Deanna Mitchell

A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma

Background Neuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB. Methods and Findings Twenty-one patients participated in a phase I study of daily oral DFMO alone for three weeks, followed by additional three-week cycles of DFMO plus daily oral etoposide. No dose limiting toxicities (DLTs) were identified in patients taking doses of DFMO between 500-1500 mg/m2 orally twice a day. DFMO pharmacokinetics, single nucleotide polymorphisms (SNPs) in the ODC gene and urinary levels of substrates for the tissue polyamine exporter were measured. Urinary polyamine levels varied among patients at baseline. Patients with the minor T-allele at rs2302616 of the ODC gene had higher baseline levels (p=0.02) of, and larger decreases in, total urinary polyamines during the first cycle of DFMO therapy (p=0.003) and had median progression free survival (PFS) that was over three times longer, compared to patients with the major G allele at this locus although this last result was not statistically significant (p=0.07). Six of 18 evaluable patients were progression free during the trial period with three patients continuing progression free at 663, 1559 and 1573 days after initiating treatment. Median progression-free survival was less among patients having increased urinary polyamines, especially diacetylspermine, although this result was not statistically significant (p=0.056). Conclusions DFMO doses of 500-1500mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway. Trial Registration Clinicaltrials.gov NCT#01059071

Targeting receptor-activator of nuclear kappaB ligand in aneurysmal bone cysts: verification of target and therapeutic response.

Aneurysmal bone cyst (ABC) is a benign tumor of bone presenting as a cystic, expansile lesion in both the axial and appendicular skeleton. Axial lesions demand special consideration, because treatment-related morbidity can be devastating. In similar lesions, such as giant cell tumor of bone (GCTB), the receptor-activator of nuclear kappaB ligand (RANKL)-receptor-activator of nuclear kappaB (RANK) signaling axis is essential to tumor progression. Although ABC and GCTB are distinct entities, they both contain abundant multinucleated giant cells and are osteolytic characteristically. We hypothesize that ABCs express both RANKL and RANK similarly in a cell-type specific manner, and that targeted RANKL therapy will mitigate ABC tumor progression. Cellular expression of RANKL and RANK was determined in freshly harvested ABC samples using laser confocal microscopy. A consistent cell-type-specific pattern was observed: fibroblastlike stromal cells expressed RANKL strongly whereas monocyte/macrophage precursor and multinucleated giant cells expressed RANK. Relative RANKL expression was determined by quantitative real-time polymerase chain reaction in ABC and GCTB tissue samples; no difference in relative expression was observed (P > 0.05). In addition, we review the case of a 5-year-old boy with a large, aggressive sacral ABC. After 3 months of targeted RANKL inhibition with denosumab, magnetic resonance imaging demonstrated tumor shrinkage, bone reconstitution, and healing of a pathologic fracture. Ambulation, and bowel and bladder function were restored at 6 months. Denosumab treatment was well tolerated. Post hoc analysis demonstrated strong RANKL expression in the pretreatment tumor sample. These findings demonstrate that RANKL-RANK signal activation is essential to ABC tumor progression. RANKL-targeted therapy may be an effective alternative to surgery in select ABC presentations.

Using a rhabdomyosarcoma patient‐derived xenograft to examine precision medicine approaches and model acquired resistance

Precision (Personalized) medicine has the potential to revolutionize patient health care especially for many cancers where the fundamental disease etiology remains either elusive or has no available therapy. Here we outline a study in alveolar rhabdomyosarcoma, in which we use gene expression profiling and a series of drug prediction algorithms combined with a matched patient‐derived xenograft (PDX) model to test bioinformatically predicted therapies.

Feasibility of implementing molecular-guided therapy for the treatment of patients with relapsed or refractory neuroblastoma

The primary objective of the study was to evaluate the feasibility and safety of a process which would utilize genome‐wide expression data from tumor biopsies to support individualized treatment decisions. Current treatment options for recurrent neuroblastoma are limited and ineffective, with a survival rate of <10%. Molecular profiling may provide data which will enable the practitioner to select the most appropriate therapeutic option for individual patients, thus improving outcomes. Sixteen patients with neuroblastoma were enrolled of which fourteen were eligible for this study. Feasibility was defined as completion of tumor biopsy, pathological evaluation, RNA quality control, gene expression profiling, bioinformatics analysis, generation of a drug prediction report, molecular tumor board yielding a treatment plan, independent medical monitor review, and treatment initiation within a 21 day period. All eligible biopsies passed histopathology and RNA quality control. Expression profiling by microarray and RNA sequencing were mutually validated. The average time from biopsy to report generation was 5.9 days and from biopsy to initiation of treatment was 12.4 days. No serious adverse events were observed and all adverse events were expected. Clinical benefit was seen in 64% of patients as stabilization of disease for at least one cycle of therapy or partial response. The overall response rate was 7% and the progression free survival was 59 days. This study demonstrates the feasibility and safety of performing real‐time genomic profiling to guide treatment decision making for pediatric neuroblastoma patients.

A Phase 1 Trial of TPI 287 as a Single Agent and in Combination With Temozolomide in Patients with Refractory or Recurrent Neuroblastoma or Medulloblastoma

The primary aim of this Phase I study was to determine the maximum tolerated dose (MTD) of TPI 287 and the safety and tolerability of TPI 287 alone and in combination with temozolomide (TMZ) in pediatric patients with refractory or recurrent neuroblastoma or medulloblastoma. The secondary aims were to evaluate the pharmacokinetics of TPI 287 and the treatment responses.

Focal nodular hyperplasia in oncology patients

Sir, A case of multiple focal nodular hyperplasia (FNH) in a patient treated for stage III neuroblastoma was presented at the Midwest Society for Pediatric Radiology Meeting in September 2005 at Madison, Wisconsin. The patient received carboplatin, cyclophosphamide, Adriamycin, vincristine, cisplatin, and etoposide chemotherapy, right paraspinal thoracic irradiation, and stem cell bone marrow transplantation. Two years after initiation of retinoic acid therapy and 3 years after the diagnosis of neuroblastoma, numerous hepatic lesions (hyperdense on portal venous phase and isodense on delayed phase) were noted on surveillance CT imaging. Several new lesions were found on a short-term follow-up CT examination. This case complements the article by Joyner et al. [1] in Pediatric Radiology and allows some additional points: (1) other drugs may be implicated in the development of FNH, (2) chemotherapy-induced FNH may not necessarily be a late complication, and (3) knowledge of this complication may not necessarily obviate the need for biopsy. While many of the drugs used to treat this patient are associated with the development of FNH, retinoic acid should also be considered. The chemotherapeutic effect of retinoic acid is related to its promotion of cytodifferentiation and apoptosis. However, retinoic acid also has prothrombotic effects by inducing endothelial coupling of coagulation factors. Retinoic acid has been implicated in various thrombotic events including myocardial infarction, pulmonary embolism, venous thrombosis and stroke [2]. The time to development of FNH noted by Bouyn et al. [3] is 8.5 years for cytoreductive chemotherapy and 12.3 years for other chemotherapy. One of three cases presented by Joyner et al. occurred 3 years after diagnosis. The case presented here also occurred 3 years after diagnosis. While development of FNH is typically late, lesions can occur early and could be confused with metastatic disease. FNH can have many imaging appearances, and there is overlap with hepatic adenoma, hypervascular metastasis, and other hepatic malignancies [4]. While the diagnosis of FNH was suggested in the current patient, the lack of a central scar and the number of lesions resulted in a shortterm follow-up examination. The increase in the number of lesions on the follow-up examination was unsettling and resulted in confirmation of the diagnosis with biopsy. In conclusion, retinoic acid may be another drug implicated in development of FNH, chemotherapy-induced FNH may occur early, and biopsy may be necessary to confirm the diagnosis in atypical cases.

Maintenance DFMO Increases Survival in High Risk Neuroblastoma

High risk neuroblastoma (HRNB) accounts for 15% of all pediatric cancer deaths. Despite aggressive therapy approximately half of patients will relapse, typically with only transient responses to second-line therapy. This study evaluated the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) as maintenance therapy to prevent relapse following completion of standard therapy (Stratum 1) or after salvage therapy for relapsed/refractory disease (Stratum 2). This Phase II single agent, single arm multicenter study enrolled from June 2012 to February 2016. Subjects received 2 years of oral DFMO (750 ± 250 mg/m2 twice daily). Event free survival (EFS) and overall survival (OS) were determined on an intention-to-treat (ITT) basis. 101 subjects enrolled on Stratum 1 and 100 were eligible for ITT analysis; two-year EFS was 84% (±4%) and OS 97% (±2%). 39 subjects enrolled on Stratum 2, with a two-year EFS of 54% (±8%) and OS 84% (±6%). DFMO was well tolerated. The median survival time is not yet defined for either stratum. DFMO maintenance therapy for HRNB in remission is safe and associated with high EFS and OS. Targeting ODC represents a novel therapeutic mechanism that may provide a new strategy for preventing relapse in children with HRNB.

Abstract B01: Sustained clinical response to treatment directed by genomic expression profiling suggests mTOR signaling is an effective target in choroid plexus carcinoma

Background: Choroid plexus tumors comprise 10-20% of intracranial tumors in children less than one year of age, the majority of these are benign papillomas, however some are highly aggressive carcinomas. Choroid Plexus Carcinoma (CPC) is derived from the choroid plexus which is neuroepithelial tissue that normally produces CSF and lines the intracranial ventricles. The prognosis of choroid plexus carcinomas is poor with 5 year event free survival rates varying between 10%-50% while relapsed or metastatic CPC is usually fatal. A patient with relapsed CPC who had progressed on 5 previous salvage chemotherapy combinations was enrolled on Neuroblastoma Medulloblastoma Translational Research Consortium (NMTRC) Molecular-Guided Therapy Trial for the Treatment of Patients with Relapsed or Refractory Childhood Cancer in which we performed genomic profiling allowing a targeted approach to therapeutic decision making. Methodology: The patient with multiply relapsed metastatic CPC enrolled on NMTRC Molecular Guided Therapy Clinical Trial after obtaining written informed consent. A tumor biopsy was sent to the Clinical Reference Laboratory (CRL) for mRNA expression analysis using U133 2.0 Plus GeneChip, and to Translational Genomics Research Institute (TGen) for high-performance RNA-seq analysis and DNA exome analysis. The differential expression data was interpreted in the context of systems biology annotation. Analysis of RNA expression results were discussed in a NMTRC tumor board leading to a therapeutic plan using study targeted treatments. Patient response was determined by clinical examination with serial MRI of the brain. Results: In this CPC specimen the PI3K/Akt/mTOR pathway was found to be highly expressed as well as PDGF, FGF2 and HDAC3 which were chosen by the tumor board for targeted therapy. Exomes analysis confirms mutation in RPTOR involved in mTOR activation. Treatment with sirolimus (mTOR), thalidomide (FGF2), Sunitinib (PDGF), and vorinostat (HDAC3) resulted in a 68% tumor reduction and the patient maintains a continuous response after 11 months while continuing to receive this therapy. This treatment combination has been well tolerated with no serious adverse events and excellent quality of life. Conclusion: Genomic Profiling analyses revealed activation of the mTOR pathway in this chemo-resistant Choroid Plexus Carcinoma. Targeted therapy has demonstrated clinical benefit suggesting a novel therapeutic approach. Further investigation of the mTOR pathway as a therapeutic target in CPC warranted. Citation Format: Albert S. Cornelius, Jessica Foley, Deanna Mitchell, Abhinav Nagulapally, Jeff Bond, Matthew Huntelman, Jason Corneveaux, Jeff Trent, Giselle Sholler. Sustained clinical response to treatment directed by genomic expression profiling suggests mTOR signaling is an effective target in choroid plexus carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B01.

Radiation-induced osteosarcoma of the hand: case report.

Radiation-associated sarcomas represent less than 5% of all sarcomas and can arise from previously irradiated bone or soft tissue. We report a case of radiation-associated osteosarcoma that developed in the hand of a patient who had previously been treated for synovial sarcoma. Despite aggressive, multimodality treatment, the disease progressed rapidly. This case highlights the need for patients and treating physicians to be aware of this potential complication of radiotherapy to the hand.

Abstract LB-160: A feasibility trial using molecular-guided therapy for the treatment of patients with refractory or recurrent neuroblastoma.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: Neuroblastoma is the most common extracranial solid tumor in children, and treatment options for recurrent neuroblastoma are limited. Using molecular profiling to target the molecular vulnerabilities of individual patient tumors with existing therapeutic agents may result in a rational, data-driven approach to treatment with potential to improve clinical outcomes. Methods: This was a multicenter study through the Neuroblastoma and Medulloblastoma Translational Research Consortium. The primary objective of this study was to evaluate the feasibility of supporting real-time treatment decisions through predictive modeling of genome-wide mRNA gene expression data from neuroblastoma tumor biopsies. Feasibility was defined as completion of tumor biopsy, histopathological evaluation, RNA extraction and quality control, gene expression profiling within a CLIA-certified laboratory, bioinformatic analysis, generation of a drug prediction report, molecular tumor board review yielding a formulated treatment plan, independent medical monitor review, treatment initiation within a 2-week period and completion of one cycle of therapy. The secondary objectives included a reproducibility study of patient biopsies, safety and response to therapy. Research validation in cell culture models of patient tumors was performed. Results: Fourteen patients with multiply relapsed neuroblastoma were enrolled between July 2011 and November 2012. All biopsies passed histopathology and RNA quality control. Generation of gene expression data and its analysis (3-8 days), reports which linked this data into medically actionable drug candidates (0-3 days), molecular tumor board (1-6 days) and independent medical monitor review (1 -4 days) were all completed in real-time. The average time was 12.4 days from biopsy to initiation of treatment. There were no unexpected serious adverse events on study and patients tolerated therapy well. Clinical benefit was seen 50% of patients. Triplicate biopsies showed reproducible sets of drugs and the comparatively large differences in drug lists between patients show that the drug lists are tailored to patients. Comparison of RNA expression profiles with RNA sequencing from each patient showed strong correlation. Conclusion: This study shows that it is feasible to create therapeutic treatment plans based on genomic profiling in real time and that patients are able to be treated safely on a tumor board derived molecular guided therapy using existing medications. Incorporation of further genomic studies to evaluate additional molecular profiling techniques in order to make more informed individual therapeutic treatment plans will be evaluated in future studies. Citation Format: Giselle L. Sholler, Genevieve Bergendahl, Alyssa VanderWerff, William Ferguson, William Roberts, Don Eslin, Jacqueline Kraveka, Joel Kaplan, Deanna Mitchell, Nehal Parikh, Kathleen Neville, Takamaru Ashikaga, Jeffrey Bond, Gina Hanna, Melinda Merchant, Matt Huentelman, Jason Corneveaux, Jeffrey Trent. A feasibility trial using molecular-guided therapy for the treatment of patients with refractory or recurrent neuroblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-160. doi:10.1158/1538-7445.AM2013-LB-160