FDA and EMA approval of panobinostat offers an additional therapeutic option for multiple myeloma; however, adoption of panobinostat has been limited by its adverse event profile. Trials are ongoing ...to optimize the dosing of panobinostat and to identify its best partners, in order to fully realize the potential of this drug class.
The high rate of clinical response to protein-kinase-targeting drugs matched to cancer patients with specific genomic alterations has prompted efforts to use cancer cell line (CCL) profiling to ...identify additional biomarkers of small-molecule sensitivities. We have quantitatively measured the sensitivity of 242 genomically characterized CCLs to an Informer Set of 354 small molecules that target many nodes in cell circuitry, uncovering protein dependencies that: (1) associate with specific cancer-genomic alterations and (2) can be targeted by small molecules. We have created the Cancer Therapeutics Response Portal (http://www.broadinstitute.org/ctrp) to enable users to correlate genetic features to sensitivity in individual lineages and control for confounding factors of CCL profiling. We report a candidate dependency, associating activating mutations in the oncogene β-catenin with sensitivity to the Bcl-2 family antagonist, navitoclax. The resource can be used to develop novel therapeutic hypotheses and to accelerate discovery of drugs matched to patients by their cancer genotype and lineage.
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•A therapeutics resource identifies cancer genotype-compound sensitivity relationships•Genetic features of cancer cell lines correlate with their response to compounds•The resource controls for possible confounding factors of genomic cell-line profiling•Results suggest a strategy for treating cancers with mutations in β-catenin
The Cancer Therapeutics Response Portal catalogs the sensitivity of more than 200 cancer cell lines to specific small molecules. This resource should accelerate the development of individualized therapies tailored to specific cancers and patients.
A number of new magnesium and lithium silyl reagents were prepared and shown to be outstanding nucleophiles in reactions with industrially relevant fluoroolefins. These reactions result in a net ...transformation of either sp2 or sp3 C−F bonds into C−Si bonds by two modes of nucleophilic attack (SNV or SN2′). The methods are mild, proceeding with high chemo‐ and regioselectivity. Mechanistic pathways are described that lead to new substitution patterns from HFO‐1234yf, HFO‐1234ze, and HFO‐1336mzz, previously inaccessible by transition metal catalyzed difluorosilylation routes.
Magnesium and lithium silyl reagents are outstanding nucleophiles for upgrading industrially relevant fluoroolefins to fluorinated organosilanes by two modes of nucleophilic attack (SNV or SN2′).
Particles with a diameter of ∼0.5 µm in a dilute (volume fractions φ∞ < 4 × 10−3) suspension assemble into highly elongated structures called “bands” under certain conditions in combined Poiseuille ...and electroosmotic flows in opposite directions through microchannels at particle‐based Reynolds numbers Rep < < 1. The particles are first concentrated near, then form “bands” within ∼6 µm of, the channel wall. The experiments described here examine the near‐wall dynamics of individual “tracer” particles during the initial concentration, or accumulation, of particles, and the steady‐state stage when the particles have formed relatively stable bands at different near‐wall shear rates and electric field magnitudes. Surprisingly, the near‐wall upstream particle velocities are found to be consistently greater in magnitude than the expected values based on the particles being convected by the superposition of both flows and subject to electrophoresis, which is in the same direction as the Poiseuille flow. However, the particle velocities scale linearly with the change in electric field magnitude, suggesting that the particle dynamics are dominated by linear electrokinetic phenomena. If this discrepancy with theory is only due to changes in particle electrophoresis, electrophoresis is significantly reduced to values as small as 20%–50% of the Smoluchowski relation, or well below previous model predictions, even for high particle potentials.
On the basis of previous studies, the particles in a dilute (volume fractions φ∞ < 4 × 10–3) suspension in combined Poiseuille and electroosmotic “counterflow” at flow Reynolds numbers Re ≤ 1 ...accumulate, then assemble into structures called “bands,” within ∼6 μm of the channel wall. The experimental studies presented here use a small fraction of tracer particles labeled with a different fluorophore from the majority “bulk” particles to visualize the dynamics of individual particles in a φ∞ = 1.7 × 10–3 suspension. The results at two different near‐wall shear rates and three electric field magnitudes E show that the near‐wall particles are concentrated about 150‐fold when the bands start to form, and are then concentrated about 200‐fold to a maximum near‐wall volume fraction of ∼0.34. The growth in the near‐wall particles during this accumulation stage appears to be exponential.
This near‐wall particle accumulation is presumably driven by a wall‐normal “lift” force. The observations of how the particles accumulate near the wall are compared with recent analyses that predict that suspended particles subject to shear flow and a dc electric field at small particle Reynolds numbers experience such a lift force. A simple model that assumes that the particles are subject to this lift force and Stokes drag suggests that the force driving particles toward the wall, of O(10–17 N), is consistent with the time scales for particle accumulation observed in the experiments.
Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease. The etiology remains unknown. The efficacy of B ...cell-targeted therapies in some patients, together with the known proteinuric effect of anti-nephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease.
We evaluated sera from patients with minimal change disease, enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort and from our own institutions, for circulating nephrin autoantibodies by indirect ELISA and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. We also evaluated renal biopsies from our institutions for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence.
In two independent patient cohorts, we identified circulating nephrin autoantibodies during active disease that were significantly reduced or absent during treatment response in a subset of patients with minimal change disease. We correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies from our institutions. We also identified a patient with steroid-dependent childhood minimal change disease that progressed to end stage kidney disease; she developed a massive post-transplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies.
Our discovery of nephrin autoantibodies in a subset of adults and children with minimal change disease aligns with published animal studies and provides further support for an autoimmune etiology. We propose a new molecular classification of nephrin autoantibody minimal change disease to serve as a framework for instigation of precision therapeutics for these patients.
Improvements in multiple myeloma therapy have led to deeper responses that are beyond the limit of detection by historical immunohistochemistry and conventional flow cytometry in bone marrow samples. ...In parallel, more sensitive techniques for assessing minimal residual disease (MRD) through next-generation flow cytometry and sequencing have been developed and are now routinely available. Deep responses when measured by these assays correspond with improved outcomes and survival. We review the data supporting MRD testing as well as its limitations and how it may fit in with current and future clinical practice.
Summary Background Histone deacetylase (HDAC) inhibitors are an important new class of therapeutics for treating multiple myeloma. Ricolinostat (ACY-1215) is the first oral selective HDAC6 inhibitor ...with reduced class I HDAC activity to be studied clinically. Motivated by findings from preclinical studies showing potent synergistic activity with ricolinostat and lenalidomide, our goal was to assess the safety and preliminary activity of the combination of ricolinostat with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. Methods In this multicentre phase 1b trial, we recruited patients aged 18 years or older with previously treated relapsed or refractory multiple myeloma from five cancer centres in the USA. Inclusion criteria included a Karnofsky Performance Status score of at least 70, measureable disease, adequate bone marrow reserve, adequate hepatic function, and a creatinine clearance of at least 50 mL per min. Exclusion criteria included previous exposure to HDAC inhibitors; previous allogeneic stem-cell transplantation; previous autologous stem-cell transplantation within 12 weeks of baseline; active systemic infection; malignancy within the last 5 years; known or suspected HIV, hepatitis B, or hepatitis C infection; a QTc Fridericia of more than 480 ms; and substantial cardiovascular, gastrointestinal, psychiatric, or other medical disorders. We gave escalating doses (from 40–240 mg once daily to 160 mg twice daily) of oral ricolinostat according to a standard 3 + 3 design according to three different regimens on days 1–21 with a conventional 28 day schedule of oral lenalidomide (from 15 mg in one cohort to 25 mg in all other cohorts once daily) and oral dexamethasone (40 mg weekly). Primary outcomes were dose-limiting toxicities, the maximum tolerated dose of ricolinostat in this combination, and the dose and schedule of ricolinostat recommended for further phase 2 investigation. Secondary outcomes were the pharmacokinetics and pharmacodynamics of ricolinostat in this combination and the preliminary anti-tumour activity of this treatment. The trial is closed to accrual and is registered at ClinicalTrials.gov , number NCT01583283. Findings Between July 12, 2012, and Aug 20, 2015, we enrolled 38 patients. We observed two dose-limiting toxicities with ricolinostat 160 mg twice daily: one (2%) grade 3 syncope and one (2%) grade 3 myalgia event in different cohorts. A maximum tolerated dose was not reached. We chose ricolinostat 160 mg once daily on days 1–21 of a 28 day cycle as the recommended dose for future phase 2 studies in combination with lenalidomide 25 mg and dexamethasone 40 mg. The most common adverse events were fatigue (grade 1–2 in 14 37% patients; grade 3 in seven 18%) and diarrhoea (grade 1–2 in 15 39% patients; grade 3 in two 5%). Our pharmacodynamic studies showed that at clinically relevant doses, ricolinostat selectively inhibits HDAC6 while retaining a low and tolerable level of class I HDAC inhibition. The pharmacokinetics of ricolinostat and lenalidomide were not affected by co-administration. In a preliminary assessment of antitumour activity, 21 (55% 95% CI 38–71) of 38 patients had an overall response. Interpretation The findings from this study provide preliminary evidence that ricolinostat is a safe and well tolerated selective HDAC6 inhibitor, which might partner well with lenalidomide and dexamethasone to enhance their efficacy in relapsed or refractory multiple myeloma. Funding Acetylon Pharmaceuticals.
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