor-negative (ER-) breast cancer subtypes; HER2 overexpressing (HER2+) tumors and triple-negative (TN) (ER-, progesterone receptor-negative (PR-) and normal HER2) tumors. Young age is an independent risk factor for the development of BM, thus we speculated that higher circulating estrogens in young, pre-menopausal women could exert paracrine effects through the highly estrogen-responsive brain microenvironment. Using a TN experimental metastases model, we demonstrate that ovariectomy decreased the frequency of magnetic resonance imaging-detectable lesions by 56% as compared with estrogen supplementation, and that the combination of ovariectomy and letrozole further reduced the frequency of large lesions to 14.4% of the estrogen control. Human BM expressed 4.2-48.4% ER+ stromal area, particularly ER+ astrocytes. In vitro, E2-treated astrocytes increased proliferation, migration and invasion of 231BR-EGFP cells in an ER-dependent manner. E2 upregulated epidermal growth factor receptor (EGFR) ligands Egf, Ereg and Tgfa mRNA and protein levels in astrocytes, and activated EGFR in brain metastatic cells. Co-culture of 231BR-EGFP cells with E2-treated astrocytes led to the upregulation of the metastatic mediator S100 Calcium-binding protein A4 (S100A4) (1.78-fold, P<0.05). Exogenous EGF increased S100A4 mRNA levels in 231BR-EGFP cells (1.40±0.02-fold, P<0.01 compared with vehicle control) and an EGFR/HER2 inhibitor blocked this effect, suggesting that S100A4 is a downstream effector of EGFR activation. Short hairpin RNA-mediated S100A4 silencing in 231BR-EGFP cells decreased their migration and invasion in response to E2-CM, abolished their increased proliferation in co-cultures with E2-treated astrocytes and decreased brain metastatic colonization. Thus, S100A4 is one effector of the paracrine action of E2 in brain metastatic cells. These studies provide a novel mechanism by which estrogens, acting through ER+ astrocytes in the brain microenvironment, can promote BM of TN breast cancers, and suggests existing endocrine agents may provide some clinical benefit towards reducing and managing BM.

Adaptive and robust statistical methods for processing near-field scanning microwave microscopy images.

Near-field scanning microwave microscopy offers great potential to facilitate characterization, development and modeling of materials. By acquiring microwave images at multiple frequencies and amplitudes (along with the other modalities) one can study material and device physics at different lateral and depth scales. Images are typically noisy and contaminated by artifacts that can vary from scan line to scan line and planar-like trends due to sample tilt errors. Here, we level images based on an estimate of a smooth 2-d trend determined with a robust implementation of a local regression method. In this robust approach, features and outliers which are not due to the trend are automatically downweighted. We denoise images with the Adaptive Weights Smoothing method. This method smooths out additive noise while preserving edge-like features in images. We demonstrate the feasibility of our methods on topography images and microwave |S11| images. For one challenging test case, we demonstrate that our method outperforms alternative methods from the scanning probe microscopy data analysis software package Gwyddion. Our methods should be useful for massive image data sets where manual selection of landmarks or image subsets by a user is impractical.

Progesterone downregulation of miR-141 contributes to expansion of stem-like breast cancer cells through maintenance of progesterone receptor and Stat5a.

Progesterone (P4) has emerged as an important hormone-regulating mammary stem cell (MaSC) populations. In breast cancer, P4 and synthetic analogs increase the number of stem-like cells within luminal estrogen receptor (ER)- and progesterone receptor (PR)-positive breast cancers. These cells gain expression of de-differentiated cell markers CD44 and cytokeratin 5 (CK5), lose luminal markers ER and PR, and are more therapy resistant. We previously described that P4 downregulation of microRNA (miR)-29a contributes to the expansion of CD44(high) and CK5(+) cells. Here we investigated P4 downregulation of miR-141, a member of the miR-200 family of tumor suppressors, in facilitating an increase in stem-like breast cancer cells. miR-141 was the sole member of the miR-200 family P4-downregulated at the mature miRNA level in luminal breast cancer cell lines. Stable inhibition of miR-141 alone increased the CD44(high) population, and potentiated P4-mediated increases in both CD44(high) and CK5(+) cells. Loss of miR-141 enhanced both mammosphere formation and tumor initiation. miR-141 directly targeted both PR and signal transducer and activator of transcription 5A (Stat5a), transcription factors important for MaSC expansion. miR-141 depletion increased PR protein levels, even in cell lines where PR expression is estrogen dependent. Stat5a suppression via small interfering RNA or a small-molecule inhibitor reduced the P4-dependent increase in CK5(+) and CD44(high) cells. These data support a mechanism by which P4-triggered loss of miR-141 facilitates breast cancer cell de-differentiation through deregulation of PR and Stat5a, two transcription factors important for controlling mammary cell fate.

Transfected parvalbumin alters calcium homeostasis in teratocarcinoma PCC7 cells.

Indirect evidence supports a protective role of some EF-hand calcium-binding proteins against calcium-induced neurotoxicity. Little is known about how these proteins influence cytosolic calcium levels. After cloning the parvalbumin cDNA into an expression vector, teratocarcinoma cells (PCC7) were transfected. Parvalbumin-transfected and mock-transfected cells were loaded with the calcium indicator fura-2 and were exposed, in the same dish, to different concentrations of the calcium ionophore A23187 or to KCI. The results show that parvalbumin-transfected PCC7 cells had much better calcium buffering capacity than control cells.

Dynamic constitutive relations for polarization and magnetization.

In this paper we develop constitutive relations for materials where the magnetization and polarization may depend on both the electric and magnetic fields. The approach is general, and is based on a previously developed statistical-mechanical theory. We include the quadrupole-moment density as well as the dipole-moment density in the microscopic displacement field. This yields an electric gradient term in the constitutive equations. This leads to origin invariance in the multipole moments from which Maxwell's equations are defined. We present generalizations of Debye and Landau-Lifshitz equations of motion which are valid for nonequilibrium and contain memory. The reversible and relaxation terms in the polarization and magnetization evolution equations include the possibility of magnetoelectric coupling. Using constitutive relationship, we derive evolution equations for the displacement and induction fields from a Hamiltonian approach.

A near-field scanning microwave microscope for characterization of inhomogeneous photovoltaics.

We present a near-field scanning microwave microscope (NSMM) that has been configured for imaging photovoltaic samples. Our system incorporates a Pt-Ir tip inserted into an open-ended coaxial cable to form a weakly coupled resonator, allowing the microwave reflection S(11) signal to be measured across a sample over a frequency range of 1 GHz - 5 GHz. A phase-tuning circuit increased impedance-measurement sensitivity by allowing for tuning of the S(11) minimum down to -78 dBm. A bias-T and preamplifier enabled simultaneous, non-contact measurement of the DC tip-sample current, and a tuning fork feedback system provided simultaneous topographic data. Light-free tuning fork feedback provided characterization of photovoltaic samples both in the dark and under illumination at 405 nm. NSMM measurements were obtained on an inhomogeneous, third-generation Cu(In,Ga)Se(2) (CIGS) sample. The S(11) and DC current features were found to spatially broaden around grain boundaries with the sample under illumination. The broadening is attributed to optically generated charge that becomes trapped and changes the local depletion of the grain boundaries, thereby modifying the local capacitance. Imaging provided by the NSMM offers a new RF methodology to resolve and characterize nanoscale electrical features in photovoltaic materials and devices.

Calibrated nanoscale capacitance measurements using a scanning microwave microscope.

A scanning microwave microscope (SMM) for spatially resolved capacitance measurements in the attofarad-to-femtofarad regime is presented. The system is based on the combination of an atomic force microscope (AFM) and a performance network analyzer (PNA). For the determination of absolute capacitance values from PNA reflection amplitudes, a calibration sample of conductive gold pads of various sizes on a SiO(2) staircase structure was used. The thickness of the dielectric SiO(2) staircase ranged from 10 to 200 nm. The quantitative capacitance values determined from the PNA reflection amplitude were compared to control measurements using an external capacitance bridge. Depending on the area of the gold top electrode and the SiO(2) step height, the corresponding capacitance values, as measured with the SMM, ranged from 0.1 to 22 fF at a noise level of ~2 aF and a relative accuracy of 20%. The sample capacitance could be modeled to a good degree as idealized parallel plates with the SiO(2) dielectric sandwiched in between. The cantilever/sample stray capacitance was measured by lifting the tip away from the surface. By bringing the AFM tip into direct contact with the SiO(2) staircase structure, the electrical footprint of the tip was determined, resulting in an effective tip radius of ~60 nm and a tip-sample capacitance of ~20 aF at the smallest dielectric thickness.