PROGRESS UPDATE. A Kids Brain Tumor Cure Foundation

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1 PROGRESS UPDATE A Kids Brain Tumor Cure Foundation September 2016

2 EXECUTIVE SUMMARY Primary cancers of the brain have surpassed leukemias to become the number one cause of cancer-related death in children. Pediatric low-grade astrocytomas (PLGAs) are the most common brain tumor of childhood. The current standard of care for PLGA patients is surgery, chemotherapy, and radiation, all carrying long-lasting, adverse side effects. Therefore, there is an urgent need for a new therapeutic approach, smart drugs, that specifically target the underlying molecular causes of cancer with minimal collateral damage. The Pediatric Low-Grade Astrocytoma Program at Dana-Farber is a group of internationally renowned experts devoted to advancing targeted therapy treatments for this devastating disease. Under the leadership of Mark Kieran, MD, PhD, Director of Pediatric Neuro-Oncology, and Charles Stiles, PhD, the group is spearheading basic science investigations that are revealing key biologic and molecular information, the foundation for developing new targeted therapies in current and planned clinical trials. Mark Kieran, MD, PhD, Director, Pediatric Neuro- Oncology Please continue to read to learn about the groundbreaking findings that offer hope in fighting this horrible childhood cancer. As we advance discoveries and care, we are grateful for your partnership in supporting this important work, which will impact patients and their families for many years to come. IDENTIFYING THE MOLECULAR DAMAGE IS THE KEY TO THE CURE Smart drugs for the most common oncogenic mutation in PLGA Approximately 70 percent of PLGA tumors have mutations in a gene known as BRAF, which encodes an enzyme critical to the control of cell growth and division. There are two common forms of mutant BRAF found in PLGAs. One form (known as BRAFV600E ) is found also in malignant melanoma a deadly and very common skin tumor of adults. It is fortuitous that a drug, dabrafenib, is already approved to treat adult BRAF tumors. Taking advantage of this opportunity, Dr. Kieran is leading an international clinical trial of dabrafenib for pediatric patients with advanced tumors that have BRAFV600E. After a phase I trial resulted in a promising response rate, Dr. Charles Stiles, PhD 2

3 Kieran and his colleagues launched the phase II trial to further test dabrafenib across several additional types of pediatric cancer. Dr. Kieran presented these encouraging early results at the June 2015 American Society of Clinical Oncology meeting. Unfortunately the most common BRAF mutation in PLGAs is not BRAFV600E but rather a mutation known as KIAA1549BRAF. This mutation is resistant to dabrafenib and other drugs approved for the BRAFV600E mutations found in adult melanomas. Dr. Stiles and PLGA Program investigators Nathalie Agar, PhD, Sara Buhrlage, PhD, and Rosalind Segal, MD/PhD have identified a promising new drug, TAK580, which can target both types of BRAF mutation. Dr. Kieran will be taking TAK580 forward into clinical trials that will hopefully begin enrolling patients by December of this year. In a third avenue, Dr. Stiles and his collaborators discovered that the BRAF fusion mutation may lead to abnormal activity in a downstream gene called MEK, causing uncontrolled cellular growth. Dr. Stiles and his team are exploring whether targeting MEK can indirectly block abnormal BRAF activity. Toward this goal, Dr. Kieran launched a multi-center clinical trial in 2015 to test the drug MEK162 in patients with the BRAF fusion gene. Accounting for the other 30 percent of PLGAs: MYB-QKI Thirty percent of PLGA tumors do not contain a BRAF mutation. Using data collected during genomic studies at Dana-Farber and other cancer centers, Rameen Beroukhim, MD, PhD, Pratiti Bandopadhayay, MD, PhD, and Keith Ligon, MD, PhD, recently identified an alteration in angiocentric gliomas, a rare form of low-grade glioma for which the causes were previously unknown. The team specifically identified the MYB-QKI fusion mutation an abnormality that occurs when two genes fuse together as an important driver of this disease. Through further preclinical studies, they determined that this fusion mutation promoted tumor growth through three distinct mechanisms, representing the first known example of three impacts derived from a single mutational change. This discovery was published in the March 2016 issue of Nature Genetics. Since this recently identified tumor type is challenging to diagnose, the disease is often misidentified and over-treated with extra chemotherapy or radiation, which can have negative long-term impacts. The MYB-QKI fusion Rameen Beroukhim, MD, PhD Pratiti Bandopadhayay, MD, PhD Keith Ligon, MD, PhD, Director, Neuro-Oncologic Pathology 3

4 mutation is unique to angiocentric gliomas, and could thereby help investigators to better diagnose and treat the disease effectively while reducing side effects. The team is conducting additional studies in cell lines and mouse models to learn more about how best to block this mechanism with therapy. Homing in on p53 and Olig2 As one of the most commonly altered genes linked to cancer, p53 remains an important therapeutic target in PLGA. In addition, Dr. Stiles and his colleagues learned that a protein called Olig2 is expressed in cells that give rise to PLGAs. While previous efforts to block the cancer-driving activities of these genes have not yet proven to be successful, Dr. Stiles and his team are exploring novel strategies to block these altered genes. Through their work in laboratory models, they aim to learn more about how inhibiting these targets impacts PLGA to clarify how these genes function and to develop better strategies to target them with therapy. The road ahead: Bolstering PLGA research through sample collection and mouse models To learn more about the key drivers of pediatric gliomas, Dana-Farber investigators continue to develop their bank of tumor samples from patients at Dana-Farber and PLGA consortium sites. All patients with PLGA at Dana- Farber have the opportunity to contribute samples, helping to build a longterm research tool that investigators can use to conduct genomic sequencing and pre-clinical research aimed to further elucidating the biology underlying these tumors (see Profile sidebar). With a consent rate of more than 90 percent, the pediatric glioma tumor bank now has more than 350 samples available to bolster research efforts. As part of this project, the team is developing mouse models of PLGA that recapitulate key characteristics of patient tumors. Using these models, the team is continuing to identify other alterations linked to PLGA and collaborating with Dana-Farber s chemical biologists to explore strategies for targeting these activities. These multifaceted studies are uniting Dana-Farber s finest leaders to accelerate drug discovery and development. 4

5 Since its inception, the PLGA Program has initiated several landmark projects, including the tissue bank. This pie chart depicts the breakdown of pediatric glioma subtypes identified through the tissue bank, with low-grade astrocytomas as the most common form of childhood brain cancer. Image on left courtesy of Dr. Stiles NEURO-ONCOLOGY OUTCOMES AND SURVIVORSHIP Today, there are more than 350,000 survivors of pediatric cancers in the United States. This progress can be attributed to many key advances in the field, allowing for improved treatments to help young patients. With this increase in the number of survivors, investigators can now explore ways to fine-tune treatment plans that will maximize efficacy while minimizing the potential late effects of therapy. As discovery science reveals more about the specific drivers of childhood brain tumors, investigators are increasingly able to personalize treatment and deliver therapies that are maximally effective while also considering the longterm health of young patients. Peter Manley, MD, Director of the Stop & Shop Family Pediatric Neuro-Oncology Outcomes Clinic, and his team aim to better understand and reduce treatment side effects, ensuring that patients with pediatric brain tumors receive optimal care and that survivors experience ongoing support. The Stop & Shop Family Pediatric Neuro- Oncology Outcomes Clinic provides patients and their families with the resources and assistance that they need to navigate a pediatric brain tumor diagnosis, treatment, and survivorship. Peter Manley, MD, Director, Stop & Shop Family Pediatric Neuro-Oncology Outcomes Clinic 5

6 THE POWER OF PHILANTHROPY Thank you for your commitment, which helps Dana-Farber investigators to lead pioneering projects that advance our understanding of pediatric lowgrade astrocytoma. These discoveries strengthen our ability to uncover and deliver new therapeutic options for patients, keeping Dana-Farber at the forefront of pediatric cancer research and care. On behalf of our patients and their families, thank you for your generous support in these critical efforts. Report written by Brittany Flaherty. FOR MORE INFORMATION Amy Trapasso Director, Corporate and Foundation Relations Telephone: (617) Dana-Farber Cancer Institute. All Rights Reserved. No part of this report may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or by an information storage or retrieval system, without permission in writing from Dana-Farber Cancer Institute. For additional information, please contact Jane Anderson at or % of all designated gifts will support our Faculty Research Fund to advance Dana-Farber s research mission. 6