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Establishing a Preclinical Multidisciplinary Board for Brain Tumors Birgit V Published OnlineFirst January 4, 2018; DOI: 10.1158/1078-0432.CCR-17-2168 Cancer Therapy: Preclinical Clinical Cancer Research Establishing a Preclinical Multidisciplinary Board for Brain Tumors Birgit V. Nimmervoll1, Nidal Boulos2, Brandon Bianski3, Jason Dapper4, Michael DeCuypere5, Anang Shelat6, Sabrina Terranova1, Hope E. Terhune4, Amar Gajjar7, Yogesh T. Patel8, Burgess B. Freeman9, Arzu Onar-Thomas10, Clinton F. Stewart11, Martine F. Roussel12, R. Kipling Guy6,13, Thomas E. Merchant3, Christopher Calabrese14, Karen D. Wright15, and Richard J. Gilbertson1 Abstract Purpose: Curing all children with brain tumors will require an Results: Mouse models displayed distinct patterns of response understanding of how each subtype responds to conventional to surgery, irradiation, and chemotherapy that varied with tumor treatments and how best to combine existing and novel therapies. subtype. Repurposing screens identified 3-hour infusions of It is extremely challenging to acquire this knowledge in the clinic gemcitabine as a relatively nontoxic and efficacious treatment of alone, especially among patients with rare tumors. Therefore, we SEP and CPC. Combination neurosurgery, fractionated irradia- developed a preclinical brain tumor platform to test combina- tion, and gemcitabine proved significantly more effective than tions of conventional and novel therapies in a manner that closely surgery and irradiation alone, curing one half of all animals with recapitulates clinic trials. aggressive forms of SEP. Experimental Design: A multidisciplinary team was established Conclusions: We report a comprehensive preclinical trial to design and conduct neurosurgical, fractionated radiotherapy platform to assess the therapeutic activity of conventional and chemotherapy studies, alone or in combination, in accurate and novel treatments among rare brain tumor subtypes. It mouse models of supratentorial ependymoma (SEP) subtypes and also enables the development of complex, combination choroid plexus carcinoma (CPC). Extensive drug repurposing treatment regimens that should deliver optimal trial designs screens, pharmacokinetic, pharmacodynamic, and efficacy studies for clinical testing. Postirradiation gemcitabine infusion were used to triage active compounds for combination preclinical should be tested as new treatments of SEP and CPC. Clin trials with "standard-of-care" surgery and radiotherapy. Cancer Res; 24(7); 1654–66. Ó2018 AACR. 1Cancer Research UK Cambridge Institute and Department of Oncology, Uni- versity of Cambridge, Cambridge, England, United Kingdom. 2Department of Introduction Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee. Despite decades of research, the treatment of brain tumors 3 Department of Radiological Sciences, St. Jude Children's Research Hospital, has remained largely unchanged. These cancers are treated with Memphis, Tennessee. 4Department of Developmental Neurobiology, St. Jude 5 an aggressive combination of neurosurgery, radiotherapy, and Children's Research Hospital, Memphis, Tennessee. Department of Surgery, St. fl fi Jude Children's Research Hospital, Memphis, Tennessee. 6Department of Chem- chemotherapy that frequently fails to cure but in icts signi - ical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, cant side effects (1–4). This limited progress has occurred Tennessee. 7Department of Oncology, St. Jude Children's Research Hospital, despite an active clinical trials effort: more than 2,580 brain Memphis, Tennessee. 8Department of Pharmaceutical Sciences, St. Jude Chil- tumor trials are currently registered with clinicaltrials.gov, but 9 dren's Research Hospital, Memphis, Tennessee. Preclinical Pharmacokinetics only six drugs are approved for treatment of brain tumors, of Core, St. Jude Children's Research Hospital, Memphis, Tennessee. 10Department which only two—Everolimus, an inhibitor of the mTOR (5), of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee. — 11Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, and Bevacizumab, an inhibitor of VEGFA (1) are molecular- Memphis, Tennessee. 12Department of Tumor Cell Biology, St. Jude Children's targeted treatments. Research Hospital, Memphis, Tennessee. 13University of Kentucky College of So why have we failed to identify effective new brain tumor Pharmacy, Lexington, Kentucky. 14Preclinical Imaging Core, St. Jude Children's therapies? One possibility is that the preclinical systems used to 15 Research Hospital, Memphis, Tennessee. Boston Children's Hospital and Har- select drugs for clinical trial do not predict therapeutic activity in vard Medical School, Boston, Massachusetts. patients (6). This explanation is plausible when one considers that Note: Supplementary data for this article are available at Clinical Cancer most preclinical studies are conducted in mice harboring subcu- Research Online (http://clincancerres.aacrjournals.org/). taneous brain tumor xenografts that cannot recapitulate accurate- B.V. Nimmervoll and N. Boulos contributed equally to this article. ly the pharmacology or biology of brain tumor treatment. Fur- Corresponding Authors: Richard J. Gilbertson, Cambridge University, Cam- thermore, although brain tumor patients receive complex, multi- bridge CB2 0RE, England, United Kingdom. Phone: 01223769590; E-mail: modality therapy, mice in preclinical studies usually receive drugs [email protected]; and Karen D. Wright, Boston Children's as monotherapies. Such studies are unlikely to predict the survival Hospital and Harvard Medical School, 450 Brookline Avenue, Boston, MA benefit of a new treatment above that afforded by standard of care. 02215. E-mail: [email protected] Prioritizing treatments with the greatest potential for clinical doi: 10.1158/1078-0432.CCR-17-2168 efficacy is especially important for rare tumors that have limited Ó2018 American Association for Cancer Research. patient populations available for clinical trial. 1654 Clin Cancer Res; 24(7) April 1, 2018 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst January 4, 2018; DOI: 10.1158/1078-0432.CCR-17-2168 A Preclinical Multidisciplinary Brain Tumor Board discussed in detail in the Supplementary Methods, host mice for Translational Relevance all allografts and xenografts were CD-1 nude mice (strain code: Existing drug development pipelines have failed to bring 086; Charles River). All preclinical surgery, radiotherapy, and new treatments to children with brain tumors. A lack of chemotherapy studies were performed among randomized faithful preclinical models has prevented the discovery and cohorts of mice harboring tumors with 1e107 photons/sec prioritization of potential new therapies, and the rarity of these bioluminescence (16). Tumor progression and treatment diseases presents an insurmountable hurdle for drug devel- response were assessed clinically and by weekly bioluminescence opment through clinical trial alone. Therefore, we established (16). Mice displaying signs of excessive clinical morbidity (20% a preclinical multidisciplinary tumor board comprising biol- weight loss and/or neurological impairment) were euthanized. ogists, statisticians, pharmacologists, and clinicians to conduct preclinical studies that mimic the clinic. Mouse models includ- Preclinical neurosurgery, radiotherapy, and chemotherapy ed those of specific ependymoma and choroid plexus carci- Following baseline bioluminescence imaging, mice were noma subtypes—two rare pediatric brain tumors. In contrast appropriately anaesthetized, a craniotomy fashioned over the with previous brain tumor preclinical platforms, our approach site of maximum bioluminescence, and tumors resected using enables the testing of potential new treatments of very rare a small suction tip. Postoperative hemostasis was achieved tumors, in the context of "standard-of-care" neurosurgery and with thrombin-soaked gel foam prior to skin closure. Mice fractionated irradiation. This approach enables assessment of were reimaged in the immediate postoperative period, mon- the potential therapeutic "value added" of candidate treat- itored on heating pads, and treated for 3 days with ibuprofen- ments and thereby prioritizes novel treatment combinations supplemented drinking water, dexamethasone (0.6 mg/kg/ for clinical trial. 6 hours), and mannitol (100 mg/kg/6 hours). Note that 54 Gy of radiotherapy was delivered to appropriately anesthetized mice as 2 Gy/day fractions via an orthovoltage irradiator or image-guided rodent irradiator (SARRP, Xstrahl). Drugs were Modifying long-established treatment regimens that have delivered via tail vein bolus injections or using Alzet m evolved empirically over many years is also challenging. For pumps (2001D, mean pumping rate 8.0 L/h; loaded with example, the treatment of supratentorial ependymoma (SEP) and 150 mg/mL gemcitabine solution prepared in 50:50 PEG300: choroid plexus carcinoma (CPC)—two rare pediatric brain propylene glycol; Supplementary Methods; Supplementary – tumors—has evolved over decades to include maximum surgical Table S2). For combination surgery radiotherapy or sur- – – resection and postoperative cranial irradiation (7–14). These gery radiotherapy chemotherapy studies, mice were rested for treatments are effective, but evidence suggests that this efficacy 72 hours in between therapeutic modalities. varies with tumor subtype. For example, although most SEPs containing
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