Pediatr Blood Cancer 2014;61:765–767

COMMENTARY A Diffuse Intrinsic Pontine Glioma Roadmap: Guiding Research Toward a Cure Sandra E. Smith,1 John C. Waller,1 Isaiah A. Bingham,1 Danah M. Jewett,1 M. Simone Nsouli,1 and John J. Mackintosh1*

INTRODUCTION Diffuse intrinsic pontine glioma (DIPG) is a devastating glioma of the brainstem that most often occurs in children. Treatment outcomes have not improved for over 30 years [1], and more than 90% of patients die within 2 years of diagnosis [2]. The Chordoma Foundation, dedicated to improving treatment of chordoma, an equally lethal and rare form of cancer, has established a roadmap to guide research toward a cure [3]. Using this approach 10 promising therapeutic agents for chordoma have been identified, and a vaccine trial was recently modified to include recurrent chordoma patients [4,5]. While the success of this roadmap is yet to be proven, it is an attractive model for the strategic research of rare diseases. We believe that research of rare diseases would benefit from a coordinated approach that strongly involves the community. We propose the use of the Chordoma Foundation Research Roadmap, modified to include the challenge of drug delivery to the pons, to measure progress in DIPG research and identify barriers where they exist.

presence of this mutation, supporting the existence of DIPG subtypes. This is consistent with previous work indicating that specific mutations affect survival time [13]. Since 2009 DIPG cell lines originating from tissue retrieved through biopsy or autopsy have been established at various institutions throughout the world [6,8]. The DIPG Preclinical Consortium was formed in 2011 to study cell lines (Table I) [14] and test potential drugs as part of the project Rapid Preclinical Development of a Targeted Therapy Combination for DIPG [14]. While the current availability of cell lines is promising, optimism must be balanced with the understanding that primary cell cultures, as tumor cells undergo selection to become immortalized cell lines, grow to be less like the original tumors from which they were derived. For this reason, and to represent the heterogeneity of DIPG tumors with a range of cell lines, continuing to encourage the donation of fresh tumor tissue and the development of new cell lines is vital.

PROGRESS ON THE DIPG ROADMAP

Drug Delivery

The roadmap is divided into four phases (Fig. 1): Resource Development, Discovery, Target Identification and Translation. DIPG research has historically occurred with little tumor tissue available to scientists and without realistic animal models [6]. The fusion of advances in technological capability [7] and the increase in post-mortem tumor donations [8], however, have resulted in substantial progress.

Poor drug penetration to the pons is a major challenge. Improved techniques for drug delivery are critical to move promising therapies into the clinic. A recent phase 1 study of Convection Enhanced Delivery for DIPG [15] demonstrated safety of the procedure and potential for wider use in future clinical trials. This technology should be refined in parallel with therapeutic agent evaluation.

International DIPG Registry

Removing Barriers

Established in 2011, the International DIPG Registry [9] collects information from patients across the world, making demographic and clinical data available to those studying the disease. In early May 2013, 92 patients were fully enrolled, and inclusion of the data for 200–300 more patients is in process [10]. Registry goals include an improved understanding of DIPG biology and the development of better therapies. The registry has passed through IRB approval [11]. Data are shared with scientists upon request, however individual identifiers will not be released. Though the registry has the potential to support projects related to DIPG, the impact of this effort is not yet clear. Participation by families, physicians, and institutions is key, along with strong commitment on the part of registry personnel to careful stewardship of the data entrusted to them.

Moving preclinical discoveries through the translation phase and into the clinic has been hindered by barriers including tissue availability for therapy design, drug delivery through the blood– brain and blood–pontine barriers, clinical trial design of targeted therapies with a limited pool of participants and sustained funding to support the research roadmap.

Genomics, Cell Line Availability, and The DIPG Preclinical Consortium Genomic discoveries are leading researchers toward appropriate targeted therapies and furthering their understanding of the biological causes and classifications of DIPG. DNA sequencing shows a frequent mutation in the genes encoding histone 3.1 and 3.3 [12]. Researchers associated shorter survival time with the

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2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.24923 Published online 30 January 2014 in Wiley Online Library (wileyonlinelibrary.com).

Clinical Trial Design Genomic and proteomic discoveries indicate some future DIPG trials measuring efficacy will likely involve multiple targeted agents. Based on interpatient variation in DIPG tumor biology [7,13], it may be necessary to choose the most effective therapy

1

Parent and patient advocates. 2012 Participants of the Pediatric Cancer Nanocourse, Pediatric Cancer Biology Program, Department of Pediatrics, Pape´ Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon 97239

 Correspondence to: John J. Mackintosh, 12 Highland Meadow Drive, North Attleboro, MA 02760. E-mail: [email protected]

Received 6 March 2013; Accepted 11 December 2013

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Fig. 1. A DIPG Roadmap: Guiding Research toward a Cure. This research roadmap has been adapted from the Chordoma Foundation strategic plan [3] which was widely praised at the 2009 NCI Rare Cancers Workshop. The DIPG Roadmap, divided into four phases, provides a systematic way to measure progress in research and to highlight areas where more work is necessary. The roadmap may be modified to guide research of other rare diseases.

a,b

TABLE I. DIPG Preclinical Consortium Primary Cell Lines Participating institutions Oregon Health and Science University Duke University Medical Center

Stanford University University of Toronto Baylor College of Medicine VU Cancer Center Amsterdam Institut Gustave-Roussy, Villejuif, France Johns Hopkins University/NIH Nationwide Children’s Hospital University of Florida, Gainesville a

DIPG cell lines 2 cell lines 1 cell line, from mouse 11.1003.2 derived by PDGF-B and Cre overexpression in GFAP tv-a; p53 floxed mice 6 cell lines 2 cell lines 6 cell lines 2 cell lines 12 cell lines 1 cell line 1 cell line 1 cell line

Cell lines analyzed by the DIPG Preclinical Consortium as part of the project Rapid Preclinical Development of a Targeted Therapy Combination for DIPG [14]. This is not an exhaustive list of existing DIPG cell lines; bMost cell lines were derived from autopsy tissue. Pediatr Blood Cancer DOI 10.1002/pbc

combination for individual patients. Traditionally drug efficacy is measured in a broad group of patients with a shared diagnosis. Food and Drug Administration leadership recognizes the need for clinical trials that accommodate risk stratified therapy [16].

Funding the Roadmap DIPG is rare and thus lacks research investment by the pharmaceutical industry. Limited government grants are likely to become more scarce due to the current federal budget crisis. Substantial progress has been made possible through communitybased funding. A limited survey of DIPG foundations showed that they contributed at least $2.6 million toward DIPG research between 2007 and 2012. Sustained funding is critical in order to continue to make progress on the roadmap. Community based foundations have a role in helping to make up the deficit in investment by industry and government. Foundations are more likely to succeed in this effort if they work together to adopt a shared vision and a strategic plan to pool resources, including capital, advisory councils and information systems. The organization of 19 foundations as the DIPG Collaborative (http://www.dipg.org) at the May 2013 DIPG Symposium demonstrates that this cooperation has already begun.

A Community-Based Diffuse Intrinsic Pontine Glioma Research Roadmap

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CONCLUSION

REFERENCES

Significant strides have been made on the DIPG roadmap. Researchers have worked collaboratively to develop the DIPG Registry and to create the DIPG Preclinical Consortium. Clinicians are now working to organize an international DIPG clinical cooperative group to collaborate on the design, execution, and reporting of DIPG clinical trials. This will hopefully reduce duplication of efforts, give patients access to therapies with the greatest potential for success and help researchers acquire the most useful data from a limited number of patients. The formation of a DIPG clinical cooperative brings hope for collaboration across the entire roadmap. The adoption of a common roadmap and cooperation among foundations increase the potential for success and provide a model for the strategic research of rare diseases.

1. V.C. pioneering preclinical research in diffuse intrinsic pontine glioma: Towards new treatment strategies. Amsterdam: Vrije Universiteit; 2012. 176 p. 2. Jansen MH, van Vuurden DG, Vandertop WP, et al. Diffuse intrinsic pontine gliomas: A systematic update on clinical trials and biology. Cancer Treat Rev 2012;38:27–35. 3. 2012 September 30. Research Roadmap. The Chordoma Foundation . Accessed September 30, 2012. 4. 2013 June 30. Moving Research Forward. The Chordoma Foundation . Accessed June 30, 2013. 5. 2013 June 30. Open label study to evaluate the safety and tolerability of GI-6301 (whole heat-killed recombinant yeast modified to express brachyury protein) in adults with solid tumors. National Institute of Health . Accessed June 30, 2013. 6. Monje M, Mitra SS, Freret ME, et al. Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. Proc Natl Acad Sci USA 2011;108:4453–4458. 7. Warren KE. Diffuse intrinsic pontine glioma: Poised for progress. Front Oncol 2012;2:205. 8. Jansen MH, Kaspers GJ. A new era for children with diffuse intrinsic pontine glioma: Hope for cure? Expert Rev Anticancer Ther 2012;12:1109–1112. 9. 2011 June 30. The DIPG Registry. Cincinnati Children’s Hospital Medical Center . Accessed June 30, 2013. 10. Fouladi M. DIPG registry application and results. DIPG Collaborative & Symposium. Cincinnati Children’s Hospital, Cincinnati, OH, 2013. 11. 2013 January 8. The DIPG Registry. Cincinnati Children’s Hospital Medical Center . Accessed November 2, 2013. 12. Khuong-Quang DA, Buczkowicz P, Rakopoulos P, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 2012;124:439–447. 13. Puget S, Philippe C, Job B, et al. Molecular profiling of pediatric diffuse intrinsic pontine gliomas at diagnosis identifies two biologically distinct entities. Neuro Oncol 2010;12:ii8–ii9. 14. 2011 June 30. Pediatric preclinical testing initiative. Oregon Health and Science University . Accessed June 30, 2013. 15. 2013 June 30. Convection-enhanced delivery of 124I-8H9 for patients with non-progressive diffuse pontine gliomas previously treated with external beam radiation therapy. National Institute of Health . Accessed June 30, 2013. 16. Pittman D. 2013 May 22. FDA Rethinking Personalized Drug Trials. . Accessed May 22, 2013.

ACKNOWLEDGMENTS We are grateful to Charles Keller, Michelle Monje, and Gloria Garcia for their thoughtful comments during the development of this manuscript and to Lisa Mackintosh and Shawn Smith for their faithful support. Special thanks to Josh Sommer and the Chordoma Foundation. Finally we would like to acknowledge our inspiration: Andrew, Charlie, Dylan, Lyla, Nicole, and every child who faces DIPG.

Pediatr Blood Cancer DOI 10.1002/pbc

A diffuse intrinsic pontine glioma roadmap: guiding research toward a cure.

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