Fibroblast Growth Factor Receptors and Ligands in Context of Bevacizumab Response in Ovarian Carcinoma: An Exploratory Analysis of AGO-OVAR11/ICON-7.

With more novel drugs being approved for the treatment of ovarian carcinoma, the question remains to what extent patients benefit from antiangiogenic treatment with bevacizumab, either in combination with poly-(ADP-ribose) polymerase inhibitors or as single-agent maintenance. As fibroblast growth factor receptors and their ligands (FGFRs/FGFs) are key players in angiogenic signaling and have been linked to resistance to several drugs, we investigated the prognostic or predictive potential of FGFs/FGFRs signaling in the context of bevacizumab treatment within the prospective phase III AGO-OVAR11/ICON-7 study. FGFR1, FGFR2, FGFR3, FGFR4, FGF1, and FGF19 gene expressions were determined in 380 ovarian carcinoma tumor samples collected from German centers in the multicenter phase III AGO-OVAR11 trial/ICON-7 trial. All patients received carboplatin and paclitaxel, administered every 3 weeks for 6 cycles, and were randomized to bevacizumab. Expressions of FGFR1, FGFR2, FGF1, and FGF19 were associated with progression-free survival in both uni- and multivariate (FGFR1: HR, 1.6, P < .001; FGFR2: HR, 1.6, P = .002; FGF1: HR, 2.3, P < .001; and FGF19: HR, 0.7; P = .007) analysis. A signature built by FGFR1, FGFR4, and FGF19 defined a subgroup (n = 62) of patients that derived the greatest bevacizumab-associated improvement of progression-free survival (HR, 0.3; P = .004). In this exploratory analysis of a prospective randomized phase III trial, we provide evidence that the expression of FGFRs/FGFs might have independent prognostic values. An FGFR/FGF-based gene signature identified in our study appears to predict long-term benefit from bevacizumab. This observation is hypothesis-generating and requires validation on independent cohorts.

NCT/DKFZ MASTER handbook of interpreting whole-genome, transcriptome, and methylome data for precision oncology.

Analysis of selected cancer genes has become an important tool in precision oncology but cannot fully capture the molecular features and, most importantly, vulnerabilities of individual tumors. Observational and interventional studies have shown that decision-making based on comprehensive molecular characterization adds significant clinical value. However, the complexity and heterogeneity of the resulting data are major challenges for disciplines involved in interpretation and recommendations for individualized care, and limited information exists on how to approach multilayered tumor profiles in clinical routine. We report our experience with the practical use of data from whole-genome or exome and RNA sequencing and DNA methylation profiling within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) program of the National Center for Tumor Diseases (NCT) Heidelberg and Dresden and the German Cancer Research Center (DKFZ). We cover all relevant steps of an end-to-end precision oncology workflow, from sample collection, molecular analysis, and variant prioritization to assigning treatment recommendations and discussion in the molecular tumor board. To provide insight into our approach to multidimensional tumor profiles and guidance on interpreting their biological impact and diagnostic and therapeutic implications, we present case studies from the NCT/DKFZ molecular tumor board that illustrate our daily practice. This manual is intended to be useful for physicians, biologists, and bioinformaticians involved in the clinical interpretation of genome-wide molecular information.

The Role of 68Ga-FAPI PET/CT for Patients with Malignancies of the Lower Gastrointestinal Tract: First Clinical Experience.

For oncologic management or radiotherapy planning, reliable staging tools are essential. The recent development of quinoline-based ligands targeting cancer-associated fibroblasts demonstrated promising preclinical and clinical results. The current study aimed to evaluate the role of fibroblast activation protein inhibitor (FAPI) PET/CT as a first clinical analysis for primary malignancies within the lower gastrointestinal tract (LGT). Methods:68Ga-FAPI PET/CT was performed on a cohort of 22 patients with LGT tumors, including 15 patients with metastatic disease, 1 patient with suspected local relapse, and 6 treatment-naïve patients. Uptake of 68Ga-FAPI-04 and 68Ga-FAPI-46 was quantified by SUVmax and SUVmean After comparison with standard imaging, changes in tumor stage or localization and in oncologic or radiooncologic management were recorded. Results: The highest uptake of FAPI tracer was observed in liver metastases and anal cancer, with an SUVmax of 9.1 and 13.9, respectively. Because of low background activity in normal tissue, there was a high tumor-to-background ratio of more than 3 in most lesions. In treatment-naïve patients, TNM was changed in 50%, whereas in patients with metastases, new findings occurred in 47%. In total, FAPI imaging caused a high, medium, and low change in oncologic or radiooncologic management in 19%, 33%, and 29%, respectively. For almost every patient undergoing irradiation, target volume delineation was improved by 68Ga-FAPI PET/CT. Conclusion: The present study demonstrated that both primary and metastatic LGT tumors were reliably detected by 68Ga-FAPI PET/CT, leading to relevant changes in TNM status and oncologic or radiooncologic management. 68Ga-FAPI PET/CT seems to be a highly promising imaging agent for the diagnosis and management of LGT tumors, potentially opening new applications for tumor staging or restaging.

Identification of a synergistic combination of Smac mimetic and Bortezomib to trigger cell death in B-cell non-Hodgkin lymphoma cells.

Recently, copy number gains and increased expression levels of cIAP1 and cIAP2 have been reported in B-cell non-Hodgkin lymphomas (NHL). Therefore, we investigated the therapeutic potential of the Smac mimetic BV6 that antagonizes cIAP1/2 and XIAP. Here, we discover that subtoxic concentrations of BV6 prime B-cell NHL cells to proteasome inhibitor Bortezomib-induced cell death. Synergistic induction of cell death by BV6 and Bortezomib is confirmed by calculation of combination index in different cell lines, emphasizing the broader relevance of this combination. Interestingly, addition of the caspase inhibitor zVAD.fmk provides no or only partial protection from BV6/Bortezomib-stimulated cell death. Consistently, BV6/Bortezomib co-treatment alone or in combination with zVAD.fmk increases phosphorylation of MLKL, a typical marker of necroptosis. Importantly, genetic silencing of key components of necroptosis signaling such as MLKL or RIP3 significantly protects DG-75 cells from BV6/Bortezomib-induced cell death in the presence and even the absence of zVAD.fmk. Similarly, pharmacological inhibitors of MLKL (i.e. NSA), RIP3 (i.e. GSK'872, Dabrafenib) or RIP1 (i.e. Necrostatin-1s) significantly rescue DG-75 cells from BV6/Bortezomib-induced cell death irrespective of the presence of zVAD.fmk. In addition, NSA or Nec-1s act in concert with zVAD.fmk to reduce BV6/Bortezomib-induced cell death in U-2932 cells. Together, these findings demonstrate that BV6 and Bortezomib synergize to induce cell death in B-cell NHL cells. BV6/Bortezomib co-treatment primarily triggers necroptosis or, alternatively, engages both apoptotic and necroptotic cell death. The discovery of this synergistic combination that is effective even when apoptosis is blocked has important implications for the development of new treatment strategies for B-cell NHL.

A retrospective study of amitriptyline in youth with autism spectrum disorders.

We performed a retrospective chart review of 50 youths with Autism Spectrum Disorder (ASD), prescribed amitriptyline (AMI) for hyperactivity and impulsivity. Data was systematically extracted from 50 outpatient clinic charts, including AMI treatment duration, dose, trough levels and adverse events. Mean age was 9.4 years (4.6-17.9); 40 were males and 10 females. 30 % had failed atomoxetine and 40 % had failed ≥3 ADHD medications. Mean dose was 1.3 ± 0.6 mg/kg/day, mean trough level 114.1 ± 50.5 ng/ml, mean duration 3.4 years. Clinical Global Impressions Scale-Improvement (CGI-I) was ≤2 in 60 % of patients at the final visit, and in 82 % of patients for at least 50 % of follow-ups. Cautious use of low dose AMI shows promise for treatment-resistant youth with ASD accompanied by hyperactivity, impulsivity, aggression and self injury.