April 2016 – Page 165 – 1stOncology™: Cancer Intelligence Service

Functional and Structural Characterization of Bub3-BubR1 Interactions Required for Spindle Assembly Checkpoint Signaling in Human Cells.

The spindle assembly checkpoint (SAC) is an essential safeguarding mechanism devised to ensure equal chromosome distribution in daughter cells upon mitosis. The proteins Bub3 and BubR1 are key components of the mitotic checkpoint complex (MCC), an essential part of the molecular machinery on which the SAC relies. In the present work we have performed a detailed functional and biochemical characterization of the interaction between human Bub3 and BubR1 in cells and in vitro. Our results demonstrate that genetic knock down of Bub3 abrogates the SAC, promotes apoptosis and inhibits the proliferation of human cancer cells. We also show that the integrity of the human MCC depends on the specific recognition between BubR1 and Bub3, for which the BubR1 GLEBS motif is essential. This 1:1 binding event is high affinity, enthalpy-driven and with slow dissociation kinetics. The affinity, kinetics and thermodynamic parameters of the interaction are differentially modulated by small regions in the N- and C-termini of the GLEBS domain sequence, suggesting the existence of &quot;hotspots&quot; for this protein-protein interaction. Furthermore, we show that specific disruption of endogenous BubR1-Bub3 complexes in human cancer cells phenocopies the effects observed in gene targeting experiments. Our work enhances the current understanding of key members of the SAC and paves the road for the pursuit of novel targeted cancer therapies based on SAC inhibition.
Copyright © 2016, The American Society for Biochemistry and Molecular Biology.

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Regioselective Synthesis of 3-Hydroxy-4,5-alkyl-Substituted Pyridines Using 1,3-Enynes as Alkynes Surrogates.

The poor regioselectivity of the [4 + 2] cycloaddition of 3-azetidinones with internal alkynes bearing two alkyl substituents via nickel-catalyzed carbon-carbon activation is addressed using 1,3-enynes as substrates. The judicious choice of substitution on the enyne enables complementary access to each regioisomer of 3-hydroxy-4,5-alkyl-substituted pyridines, which are important building blocks in medicinal chemistry endeavors.

Primary Analysis of a Prospective, Randomized, Single-Blinded Phase II Trial Evaluating the HER2 Peptide AE37 Vaccine in Breast Cancer Patients to Prevent Recurrence.

AE37 is the Ii-Key hybrid of the MHC class II peptide, AE36 (HER2 aa:776-790). Phase I studies showed AE37 administered with granulocyte macrophage colony-stimulating factor (GM-CSF) to be safe and highly immunogenic. A prospective, randomized, multicenter phase II adjuvant trial was conducted to evaluate the vaccine’s efficacy.
Clinically disease-free node-positive and high-risk node-negative breast cancer patients with tumors expressing any degree of HER2 (immunohistochemistry (IHC) 1-3+) were enrolled. Patients were randomized to AE37+GM-CSF versus GM-CSF alone. Toxicity was monitored. Clinical recurrences were documented and disease-free survival (DFS) analyzed.
The trial enrolled 298 patients; 153 received AE37+GM-CSF and 145 received GM-CSF alone. The groups were well-matched for clinicopathologic characteristics. Toxicities have been minimal. At the time of the primary analysis, the recurrence rate in the vaccinated group was 12.4% versus 13.8% in the control group (relative risk reduction 12%, HR 0.885, 95% CI: 0.472-1.659, P=0.70). The Kaplan-Meier estimated 5-year DFS rate was 80.8% in vaccinated versus 79.5% in control patients. In planned subset analyses of patients with IHC 1+/2+ HER2-expressing tumors, 5-year DFS was 77.2% in vaccinated patients (n=76) vs. 65.7% in control patients (n=78), (P=0.21). In patients with triple negative breast cancer (TNBC, HER2 IHC 1+/2+ and hormone receptor negative) DFS was 77.7% in vaccinated patients (n=25) vs. 49.0% in control patients (n=25), (P=0.12).
The overall intention to treat analysis demonstrates no benefit to vaccination. However, the results confirm that the vaccine is safe and suggest that vaccination may have clinical benefit in patients with low HER2 expressing tumors, specifically TNBC. Further evaluation in a randomized trial enrolling TNBC patients is warranted.
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

Health-related Quality of Life in Women With Recurrent Ovarian Cancer Receiving Paclitaxel Plus Trebananib or Placebo (TRINOVA-1).

To evaluate the influence of treatment on health-related quality of life (HRQoL) in 919 women with recurrent ovarian cancer enrolled in the TRINOVA-1 study, a randomized, placebo-controlled phase 3 study that demonstrated that trebananib 15 mg/kg QW plus weekly paclitaxel significantly improved PFS compared with placebo plus weekly paclitaxel (7.2 versus 5.4 months; hazard ratio, 0.66; 95% CI, 0.57-0.77; P&lt;0.001).
HRQoL was assessed with the Functional Assessment of Cancer Therapy-Ovary (FACT-O; comprising FACT-G and the ovarian cancer-specific subscale [OCS]) and EuroQOL EQ-5D instruments before treatment on day 1 of weeks 1, 5, 9, 13, 17, and every 8 weeks thereafter and at the safety follow-up visit. A pattern-mixture model was used to evaluate influence of patient dropout on FACT-O and OCS scores over time.
834 of 919 randomized patients (91%) had a baseline and ≥1 post-baseline HRQoL assessment. At baseline, scores for all instruments were similar for both arms. At 25 weeks mean±SD changes from baseline were negligible, with mean±SD changes typically &lt;1 unit from baseline: -2.4±16.6 in the trebananib arm and -1.6±15.2 in the placebo arm for FACT-O, -0.71±5.5 in the trebananib arm and -0.86±4.9 in the placebo arm for OCS, and -0.02±0.22 in the trebananib arm and 0.02±0.19 in the placebo arm for EQ-5D. Distribution of scores was similar between treatment arms at baseline and over the course of the study. In pattern-mixture models, there was no evidence that patient dropout affected differences in mean FACT-O or OCS scores. Edema had limited effect on either FACT-O or OCS scores in patients with grade ≥2 edema or those with grade 1 or no edema.
Our results demonstrate that the improvement in PFS among patients in the trebananib arm in the TRINOVA-1 study was achieved without compromising HRQoL.
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

Evaluation of an ICD-10 algorithm to detect osteonecrosis of the jaw among cancer patients in the Danish National Registry of Patients.

This study aimed to validate a predefined algorithm for osteonecrosis of the jaw (ONJ) among cancer patients in the Danish National Registry of Patients and to assess the nature of clinical information recorded in medical charts of ONJ patients.
We identified potential ONJ cases recorded in 2005-2010 among cancer patients at the hospital Departments of Oral and Maxillofacial Surgery (DOMS) in three Danish regions, using a set of codes from the International Classification of Diseases, 10th revision (ICD-10). We abstracted DOMS charts of the potential cases, had the ONJ status adjudicated by an expert ONJ adjudication committee (ONJAC), and computed positive predictive values. For patients with ONJAC-confirmed ONJ, we abstracted the charts for information on ONJ clinical course. Sensitivity of the algorithm was computed using a separate sample of 101 known ONJ cases accrued in 2005-2011.
We identified 212 potential ONJ cases, of which 197 (93%) had charts available for abstraction. Eighty-three potential cases were confirmed by ONJAC, with a positive predictive value of 42% (95% confidence interval [CI] 35%-49%). DOMS charts of these 83 cases contained complete information on ONJ clinical course. Information about antiresorptive treatment was recorded for 84% of the patients. Among the 101 known ONJ cases, 74 had at least one prespecified ICD-10 code recorded in the Danish National Registry of Patients within ±90 days of the ONJ diagnosis (sensitivity 73%; 95%CI [64%-81%]).
The predefined algorithm is not adequate for monitoring ONJ in pharmacovigilance studies. Additional case-finding approaches, coupled with adjudication, are necessary to estimate ONJ incidence accurately.
Copyright © 2015 John Wiley &amp; Sons, Ltd.

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Month: April 2016

Functional and Structural Characterization of Bub3-BubR1 Interactions Required for Spindle Assembly Checkpoint Signaling in Human Cells.

Regioselective Synthesis of 3-Hydroxy-4,5-alkyl-Substituted Pyridines Using 1,3-Enynes as Alkynes Surrogates.

Primary Analysis of a Prospective, Randomized, Single-Blinded Phase II Trial Evaluating the HER2 Peptide AE37 Vaccine in Breast Cancer Patients to Prevent Recurrence.

Health-related Quality of Life in Women With Recurrent Ovarian Cancer Receiving Paclitaxel Plus Trebananib or Placebo (TRINOVA-1).

Evaluation of an ICD-10 algorithm to detect osteonecrosis of the jaw among cancer patients in the Danish National Registry of Patients.