Publications by authors named "Catherine M Clinton"

10 Publications

  • Page 1 of 1

Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome.

N Engl J Med 2021 11;385(22):2059-2065

From the Departments of Pediatric Oncology (J.K., K.V.H., J.A.P., C.M.C., A.I., C.B.W., K.A.J., S.G.D.) and Medical Oncology (W.G.K.), Dana-Farber Cancer Institute, Harvard Medical School, the Divisions of Hematology and Oncology (J.K., J.A.P., M.M.H., K.A.J., S.G.D.) and Endocrinology (A.J.W.) and the Departments of Surgery (B.R.W.), Pathology (S.O.V.), and Radiology (S.D.V.), Boston Children's Hospital, Harvard Medical School, and the Manton Center for Orphan Disease Research and the Division of Genetics and Genomics, Boston Children's Hospital (J.A.M., J.L.) - all in Boston; Howard Hughes Medical Institute, Chevy Chase, MD (W.G.K.); and Merck, Kenilworth, NJ (R.F.P., N.J.Z.).

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in . Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).
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http://dx.doi.org/10.1056/NEJMoa2110051DOI Listing
November 2021

Retrospective evaluation of single patient investigational new drug (IND) requests in pediatric oncology.

Cancer Med 2021 Mar 9. Epub 2021 Mar 9.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.

Background: Single patient Investigational New Drug (IND) applications are one mechanism through which experimental therapies are accessed for children with cancer. The landscape of use, outcomes, and toxicity from single patient INDs remains unknown in pediatric oncology.

Methods: We performed a retrospective analysis of all single patient INDs requested and prescribed at a single institution between 1/1/2007 and 5/1/2019. We report aggregate data from the US Food and Drug Administration (FDA) on single patient IND applications over the final two years of the study (2017-2019). We report an overview of all IND applications, as well as clinical descriptions of patients, treatments, outcomes, and toxicity.

Results: Over the 2-year period, the FDA approved all 171 submitted single patient IND requests for pediatric oncology. We identified 56 requests from our center during the 12-year study period, and all were approved (median time from FDA submission to approval: 1 day (range 0-12)). 71% of requests were based on disease histology. Lack of pediatric clinical trial (65%) was the most common reason for use. 48 approved requests were ultimately administered. The median duration of treatment was 84 days (range: 4-1590), with 3 patients remaining on treatment at time of analysis. Only 7% discontinued treatment due to toxicity. Three-year overall survival was 50% (95% CI, 35-64).

Conclusions: Single patient INDs in pediatric oncology were universally approved in our national and single-center analysis. In our cohort, single patient INDs were primarily utilized based on disease histology, rather than genomics, for agents that lacked a clinical trial.
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http://dx.doi.org/10.1002/cam4.3791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982629PMC
March 2021

Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium.

Cancer Discov 2021 Jun 9;11(6):1424-1439. Epub 2021 Feb 9.

Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. SIGNIFICANCE: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations...
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http://dx.doi.org/10.1158/2159-8290.CD-20-0564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178162PMC
June 2021

Making the most of small samples: Optimization of tissue allocation of pediatric solid tumors for clinical and research use.

Pediatr Blood Cancer 2020 09 15;67(9):e28326. Epub 2020 Jul 15.

Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.

Introduction: Tissue from pediatric solid tumors is in high demand for use in high-impact research studies, making the allocation of tissue from an anatomic pathology laboratory challenging. We designed, implemented, and assessed an interdepartmental process to optimize tissue allocation of pediatric solid tumors for both clinical care and research.

Methods: Oncologists, pathologists, surgeons, interventional radiologists, pathology technical staff, and clinical research coordinators participated in the workflow design. Procedures were created to address patient identification and consent, prioritization of protocols, electronic communication of requests, tissue preparation, and distribution. Pathologists were surveyed about the value of the new workflow.

Results: Over a 5-year period, 644 pediatric solid tumor patients consented to one or more studies requesting archival or fresh tissue. Patients had a variety of tumor types, with many rare and singular diagnoses. Sixty-seven percent of 1768 research requests were fulfilled. Requests for archival tissue were fulfilled at a significantly higher rate than those for fresh tissue (P > .001), and requests from resection specimens were fulfilled at a significantly higher rate than those from biopsies (P > .0001). In an anonymous survey, seven of seven pathologists reported that the process had improved since the introduction of the electronic communication model.

Conclusions: A collaborative and informed model for tissue allocation is successful in distributing archival and fresh tissue for clinical research studies. Our workflows and policies have gained pathologists' approval and streamlined our processes. As clinical and research programs evolve, a thoughtful tissue allocation process will facilitate ongoing research.
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http://dx.doi.org/10.1002/pbc.28326DOI Listing
September 2020

DICER1-associated central nervous system sarcoma in children: comprehensive clinicopathologic and genetic analysis of a newly described rare tumor.

Mod Pathol 2020 10 14;33(10):1910-1921. Epub 2020 Apr 14.

Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

The spectrum of neoplasms associated with DICER1 variants continues to expand, with the recent addition of primary "DICER1-associated central nervous system sarcoma" (DCS). DCS is a high-grade malignancy predominantly affecting pediatric patients. Six pediatric DCS were identified through a combination of clinical diagnostic studies, archival inquiry, and interinstitutional collaboration. Clinical, histologic, immunohistologic, and molecular features were examined. Genomic findings in the 6 DCS were compared with those in 14 additional DICER1-associated tumors sequenced with the same assay. The six patients presented at ages 3-15 years with CNS tumors located in the temporal (n = 2), parietal (n = 1), fronto-parietal (n = 1), and frontal (n = 2) lobes. All underwent surgical resection. Histologic examination demonstrated high-grade malignant spindle cell tumors with pleuropulmonary blastoma-like embryonic "organoid" features and focal rhabdomyoblastic differentiation; immature cartilage was seen in one case. Immunohistochemically, there was patchy desmin and myogenin staining, and patchy loss of H3K27me3, and within eosinophilic cytoplasmic globules, alfa-fetoprotein staining. Biallelic DICER1 variants were identified in all cases, with germline variants in two of five patients tested. DCS demonstrated genomic alterations enriched for Ras pathway activation and TP53 inactivation. Tumor mutational burden was significantly higher in the 6 DCS tumors than in 14 other DICER1-associated tumors examined (mean 12.9 vs. 6.8 mutations/Mb, p = 0.035). Postoperative care included radiation (n = 5) and chemotherapy (n = 3); at the last follow-up, three patients were alive without DCS, and three had died of disease. Our analysis expands the clinical, histologic, immunohistological, and molecular spectrum of DCS, identifying distinctive features that can aid in the diagnosis, multidisciplinary evaluation, and treatment of DCS.
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http://dx.doi.org/10.1038/s41379-020-0516-1DOI Listing
October 2020

Genomic and Immunologic Characterization of INI1-Deficient Pediatric Cancers.

Clin Cancer Res 2020 06 2;26(12):2882-2890. Epub 2020 Mar 2.

Department of Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts.

Purpose: Several aggressive pediatric cancers harbor alterations in , including rhabdoid tumors, epithelioid sarcoma, and chordoma. As tumor profiling has become more routine in clinical care, we investigated the relationship between genetic variants identified by next-generation sequencing (NGS) and INI1 protein expression. Therapeutic approaches for INI1-deficient tumors are limited. Early reports suggest a potential role for immune checkpoint inhibition in these patients. Thus, we also investigated PD-L1 and CD8 expression in INI1-negative pediatric brain and solid tumors.

Experimental Design: We performed immunohistochemistry (IHC) for INI1 and immune markers (PD-L1, CD8, and CD163) and NGS on tumor samples from 43 pediatric patients who had tumors with INI1 loss on previous IHC or genomic alterations on prior somatic sequencing.

Results: two-copy deletions and inactivating mutations on NGS were associated with loss of INI1 protein expression. Single-copy deletion of was not predictive of INI1 loss in tumor histologies not known to be INI1-deficient. In the 27 cases with INI1 loss and successful tumor sequencing, 24 (89%) had a alteration detected. In addition, 47% (14/30) of the patients with INI1-negative tumors had a tumor specimen that was PD-L1 positive and 60% (18/30) had positive or rare CD8 staining. We report on 3 patients with INI1-negative tumors with evidence of disease control on immune checkpoint inhibitors.

Conclusions: A significant proportion of the INI1-negative tumors express PD-L1, and PD-L1 positivity was associated with extracranial tumor site. These results suggest that clinical trials of immune checkpoint inhibitors are warranted in INI1-negative pediatric cancers.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3089DOI Listing
June 2020

Renal medullary carcinomas depend upon loss and are sensitive to proteasome inhibition.

Elife 2019 03 12;8. Epub 2019 Mar 12.

Broad Institute of Harvard and MIT, Cambridge, United States.

Renal medullary carcinoma (RMC) is a rare and deadly kidney cancer in patients of African descent with sickle cell trait. We have developed faithful patient-derived RMC models and using whole-genome sequencing, we identified loss-of-function intronic fusion events in one allele with concurrent loss of the other allele. Biochemical and functional characterization of these models revealed that RMC requires the loss of for survival. Through integration of RNAi and CRISPR-Cas9 loss-of-function genetic screens and a small-molecule screen, we found that the ubiquitin-proteasome system (UPS) was essential in RMC. Inhibition of the UPS caused a G2/M arrest due to constitutive accumulation of cyclin B1. These observations extend across cancers that harbor loss, which also require expression of the E2 ubiquitin-conjugating enzyme, . Our studies identify a synthetic lethal relationship between -deficient cancers and reliance on the UPS which provides the foundation for a mechanism-informed clinical trial with proteasome inhibitors.
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http://dx.doi.org/10.7554/eLife.44161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436895PMC
March 2019

Response Evaluation Criteria in Solid Tumors (RECIST) following neoadjuvant chemotherapy in osteosarcoma.

Pediatr Blood Cancer 2018 04 18;65(4). Epub 2017 Dec 18.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.

Background: In osteosarcoma, patient survival has not changed in over 30 years. Multiple phase II trials have been conducted in osteosarcoma using the Response Evaluation Criteria in Solid Tumors (RECIST) as a primary endpoint; however, none of these have revealed new treatment strategies. We investigated RECIST in newly diagnosed patients who received neoadjuvant chemotherapy proven to be beneficial.

Methods: Patients treated from 1986 to 2011 for newly diagnosed osteosarcoma with paired tumor imaging before and after adequate neoadjuvant chemotherapy were included in this retrospective study. Two radiologists performed independent, blinded (to image timing) RECIST measurements of primary tumor and lung metastases at diagnosis and post-neoadjuvant chemotherapy. Association between RECIST and histological necrosis and outcome were assessed.

Results: Seventy-four patients met inclusion criteria. Five-year overall survival and progression-free survival (PFS) were 77 ± 7% and 61 ± 8%, respectively. No patients had RECIST partial or complete response in the primary tumor. Sixty-four patients (86%) had stable disease, and 10 (14%) had progressive disease (PD). PD in the primary tumor was associated with significantly worse PFS in localized disease patients (P = 0.02). There was no association between RECIST in the primary tumor and necrosis. There were an insufficient number of patients with lung nodules ≥1 cm at diagnosis to evaluate RECIST in pulmonary metastases.

Conclusions: PD by RECIST predicts poor outcome in localized disease patients. In bone lesions, chemotherapy proven to improve overall survival does not result in radiographic responses as measured by RECIST. Further investigation of RECIST in pulmonary metastatic disease in osteosarcoma is needed.
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http://dx.doi.org/10.1002/pbc.26896DOI Listing
April 2018

The beliefs, motivations, and expectations of parents who have enrolled their children in a genetic biorepository.

Genet Med 2012 Mar 26;14(3):330-7. Epub 2012 Jan 26.

Department of Medicine, Division of Genetics and Program in Genomics, Children's Hospital Boston, Boston, Massachusetts, USA.

Purpose: Little is known about parental attitudes toward return of individual research results (IRRs) in pediatric genomic research. The aim of this study was to understand the views of the parents who enrolled their children in a genomic repository in which IRRs will be returned.

Methods: We conducted focus groups with parents of children with developmental disorders enrolled in the Gene Partnership (GP), a genomic research repository that offers to return IRRs, to learn about their understanding of the GP, motivations for enrolling their children, and expectations regarding the return of IRRs.

Results: Parents hoped to receive IRRs that would help them better understand their children's condition(s). They understood that this outcome was unlikely, but hoped that their children's participation in the GP would contribute to scientific knowledge. Most parents wanted to receive all IRRs about their child, even for diseases that were severe and untreatable, citing reasons of personal utility. Parents preferred electronic delivery of the results and wanted to designate their preferences regarding what information they would receive.

Conclusions: It is important for researchers to understand participant expectations in enrolling in a research repository that offers to disclose children's IRRs in order to effectively communicate the implications to parents during the consenting process.
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http://dx.doi.org/10.1038/gim.2011.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763713PMC
March 2012

The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update.

Hum Mutat 2010 Dec;31(12):1269-79

Department of Medical Sciences, and IRCAD Università del Piemonte Orientale A. Avogadro, Alessandria, Novara, Vercelli, Italy.

Diamond-Blackfan Anemia (DBA) is characterized by a defect of erythroid progenitors and, clinically, by anemia and malformations. DBA exhibits an autosomal dominant pattern of inheritance with incomplete penetrance. Currently nine genes, all encoding ribosomal proteins (RP), have been found mutated in approximately 50% of patients. Experimental evidence supports the hypothesis that DBA is primarily the result of defective ribosome synthesis. By means of a large collaboration among six centers, we report here a mutation update that includes nine genes and 220 distinct mutations, 56 of which are new. The DBA Mutation Database now includes data from 355 patients. Of those where inheritance has been examined, 125 patients carry a de novo mutation and 72 an inherited mutation. Mutagenesis may be ascribed to slippage in 65.5% of indels, whereas CpG dinucleotides are involved in 23% of transitions. Using bioinformatic tools we show that gene conversion mechanism is not common in RP genes mutagenesis, notwithstanding the abundance of RP pseudogenes. Genotype-phenotype analysis reveals that malformations are more frequently associated with mutations in RPL5 and RPL11 than in the other genes. All currently reported DBA mutations together with their functional and clinical data are included in the DBA Mutation Database.
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http://dx.doi.org/10.1002/humu.21383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485435PMC
December 2010
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