p21-activated kinases as viable therapeutic targets for the treatment of high-risk Ewing sarcoma

10509 Background: Relapses from high-risk tumors pose a major clinical challenge in pediatric oncology. The German INFORM registry (INdividualized therapy FOr Relapsed Malignancies in children) addresses this problem using integrated next-generation sequencing to rapidly identify patient-specific therapeutic targets. Methods: Whole-exome, low-coverage whole-genome and RNA sequencing is complemented with microarray-based DNA methylation profiling. Identified alterations are discussed and prioritized according to biological significance and potential druggability in a weekly molecular tumor board. Results: To date, 214 tumor samples of high-risk pediatric cancer patients have been profiled from 47 German centers, with 39% being sarcomas, 30% brain tumors, 13% neuroblastoma and 18% hematological or other malignancies. Turnaround time from tissue arrival to molecular results was 21 calendar days on average. In 14/214 patients (7%) we identified an underlying germline predisposition syndrome. In several cases there were discrepancies between the original histological diagnosis and our molecular findings, especially in brain tumors. We detected one or more potentially druggable alterations in 147/214 (69%) cases. Tyrosine kinases, the PI3K/mTOR pathway, MAPK pathway, and cell-cycle as well as transcriptional regulators were commonly affected. Based on these findings, targeted therapeutics were incorporated into the therapy regime in one-third of patients, with anecdotal reports of marked responses, including a patient with a pleomorphic sarcoma, where we detected a previously undescribed RAF-fusion, showing a partial remission upon RAF-inhibition. Conclusions: In summary, real-time comprehensive profiling of pediatric tumors provides valuable diagnostic information and identifies potential therapeutic targets. In parallel, the implementation of a systematic program for reverse-translational evaluation is ongoing. Recently, this nationwide effort has expanded to include patients from other countries. We will also recruit patients to the complementary eSMART and INFORM2 biomarker-driven, phase I/II combination trial series, to provide unprecedented access to targeted therapies in Europe.

Download Full-text

Busulfan–Melphalan followed by autologous stem cell transplantation in patients with high-risk neuroblastoma or Ewing sarcoma: an exposed–unexposed study evaluating the clinical impact of the order of drug administration

Bone Marrow Transplantation ◽

10.1038/bmt.2016.109 ◽

2016 ◽

Vol 51 (9) ◽

pp. 1265-1267 ◽

Cited By ~ 5

Author(s):

M E Dourthe ◽

N Ternès ◽

D Gajda ◽

A Paci ◽

C Dufour ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Drug Administration ◽

Ewing Sarcoma ◽

Clinical Impact

Download Full-text

Detection of disseminated tumor cells in the bone marrow of breast cancer patients using multiplex gene expression measurements identifies new therapeutic targets in patients at high risk for the development of metastatic disease

Breast Cancer Research and Treatment ◽

10.1007/s10549-012-2279-y ◽

2012 ◽

Vol 137 (1) ◽

pp. 45-56 ◽

Cited By ~ 16

Author(s):

Chidananda M. Siddappa ◽

Mark A. Watson ◽

Sreeraj G. Pillai ◽

Kathryn Trinkaus ◽

Timothy Fleming ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Bone Marrow ◽

High Risk ◽

Cancer Patients ◽

Tumor Cells ◽

Metastatic Disease ◽

Therapeutic Targets ◽

Disseminated Tumor Cells ◽

Breast Cancer Patients

Download Full-text

The predictive role of Ki-67 protein in determining the aggressiveness of primary malignant bone tumors. A retrospective study

Romanian Journal of Orthopaedic Surgery and Traumatology ◽

10.2478/rojost-2019-0018 ◽

2019 ◽

Vol 2 (2) ◽

pp. 91-95

Author(s):

Ioan-Mihai Japie ◽

Dragoș Rădulescu ◽

Adrian Bădilă ◽

Alexandru Papuc ◽

Traian Ciobanu ◽

...

Keyword(s):

High Risk ◽

Ewing Sarcoma ◽

Bone Tumors ◽

Risk Group ◽

High Risk Group ◽

Low Risk ◽

The Other ◽

Malignant Bone Tumors ◽

Ki 67

AbstractIntroduction: In order to diagnose and stage malignant bone tumors, the pathologic examination of harvested pieces with immunohistochemistry test is necessary; they also provide information regarding the prognosis on a medium to long term. Among tissular biomarkers with potential predictive value, a raised Ki-67 protein level is used to determine the risk of local recurrence or metastasis.Material and method: This study was performed on 50 patients with primary malignant bone tumors admitted in the Traumatology and Orthopedy Department of University Emergency Hospital, Bucharest. Patients repartition according to diagnosis was the following: 21 patients with osteosarcoma, 18 patients with chondrosarcoma, 6 patients with Ewing sarcoma, 3 patients with malignant fibrous histiocytoma, and 2 with fibrosarcoma. The follow-up period was between 12 and 72 months with a mean of 26 months.Results: Patients were aged between 18 and 77 years old, with a mean age of 41,36. There were 22 women and 28 men. No sex or age difference was notable for the tumor outcome. After calculating the Ki-67 LI, 36 patients were included in the high-risk group (Ki-67 LI > 25%), while 14 had a low risk for metastasis and local relapse (Ki-67 < 25%). The low-risk patients had chondrosarcoma (8 patients), osteosarcoma (5 patients), and fibrosarcoma (1 patient). During the follow-up, 8 patients, all belonging to the high risk group, developed metastasis, while 5 patients developed local recurrences; 4 patients who relapsed belonged to the high risk group and 1 to the low risk group. Metastases developed in 3 patients with osteosarcoma, 2 with Ewing sarcoma, 2 with chondrosarcoma and 1 patient with fibrosarcoma. Most metastases occurred within one year after surgery. The other fibrosarcoma patient developed local recurrence after 6 months, while the other local recurrences occurred in osteosarcoma patients (2 cases) and 1 in a Ewing sarcoma patient and chondrosarcoma patient.Conclusions: Our study concluded that while Ki-67 LI values are useful in determining the aggressivity of primary malignant bone tumors, it should always be used in conjunction with the clinical, imaging and anatomopathological diagnosis methods in order to accurately predict the patients’ outcome.

Download Full-text