About

Joshua D. Schiffman is a principal investigator at the University of Utah Health, affiliated with the Department of Pediatrics (Division of Pediatric Hematology and Oncology), the Genomics, Epigenetics, and Metabolism Program, and the Department of Oncological Sciences (adjunct). He serves as the Medical Director of the High Risk Pediatric Cancer Clinic and is involved in the High Risk Genetics Multi-Disciplinary Group, among other roles. His research focuses on pediatric cancer, with particular emphasis on understanding the genetic and molecular mechanisms underlying cancer susceptibility and development. Schiffman’s work aims to improve the understanding of childhood cancers such as Ewing sarcoma and to develop strategies for early detection, prevention, and targeted therapies. His leadership in the field is reflected in his involvement in various cancer research programs and his commitment to advancing personalized health care.

Research topics

• Medicine
• Internal medicine
• Biology
• Pathology
• Immunology
• Genetics
• Computer Science
• Ecology
• Data Mining
• Biochemistry
• Family medicine
• Psychology
• Medical education
• Evolutionary biology
• Anesthesia
• Zoology
• Oncology
• Pediatrics
• Nursing
• Demography
• Chemistry

Selected publications

• Genome-wide association study meta-analysis identifies susceptibility loci informing Ewing sarcoma etiology and potential mechanisms of risk

  medRxiv · 2026-02-09

  articleOpen access

  Abstract Ewing sarcoma (EwS) is a rare, aggressive pediatric malignancy driven by FET :: ETS family fusions ( EWSR1 :: FLI1 in >85% of cases) with no established environmental risk factors. To investigate germline predisposition, we analyzed 2,014 EwS cases and 10,525 cancer-free controls in a two-stage analysis that combined an international genome-wide association study and a case□parent trio study. The combined meta-analysis identified 18 variants at 14 susceptibility loci (9 novel, 5 replicated) with moderate effect sizes (odds ratios≥1.25). Integrative analyses of the EwS loci revealed enrichment of expanded GGAA microsatellites, with evidence for binding of the EWSR1 :: FLI1 chimeric oncogenic activator. EWSR1::ETS knockdown in EwS cell lines resulted in dysregulated genes at susceptibility loci related to skeletal/muscle development, RNA binding/processing, and chromatin regulation. Our findings provide insights into the inherited component of EwS, highlighting a genetic architecture in which common germline variations with moderate effects interact with somatic EWSR1 :: FLI1 fusions to promote sarcomagenesis by dysregulating local genes.

  PublisherOA PDFDOI

• Divergent understandings in comparative oncology

  Proceedings of the National Academy of Sciences · 2026-02-02

  articleOpen access
  PublisherOA PDFDOI

• Development and pilot testing of AYA-RISE, a risk information and screening education intervention for adolescents and young adults with cancer risk syndromes

  Familial Cancer · 2026-01-23

  articleOpen access

  Genetic testing is increasingly recommended for adolescents and young adults (AYAs) with cancer; however, no AYA-specific models for cancer risk communication have been developed. We developed a chatbot-based patient- and family-centered cancer risk communication tool, the AYA-RISE (AYA-Risk Information and Screening Education) intervention for AYAs aged 12–24 years. The intervention was developed together with AYAs with cancer risk syndromes, their family members, and clinicians, using Invitae’s Gia® chatbot (study Phase 1). 17 AYAs participated in a group discussion and completed surveys for input regarding development. Content was developed for 9 different syndromes. AYA-RISE was then refined after iterative input (Phase 2) and evaluated for feasibility and preliminary outcomes in a pilot study (Phase 3). 100% of AYAs used the intervention through a point at which risk information was presented via the chatbot and portal demonstrating enrollment and chatbot use feasibility. Our threshold for acceptability was exceeded, with a post-test Acceptability of Intervention Measure (AIM) score of > 4 by 80% of AYAs. In the pre-visit survey, 40% of AYAs correctly reported risk of cancer by age 30, and 20% correctly reported lifetime cancer risk. Following the visit and use of the chat, 60% correctly reported risk of cancer by age 30 and 90% correctly reported lifetime risk. No significant differences in participant pre (3.4) and post (3.6, p=.34) distress thermometer mean scores were observed. The AYA-RISE intervention was feasible and acceptable for use by AYAs. Preliminary outcomes included improved knowledge when used in conjunction with a cancer risk clinic visit, without increasing distress. A randomized trial is currently ongoing.

  PublisherOA PDFDOI

• Abstract 1157: Preclinical evaluation of PEG-[SN22]4 (PEEL-224), a multivalent polymeric camptothecin prodrug, in pediatric solid tumor patient-derived xenograft models

  Cancer Research · 2026-04-03

  article

  Abstract Background: PEEL-224 is a multivalent polymeric prodrug of the topoisomerase I inhibitor SN22 designed to sustain intratumoral exposure and reduce transporter-mediated efflux. Desmoplastic small round cell tumor (DSRCT) and osteosarcoma (OS) are high-risk sarcomas of children and adolescents/young adults where irinotecan+temozolomide (I/T) provides modest, short-lived benefit. Early-phase clinical evaluation of PEEL-224 is ongoing (NCT06709495, NCT06721689, NCT05329103). However, the comparative activity of PEEL-224±TMZ versus irinotecan-based therapy has not been defined in disease-relevant models, prompting evaluation in DSRCT and OS patient-derived xenografts (PDXs). Methods: PDX-bearing NSG mice were randomized to vehicle, irinotecan, I/T, PEEL-224, or PEEL-224+TMZ. Tumor growth was assessed using Vardi’s test for area-under-the-curve comparisons. Event-free survival (EFS) was defined as time to progression (≥100% relative tumor volume [RTV] increase from baseline) or euthanasia for tumor burden and analyzed by Kaplan-Meier with log-rank tests. Response criteria: PD = ≥100% RTV increase or euthanasia; SD = <100% increase and ≤50% reduction; PR = >50% reduction; CR = >95% reduction. Objective response rate (ORR) was the proportion achieving PR or CR. Treatment arms were expanded in an adaptive manner based on disease control to increase cohort size for key comparisons. Results: In DSRCT, tumor volume comparisons showed significantly greater control with PEEL-224 monotherapy vs irinotecan (p=0.04), while PEEL-224+TMZ and I/T showed similar control at this stage; cohort expansion is ongoing. EFS analysis showed PEEL-224 significantly prolonged EFS vs irinotecan (p=0.01) and PEEL-224+TMZ vs I/T (p=0.02). At end of therapy (Day 29), ORR was 0% (vehicle), 20% (irinotecan, 1/5 PR), 20% (I/T, 1/5 PR), 100% (PEEL-224, 5/5 PR), and 100% (PEEL-224+TMZ, 5/5 PR). At end of study (Day 113), irinotecan and I/T had 0% ORR, while PEEL-224 maintained 60% (3/5 PR, 2/5 SD) and PEEL-224+TMZ 100% (5/5 PR). Regimens were well tolerated. In OS, PEEL-224±TMZ produced disease stabilization and early regression, though statistical significance has not yet emerged (n=3/arm); expansion is ongoing. Conclusions: PEEL-224 demonstrated superior disease control as monotherapy and in combination over irinotecan-based therapy in DSRCT and early activity in OS. These preclinical data, alongside ongoing clinical evaluation, support advancement of PEEL-224 for high-risk pediatric and AYA sarcomas. Citation Format: Filemon S. Dela Cruz, Kristina C. Guillan, Samantha Brosius, Armaan H. Siddiquee, Glorife Ibanez Sanchez, Daoqi You, Kristen Victor, Paul Calder, Trent Fowler, Joshua D. Schiffman, Andrew L. Kung. Preclinical evaluation of PEG-[SN22]4 (PEEL-224), a multivalent polymeric camptothecin prodrug, in pediatric solid tumor patient-derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1157.

  PublisherDOI

• Abstract 7639: Primate comparative oncology reveal humans' unique cancer susceptibility

  Cancer Research · 2026-04-03

  article

  Abstract Studying cancer from an evolutionary perspective can yield important theoretical and applied insights; however, little is known about the prevalence of cancer among non-human primates. Non-human primates are our closest living relatives, yet the primate lineage is phenotypically diverse, exhibiting wide variation in evolutionary and life-history characteristics. By integrating comparative phenotypic data with prevalence records of neoplastic disease, we assembled a dataset of 2,095 individuals from 36 species across nine primate families to examine cross-species cancer risk. Additionally, functional in vitro studies using isolated and cultured primary fibroblast cell lines from representative species show that resistance to cellular death correlates with certain life-history traits. Comparative phylogenetic modeling of human cancer risk, situated within the broader primate phylogeny, demonstrates a drastic reduction in cancer risk even among primates most closely related to humans (e.g., the great apes). Together, large-scale cancer prevalence records and functional assays provide valuable insights into the ecological and cellular dynamics of cancer in our closest living relatives—and in ourselves. Citation Format: Zachary Taylor Compton, Walker Mellon, Lisa M. Abegglen, Tara Harrison, Joshua D. Schiffman, Amy M. Boddy, Carlo C. Maley. Primate comparative oncology reveal humans' unique cancer susceptibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7639.

  PublisherDOI

• Comparative physiology and biomimetics in metabolic and environmental health: what can we learn from extreme animal phenotypes?

  Diabetologia · 2025-11-20 · 1 citations

  articleOpen access

  This review explores the remarkable metabolic adaptations of species that thrive in extreme environments, providing insights into their resilience, flexibility and disease resistance. Species such as hibernating brown bears, migratory birds, cavefish, Greenland sharks and naked mole rats exhibit unique metabolic traits that challenge conventional paradigms of metabolic regulation. These adaptations, including resistance to hypoxia and metabolic ageing, offer potential solutions to human metabolic disorders, including obesity, type 2 diabetes and CVD. Insights from comparative physiology, particularly the mechanisms by which animals cope with food scarcity, extreme temperatures and hypoxia, could help identify novel therapeutic targets for advancing human health. For example, hibernation can serve as a model for understanding metabolic diseases, providing insights into reversible insulin resistance and energy homeostasis. This review also highlights the impact of environmental stressors, including climate change, on these species, which may jeopardise their survival despite their resilience. Accelerating anthropogenic environmental change threatens even the most resilient animal species. We call for a holistic approach to conservation and environmental protection to preserve these species and the valuable lessons they offer for managing our metabolic health.

  PublisherOA PDFDOI

• Peripheral blood DNA methylation predicts the early onset of primary tumor in TP53 mutation carriers

  Nature Communications · 2025-08-26 · 1 citations

  articleOpen access

  Li-Fraumeni syndrome (LFS) confers high lifetime cancer risk due to germline TP53 pathogenic variants (PV). A comprehensive surveillance regimen termed the ‘Toronto Protocol’, has been adopted for early tumor detection, demonstrating improved survival among TP53 PV carriers. However, the protocol’s “one-size-fits-all” approach fails to consider individual cancer risk. To personalize screening, we developed a support vector machine model to predict early onset of primary tumors (age < 6) using peripheral blood methylation data of TP53 PV carriers (n = 237). Validation (n = 64) and external testing (n = 79) showed AUROC = 0.928 [0.835–1.000], F1-score = 0.692 [0.435–0.867], and NPV = 0.984 [0.946–1.000]. The model achieved 91% accuracy, correctly classifying 90% of patients with cancer before the age of six and 87% of cancer-free individuals in the external test set. Our tool enables risk stratification for early-onset malignancies, to optimize clinical surveillance and improve patient outcomes. Li-Fraumeni syndrome leads to an increased predisposition to tumour development. Here, the authors develop a support vector machine model to predict early cancer risk in individuals using peripheral blood DNA methylation profiles.

  PublisherOA PDFDOI

• Supplementary Data 2 from Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death

  2025-12-11

  articleOpen access

  &lt;p&gt;Differentially expressed genes in U2OS cells varying in p53 allelic status combined from two independent RNA library preparations&lt;/p&gt;

  PublisherDOI

• Hematologic Malignancy Frequency, Phenotypes, and Outcomes in Li-Fraumeni Syndrome

  JCO Precision Oncology · 2025-06-01 · 2 citations

  article

  PURPOSE: Hematologic malignancies (HMs) account for 4%-10% of cancers in individuals with Li-Fraumeni syndrome (LFS), but their phenotypic spectrum and clinical outcomes remain incompletely characterized. METHODS: We conducted a retrospective cohort study at The University of Utah and University of Wisconsin-Madison. Cancer genetics registries were reviewed to identify all unrelated families with LFS seen between 2010 and the present with at least one individual with a pathologically confirmed HM. A literature review was conducted to identify individuals in the published literature with LFS with an HM. HM molecular characteristics, treatment, and outcomes were recorded. RESULTS: Among 121 total families with LFS at our institutions, 17 patients from 16 (13%) families diagnosed with LFS had an HM. A literature review found an additional 83 patients with detailed descriptions, for a total of 99 patients with LFS and an HM. The spectrum of HMs included 10 subtypes with a propensity for lymphoid over myeloid diagnoses. Most HMs did not occur after cytotoxic therapy and often responded to usual sporadic HM regimens, but in a subset, unusual toxicities were encountered, especially after hematopoietic stem-cell transplantation. CONCLUSION: Our large cohort of patients with HM and LFS suggest a broad spectrum of HMs in LFS with more lymphoid than myeloid, more de novo than postcytotoxic therapy, and more favorable outcomes than previous reports.

  PublisherDOI

• Figure S1 from Germline Pathogenic &lt;i&gt;DROSHA&lt;/i&gt; Variants Are Linked to Pineoblastoma and Wilms Tumor Predisposition

  2025-05-13

  preprintOpen access

  &lt;p&gt;Figure S1&lt;/p&gt;

  PublisherOA PDFDOI

Recent grants

• Genetic Risk Factors for Ewing's Sarcoma

  NIH · $3.0M · 2012–2018

• NIH Grant R21CA187516

  NIH · $377k · 2016

Frequent coauthors

• David Malkin

  Hospital for Sick Children

  232 shared

• Lisa M. Abegglen

  Huntsman Cancer Institute

  231 shared

• Katherine A. Janeway

  Dana-Farber Cancer Institute

  197 shared

• Wendy Kohlmann

  University of Utah

  190 shared

• Constantine A. Stratakis

  National Institutes of Health

  150 shared

• Lee J. Helman

  150 shared

• Karel Pacák

  Eunice Kennedy Shriver National Institute of Child Health and Human Development

  146 shared

• Anita Villani

  116 shared

Labs

• Schiffman LabPI

  Not provided

Education

• M.D.

  Brown University School of Medicine

• Other, Pediatric Hematology/Oncology

  Stanford University

• Other, Pediatrics

  Stanford University

• Other, Pediatrics

  Stanford University