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A role for FOXO1 in BCR-ABL1-independent tyrosine kinase inhibitor resistance in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) patients who relapse on imatinib due to acquired ABL1 kinase domain mutations are successfully treated with second-generation ABL1-tyrosine kinase inhibitors (ABL-TKIs) such as dasatinib, nilotinib or ponatinib. However, ~40% of relapsed patients have uncharacterized BCR-ABL1 kinase-independent mechanisms of resistance. To identify these mechanisms of resistance and potential treatment options, we generated ABL-TKI-resistant K562 cells through prolonged sequential exposure to imatinib and dasatinib. Dual-resistant K562 cells lacked BCR-ABL1 kinase domain mutations, but acquired other genomic aberrations that were characterized by next-generation sequencing and copy number analyses. Proteomics showed that dual-resistant cells had elevated levels of FOXO1, phospho-ERK and BCL-2, and that dasatinib no longer inhibited substrates of the PI3K/AKT pathway. In contrast to parental cells, resistant cells were sensitive to growth inhibition and apoptosis induced by the class I PI3K inhibitor, GDC-0941 (pictilisib), which also induced FOXO1 nuclear translocation. FOXO1 was elevated in a subset of primary specimens from relapsed CML patients lacking BCR-ABL1 kinase domain mutations, and these samples were responsive to GDC-0941 treatment ex vivo. We conclude that elevated FOXO1 contributes to BCR-ABL1 kinase-independent resistance experienced by these CML patients and that PI3K inhibition coupled with BCR-ABL1 inhibition may represent a novel therapeutic approach.Leukemia advance online publication, 8 April 2016; doi:10.1038/leu.2016.51.

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Survival in patients with non-metastatic breast cancer treated with adjuvant trastuzumab in clinical practice.

The NSABP Trial B-31 and NCCTG Trial N9831 (B-31/N9831 trials, Romond et al. in N Engl J Med 353:1673-84, 2005. doi:10.1056/NEJMoa052122; Perez et al. in J Clin Oncol 32:3744-52, 2014. doi:10.1200/JCO.2014.55.5730) established the efficacy of adjuvant trastuzumab for patients with HER2-positive early stage breast cancer. We aimed to estimate the overall survival (OS) and relapse-free survival (RFS) of HER2-positive non-metastatic breast cancer patients treated with adjuvant trastuzumab in a clinical practice setting in the United States.
Adult women initiating adjuvant trastuzumab within 1 year of breast cancer surgery were identified in the health claims database of the US Department of Defense (01/2003-12/2012). OS and RFS unadjusted rates at 4 and 6 years after the first trastuzumab treatment following the breast cancer diagnosis were estimated from Kaplan-Meier analyses.
The study sample included 3188 women followed for a median of 3.3 years after trastuzumab initiation and treated continuously with trastuzumab for a median of 12 months. The OS rates (95 % confidence intervals) at 4 and 6 years were 90.0 % (88.6-91.2) and 87.1 (85.3-88.6), respectively. The corresponding RFS rates were 75.8 % (74.0-77.5) and 72.7 (70.7-74.7), respectively. The OS and RFS rates at 6 years reported in the B-31/N9831 trials were 89.8 and 81.4 %, respectively.
OS rates estimated in this study were in range with those estimated in the B-31/N9831 trials, while RFS rates were lower. However, patients in the B-31/N9831 trials were younger and possibly had fewer comorbidities than patients in the current study; these differences were not adjusted for in the crude OS and RFS analyses.

Multicenter Reproducibility of 18F-Fluciclatide PET Imaging in Subjects with Solid Tumors.

Integrins are upregulated on both tumor cells and associated vasculature, where they play an important role in angiogenesis and metastasis. Fluciclatide is an arginine-glycine-aspartic acid peptide with high affinity for αvβ3/αvβ5 integrin, which can be radiolabeled for PET imaging of angiogenesis. Thus, (18)F-fluciclatide is a potential biomarker of therapeutic response to antiangiogenic inhibitors. The aim of this study was to evaluate the reproducibility of (18)F-fluciclatide in multiple solid-tumor types.
Thirty-nine patients underwent PET/CT scanning at 40, 65, and 90 min after injection of (18)F-fluciclatide (maximum, 370 MBq) on 2 separate days (2-9 d apart). Patients did not receive any therapy between PET/CT scans. (18)F-fluciclatide images were reported and quantitative measures of uptake were extracted using the PERCIST methodology. Intrasubject reproducibility of PET uptake in all measurable lesions was evaluated by calculating relative differences in SUV between PET scans for each lesion during the 2 imaging sessions.
Thirty-nine measurable lesions were detected in 26 patients. Lesion uptake correlated strongly across imaging sessions (r = 0.92, P &lt; 0.05, at 40 min; r = 0.94, P &lt; 0.05, at 65 min; r = 0.94, P &lt; 0.05, at 90 min) with a mean relative difference and SD of the relative difference of 0.006 ± 0.18 at 40 min, 0.003 ± 0.19 at 65 min, and 0.025 ± 0.20 at 90 min. This reflects 95% limits of repeatability of 35%-39% for the difference between the 2 SUV measurements or a variability of 18%-20% in agreement from that observed in well-calibrated multicenter (18)F-FDG studies.
The test-retest reproducibility of (18)F-fluciclatide across multiple tumor types has been measured and shown to be acceptable. This is an important step in the development of this in vivo biomarker to identify and quantify response to antiangiogenic therapy in cancer patients.
© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

A BMP7 Variant Inhibits Tumor Angiogenesis In Vitro and In Vivo through Direct Modulation of Endothelial Cell Biology.

Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have numerous biological activities including control of growth, differentiation, and vascular development. Using an in vitro co-culture endothelial cord formation assay, we investigated the role of a BMP7 variant (BMP7v) in VEGF, bFGF, and tumor-driven angiogenesis. BMP7v treatment led to disruption of neo-endothelial cord formation and regression of existing VEGF and bFGF cords in vitro. Using a series of tumor cell models capable of driving angiogenesis in vitro, BMP7v treatment completely blocked cord formation. Pre-treatment of endothelial cells with BMP7v significantly reduced their cord forming ability, indicating a direct effect on endothelial cell function. BMP7v activated the canonical SMAD signaling pathway in endothelial cells but targeted gene knockdown using shRNA directed against SMAD4 suggests this pathway is not required to mediate the anti-angiogenic effect. In contrast to SMAD activation, BMP7v selectively decreased ERK and AKT activation, significantly decreased endothelial cell migration and down-regulated expression of critical RTKs involved in VEGF and FGF angiogenic signaling, VEGFR2 and FGFR1 respectively. Importantly, in an in vivo angiogenic plug assay that serves as a measurement of angiogenesis, BMP7v significantly decreased hemoglobin content indicating inhibition of neoangiogenesis. In addition, BMP7v significantly decreased angiogenesis in glioblastoma stem-like cell (GSLC) Matrigel plugs and significantly impaired in vivo growth of a GSLC xenograft with a concomitant reduction in microvessel density. These data support BMP7v as a potent anti-angiogenic molecule that is effective in the context of tumor angiogenesis.

Effects of Tadalafil Once-Daily or On-Demand vs Placebo on Return to Baseline Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy – Results from a Randomized Controlled Trial (REACTT).

The multicenter, randomized, double-blind, double-dummy, placebo-controlled REACTT trial suggested that treatment with tadalafil once daily (OaD) started early after bilateral nerve-sparing radical prostatectomy (nsRP) for prostate cancer may contribute to erectile function (EF)-recovery, which was predefined as achieving an International Index of Erectile Function (IIEF)-EF score ≥22. Here, we report descriptive post-hoc analyses, using the more strict definition for EF-recovery of returning back to the pre-surgery IIEF-EF-level (&quot;back-to-baseline analysis&quot;).
REACTT included 422 men &lt;68 years with adenocarcinoma of the prostate and preoperative IIEF-EF ≥22 who underwent nsRP at 50 centers from 9 European countries and Canada. Patients were randomized post-nsRP 1:1:1 to 9-month double-blind treatment (DBT) with tadalafil 5 mg OaD (n = 139), tadalafil 20 mg on-demand (pro-re-nata, PRN; n = 142), or placebo (n = 141), followed by 6-week drug-free washout (DFW) and 3-month open-label tadalafil OaD treatment (OLT).
Proportion of patients returning to their preoperative IIEF-EF category (22-25 or ≥26) at the end of DBT, DFW, and OLT.
Overall, 92.4% of patients had pre-surgery (baseline) IIEF-EF scores ≥26 (tadalafil OaD 94.2%, PRN 91.6%, placebo 91.5%), 7.4% had IIEF-EF 22-25. At the end of DBT, 22.3% of patients on tadalafil OaD had achieved &quot;back-to-baseline&quot; IIEF-EF, compared with 11.3% on tadalafil PRN and 7.8% on placebo. Of all 58 patients &quot;back-to-baseline&quot; at the end of DBT, only 1 PRN-group patient had started from a baseline IIEF-EF &lt;26. The treatment-group difference at the end of DBT was not maintained after DFW. After 3 months of OLT with tadalafil OaD, the proportion of patients with &quot;back-to-baseline&quot; IIEF-EF had almost doubled in all 3 groups.
Changing the definition for EF-recovery from IIEF-EF ≥22 to the more strict definition of &quot;returning back-to-baseline IIEF-EF&quot; had no major impact. Tadalafil OaD started early after nsRP improved drug-assisted EF, but had no effect on unassisted EF following treatment cessation after 9 months.
Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.