Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

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Clinical, radiologic, and molecular characteristics of anaplastic pleomorphic xanthoastrocytomas
Translational
Astrocytomas, Childhood (Brain Cancer)
Lay Summary

 

Pleomorphic xanthoastrocytomas (PXAs) are uncommon brain cancers in children and young adults. World Health Organization (WHO) grade II PXAs (low-grade gliomas), which account for most such tumors, can be cured by complete surgery. Aggressive variants (i.e., anaplastic PXAs), which are rare, were only recognized by the WHO classification of brain tumors as malignant (high-grade) in 2016. Although the survival of patients with anaplastic PXAs is longer than those with glioblastoma (WHO grade IV), the deadliest brain cancer in children and adults, most affected patients will die of their cancer despite the use of intensive treatment, including surgery, irradiation, and chemotherapy. Limited data are available about changes in the genetic make-up that drive the growth of anaplastic PXAs. The most detailed genetic study to date analyzed approximately 500 genes in15 tumors. Most anaplastic PXAs carry genetic abnormalities in a gene called BRAF, which is also present in other types of cancers (e.g., melanoma). We started this multi-institutional study involving 12 hospitals in the US and Australia 2 years ago to further understand the clinical and radiologic characteristics of patients with anaplastic PXAs, and to perform detailed analyses of the genetic make-up of these tumors at diagnosis and at recurrence.

A new type of anticancer medication targeting BRAF (called BRAF inhibitors), which is already approved for adults with melanoma and lung cancer, produced promising responses against anaplastic PXAs but most tumors eventually grew back in less than one year. A secondary goal of this study is to analyze the genetic make-up of tumors that grow back despite treatment with BRAF inhibitors.

Medical information and available radiologic studies (i.e., magnetic resonance imaging) at diagnosis and recurrence of all research participants was reviewed by the study principal investigator. The genetic evaluation of anaplastic PXAs will be done by using state-of-the-art tests, including those that can analyze the entire genetic make-up of cancers (i.e., tests called whole-genome (WGS)/whole-exome (WES) and RNA sequencing, and DNA methylation profiling). Twenty-two research participants were already enrolled on study. We have solid evidence based on history, imaging, and/or institutional review of tumor samples that 10 (45%) of 22 cases originated from a low-grade glioma (WHO grade II). Unlike adults, malignant transformation of pediatric WHO grade II low-grade gliomas occurs in less than 10% of cases. Approximately 75% of these 22 cases are known to have a BRAF mutation. Interestingly, BRAF-mutated pediatric low-grade gliomas were previously reported to have an increased predisposition to malignant transformation to high-grade gliomas but this phenomenon was not particularly associated with any type of tumor, including PXAs. At least two sequential samples in the trajectory of these tumors (some starting with the low-grade glioma going all the way to the malignant cancer) are available for molecular analyses in 11 (50%) of 22 cases so far. Sequencing by WGS and RNA sequencing of tumor +/- blood samples was completed for the first 8 cases. Sequencing of the remaining cases is about to start. We plan to start computational analyses of the genetic data generated in the next 4 to 6 months. Our goal is to enroll a few more participants on this study in the next 3 to 4 months to reach a goal of about 30 total cases.

We are submitting this application to partially fund the remaining planned genetic studies and to support the detailed computational analyses of the RNA sequencing data.

Genetic studies including patients with anaplastic PXA were previously reported. However, those studies did not include details about the clinical history of these patients and review of imaging. Therefore, except for case reports, the high-risk for anaplastic PXAs to arise from a malignant progression was never previously characterized. Amazingly, the study principal investigator's initial experience of anaplastic PXAs originating from malignant progression at St. Jude Children's Research Hospital (SJCRH; 2002-2017) and at the University of Pittsburgh Medical Center (UPMC) Children's Hospital of Pittsburgh (CHP; 2017 to present) was confirmed across several institutions in the US.

In summary, this study addresses two critical issues focused on pediatric gliomas: the discovery of genetic characteristics associated with anaplastic PXAs and with their high risk to originate from low-grade tumors. We hope that the detailed clinical, radiologic, and genetic analyses of a large group of patients with anaplastic PXAs in this collaborative study will uncover new abnormalities in these tumors associated with their high risk of malignant transformation and resistance to therapy. Akin to other cancers, we hope that a better understanding of these rare and deadly cancers may reveal new promising ways to treat affected patients in future clinical trials. This research study was approved at UPMC CHP and at all other participating institutions.

 

 

Executive Summary

WHO grade II tumors, which account for the vast majority of PXAs, are associated with long-term survival and good outcome when a gross-total resection is achievable. Although PXAs with aggressive clinical behavior were described in the 1990s, histopathologic criteria to define anaplastic PXAs were only defined in 1999: a high mitotic index (≥ 5 mitoses per 10 high-power fields at 400x magnification) with or without necrosis.

Anaplastic PXA represents not only a rare but also one of the most poorly understood high-grade central nervous system (CNS) cancers in adults and children. Although objective histopathologic criteria to diagnose these tumors have been available for more than 20 years, treatment of affected patients were variable since the malignant nature of this cancer was not defined by the WHO classification until 2016. Therefore, it was common until recently for therapeutic approaches for affected patients to vary widely between the use of surgery only vs. multimodal treatment including surgery, radiation therapy (RT), and chemotherapy.

A few studies reported molecular abnormalities associated with anaplastic PXAs consisting of copy number abnormalities, DNA methylation profiling, and sequencing by next generation panels of a limited set of cancer-related genes. BRAF V600E mutations are known to occur in more than 70 to 80% of anaplastic PXAs (range between 17% to 100% of cases in published manuscripts). Homozygous CDKN2A loss in combination with BRAF V600E are seen in most cases. TERT promoter mutations or amplification occur in about half of cases. DNA methylation profiling reported that WHO grade II and anaplastic PXAs mostly clustered together, which is quite counterintuitive based on the significant difference in outcome between patients affected by these two tumors.

Based on the scarcity of clinical and molecular information about anaplastic PXAs, we started this multi-institutional collaborative study involving 12 institutions in the US and Australia 2 years ago. Multiple characteristics differentiate our study compared to those previously published. First, we collected prospective detailed clinical history and performed central imaging review in 95% and 90% of cases so far, respectively. By performing this review in the first two participating institutions (SJCRH and UPMC CHP), we recognized that 5 of 8 cases had clear evidence that the anaplastic PXAs arose from a low-grade glioma by history, imaging, and histopathologic review. Likewise, expansion of this analysis to cases from 7 additional institutions so far (Arnold Palmer Medical Center, Children's Hospital of Arkansas, Children's Hospital of Minnesota, Children's Hospital of Phoenix, Perth Children's Hospital, St. Vincent Hospital, and University of Utah) confirmed our initial findings and added 5 of 14 cases which progressed from low-grade tumors. Second, we have been able to collect tumor (n=22 so far) and germline samples (n=18 so far) retrospectively and prospectively for the past 2 years by obtaining IRB approval at all participating institutions. The tumor samples were mostly derived from formalin-fixed paraffin-embedded tissue (FFPE). Collaborative agreements are at final stages before transfer of data from the three remaining institutions (Austin Children's Hospital, Cook Children's Hospital, and Murdoch Childrens Research Institute) can take place. Third, we were able to collect multiple tumor samples at diagnosis and at the time of tumor progression in 11 (50%) of 22 cases so far (median number of samples: 3 per case; range: two to four samples per case). Finally, unlike previously reported studies, we are performing a comprehensive molecular analysis of tumor (obtained at diagnosis and at recurrence) and germline samples consisting of WGS/WES, RNA sequencing, and DNA methylation profiling.

DNA and RNA from tumor and germline samples (when available) was already extracted from 21 of 22 cases. WGS and RNA sequencing of first 8 cases was completed and funded by a grant provided by the UPMC Institute of Precision Medicine. DNA and RNA sequencing of the remaining available samples is about to start. DNA methylation profiling has not been initiated yet. We expect transfer of clinical and imaging data and of tumor +/- germline samples from the last 3 institutions soon since a material transfer agreement and IRB-approval were already obtained in three and two of these collaborating sites, respectively. We also received approval from the Children’s Brain Tumor Tissue Consortium (CBTTC), which has prospectively collected more than 3,000 cases of CNS cancers in the US and abroad, to obtain clinical, radiologic, and molecular data from anaplastic PXAs already submitted to this consortium. We identified so far two cases from CBTTC who qualify for this study. In summary, we have reached a stage in this study where we are close to be able to rapidly perform and complete WES, RNA sequencing, and DNA methylation profiling as initially planned. Our plan is to start the computational biology analyses as soon as the WES and RNA sequencing, and DNA methylation profiling is concluded. Of importance, although WGS was obtained for the first 8 cases as part of the UPMC grant, the remaining samples will undergo WES.

Finally, we assembled a team of experts in the field to collaborate in this study. Dr. Alberto Broniscer, Director of Neuro-Oncology at UPMC CHP and a Full Professor in the Department of Pediatrics UPMC CHP is an expert in clinical management of high-grade gliomas. Dr. Baoli Hu and Dr. Sameer Agnihotri, both assistant professors at the Division of Neurosurgery at UPMC CHP, are collaborating in this study. Both Dr. Hu and Dr. Agnihotri are translational scientists, each with his own lab, who have great expertise in studying the molecular characteristics of CNS cancers, particularly high-grade gliomas. Dr. Hu and Agnihotri will help in the analyses of WGS/WES/RNA sequencing and DNA methylation profiling and have committed to perform validation studies based on those findings. We established a collaboration with Ocean Genomics, a company founded by colleagues from Carnegie Mellon University, to perform the computational biology analyses of RNA sequencing. The Department of Computational Biology at Carnegie Mellon University is one of the leading programs in this field in the world. This collaboration will provide great expertise in the analyses of RNA sequencing in the current study. We are still in discussions to establish a collaboration for computational biology analyses of WGS/WES and DNA methylation profiling.

We are applying for the current grant to fund DNA methylation profiling and the WES and RNA sequencing of the remaining samples. We have a commitment to obtain tumor +/- germline samples from 9 additional research participants from the three remaining institutions. We are also applying for this grant to partially fund the computational biology analyses of RNA sequencing.

Description of Research Proposal

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Budget

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.

Morbi orci urna, ornare non pretium eget, pulvinar eget magna. Ut consectetur efficitur varius. Fusce ac aliquet mauris, at mattis ligula. Quisque est libero, interdum id orci et, ornare luctus diam. Proin commodo lectus id accumsan blandit. Nulla eu turpis interdum, luctus ante ac, imperdiet tellus. In semper enim eu tristique aliquam.

Collaborations and Conflicts of Interest

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