Yael P Mosse
VerifiedUniversity of Pennsylvania · Rehabilitation Medicine
Active 2002–2025
About
Yael P Mosse, M.D., is a Professor of Pediatrics (Oncology) at the University of Pennsylvania School of Medicine and a full member of the Abramson Cancer Center. Her research focuses on neuroblastoma, with an emphasis on understanding its hereditary basis to improve clinical outcomes. She made seminal discoveries identifying gain-of-function mutations in the ALK oncogene as the cause of familial neuroblastoma and demonstrated that somatic ALK mutations often drive sporadic tumors. Her work has led to the development of molecular diagnostic tools and preclinical studies on ALK inhibitors, culminating in a multi-institutional pediatric phase 1 trial of crizotinib, which exemplifies rapid bench-to-bedside translation. Dr. Mosse is a physician-scientist committed to translating basic science discoveries into clinical applications. She has established a team integrating expertise in genomics, biochemistry, bioengineering, and pharmacology to develop rational therapeutic strategies targeting ALK and other mediators of oncogenesis in neuroblastoma. Her efforts aim to improve cure rates for this devastating disease by advancing targeted therapies and exploring new therapeutic approaches, thereby making significant contributions to pediatric oncology and translational cancer research.
Research topics
- Biology
- Genetics
- Bioinformatics
- Computational biology
- Medicine
- Oncology
- Internal medicine
- Cancer research
Selected publications
2025-09-02
articleOpen accessSenior author<p>Supplementary Figure S5 shows COG-N-424x harboring wild-type ALK does not respond to lorlatinib treatment.</p>
Cancer Research · 2025-09-25
articleAbstract Liquid biopsy surveillance of patients with neuroblastoma can be used to monitor for relapse, detect therapeutic targets, and track drug resistance. As current commercially available liquid biopsy assays are tailored to adult malignancies and do not comprehensively capture variants relevant to neuroblastoma, especially at low variant allele frequency (VAF), we developed and clinically validated a Neuroblastoma Liquid Biopsy Panel (NBLBP) focused on genes recurrently mutated in neuroblastoma to maximize sequencing depth and VAF sensitivity. The NBLBP interrogates 23 genes enriched for somatic alterations in relapsed neuroblastoma identified from comprehensive literature review (e.g., ALK, ATRX, MYCN, TP53, NF1) using anchored multiplex PCR with unique molecular identifiers, followed by next-generation sequencing, detecting both sequence and copy number variants (CNVs). The initial validation cohort contained 43 samples for single-nucleotide variant (SNV) and small insertion-deletion (indel) analysis and 21 samples for MYCN amplification. The limit of detection was established at 0.5% VAF or lower for certain variants using 30 ng input of cell-free DNA (cfDNA). Validation for additional gene amplifications and ATRX deletion was performed using &gt;80 samples following the initial phase. We conducted a retrospective review of 282 samples tested within the first 16 months of test launch from 137 individual neuroblastoma patients, most of whom had multiply relapsed high-risk disease. Tumor-associated ctDNA alterations were identified in 37.6% (106/282). Subset analysis of assay input averaged at 52 ng, with only 3.5% of samples having &lt;30 ng due to low cfDNA at extraction. The most frequent Tier 1, 2 or pathogenic SNVs and indels included TP53 (n=39), ALK (n=37, including 6 germline variants), NF1 (n=28), and ATRX (n=22). Detected VAFs ranged from ≤0.5% up to 50%[LS1] . Detected CNVs included MYCN gain or amplification (n=15), ATRX loss (n=5), and amplifications in CDK4 (n=2), MDM2 (n=2), MET (n=1), and ALK (n=1). Among patients with matched tumor testing (n=22), mutation profiles in ctDNA demonstrated high concordance with previously identified alterations in tumor tissue. Of patients tested (n=137), 58 had two or more serial samples, and some of these showed dynamic response of variants over time to treatment interventions and/or progressive disease. Individual patient analyses to assess clinical utility are ongoing and include ctDNA positivity preceding imaging confirmed relapse, adjustments in therapy based on ctDNA findings, and monitoring of ALK SNVs during targeted therapy. The NBLBP performs well at detecting disease-associated sequence and CNVs in patients with advanced neuroblastoma. Multiple variant types can be detected, including SNVs, small indels, and gene amplifications, allowing for sensitive disease tracking important for clinical decision making. NBLBP is a powerful non-invasive test that can supplement the currently available surveillance strategies for patients with advanced neuroblastoma. Citation Format: Jinhua Wu, Esther Berko, Feng Xu, Jeffrey Schubert, Jiani Chen, Virginia M Hamilton, Matthew Lueder, Minjie Luo, Grace Polkosnik, Yiming Zhong, John M Maris, Marilyn M Li, Yael P Mossé, Lea F Surrey. Implementation and Performance of a Neuroblastoma Liquid Biopsy Panel for Non-Invasive Molecular Monitoring [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr A009-PR010.
2025-09-02
articleOpen accessSenior author<p>Supplementary Table S5 shows RNA-seq p adjusted values of differentially expressed genes in COG-N-453x and NB-1643 tumor models comparing crizotinib vs lorlatinib treatment.</p>
Cancer Research · 2025-09-25
articleAbstract BACKGROUND: We recently showed that tumor-intrinsic and -extrinsic activation of NFκB is a major mediator of high-risk neuroblastoma (HRNB) chemoresistance (Grossmann et al., Cancer Discovery, ‘24). The anti-apoptotic protein BCL-xL is a downstream effector of the NFκB pathway and is upregulated in HRNB persister cells after chemotherapy. While showing efficacy, BCL-xL small molecule inhibitor development has been limited by on-target off-tumor thrombocytopenia. DT-2216 (DT), a BCLxL PROteolysis TArgeting Chimera (PROTAC), mitigates this toxicity by exploiting the E3 ligase VHL, expressed at low levels in platelets. AIMS: To validate NFκΒ-mediated BCL-xL overexpression as a HRNB chemoresistance mechanism, and exploit this therapeutic vulnerability to eradicate persister cells using DT. METHODS: Isogenic BCL-xLhigh and BCL-xL low cell lines were generated using an overexpression vector and a doxycycline-inducible CRISPRi system. Six human HRNB cell lines were treated with topotecan/cyclophosphamide (topo/cpm) and DT. DC50 and IC50 values were determined via immunoblots and cell viability assays over 5 days. Five chemotherapeutics were combined with DT in 6x6 dose-response matrices. Zero Interaction Potency (ZIP) scores were calculated using R software. Two Patient-Derived Xenograft (PDX) HRNB flank models in CB17-SCID mice were treated with two subsequent cycles of topo/cpm +/- low-dose DT (15mg/kg) for 6 weeks. Three PDXs were treated with vehicle or escalating DT doses (15mg/kg, 22.5mg/kg) for 2 weeks. Intratumoral BCL-XL degradation was determined by immunoblots. Complete blood counts were measured weekly. RESULTS: BCL-xL overexpression and knock-down significantly (p&lt;0.05) enhanced and reduced cell viability following chemotherapy, respectively. Combination of high-dose (&gt;IC50) topo/cpm and 500nM-1μM DT facilitated the eradication of persister cells in vitro. DT demonstrated synergy with all tested chemotherapeutics across multiple cell lines. The ZIP scores were higher (ZIP&gt;10) around the chemotherapy IC50 and DT DC50, indicating a clinically-relevant range-specific therapeutic synergy. However, DT monotherapy at 15mg/kg twice weekly showed incomplete degradation of BCL-xL at day 7 (55%, 37-70%) and 14 (79%, 43-112%) and no effect on tumor growth across three PDXs. Combining DT with topo/cpm in two PDXs did not lead to significant enhancement of chemotherapy anti-tumor efficacy. Escalating DT doses to 22.5 mg/kg led to further BCL-xL depletion at day 7 (44%, 27-61%) and day 14 (49%, 26-73%) across three models. Dose-dependent thrombocytopenia was the only observed side effect, with platelet counts (x10^5/uL) of 15 [10-18], 4 [2-10], 2 [1-4] in vehicle, 15mg/kg, 22.5mg/kg arms, respectively. CONCLUSIONS: BCL-xL mediates chemoresistance in HRNB. Combination of DT and chemotherapy is synergistic in vitro. DT showed incomplete BCL-xL degradation in vivo at the dose and schedule tested here, which may be required for anti-tumor efficacy. Ongoing efforts may provide insight into de novo or acquired mechanisms of DT resistance. Citation Format: Matteo Calafatti, Emily Mycek, Dana Al-halawani, Josh Kalna, David Groff, Esther Coronado Mondragón, Patel Khushbu, Mark Gerelus, Jarrett Lindsay, Kyabeth Torres-rodriguez, Gregory Connelly, Smita Matkar, Sajid Khan, Zhengyu Wang, Hong Yu Li, Jaime Font de Mora, Yael P Mossé, Daohong Zhou, Liron Grossmann, John M Maris. The potential of BCL-xL degradation as a strategy to eliminate chemotherapy-resistant neuroblastoma persister cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr A025-PR001.
UNC Libraries · 2025-10-08
articleOpen accessMutations in the tyrosine kinase domain of the Anaplastic Lymphoma Kinase (ALK) oncogene in neuroblastoma occur most frequently at one of three hotspot amino acid residues, with the F1174* and F1245* variants conferring de novo resistance to first and second generation ALK inhibitors including crizotinib and ceritinib. Lorlatinib, a third generation ALK/ROS inhibitor, overcomes de novo resistance and induces complete and sustained tumor regressions in patient-derived xenograft (PDX) models unresponsive to crizotinib. Lorlatinib has now completed Phase 1 testing in children and adults with relapsed/refractory ALK-driven neuroblastoma and entered pivotal Phase 3 testing within the Children's Oncology Group. To define mechanisms underlying the superior activity of lorlatinib, we utilized a chemical proteomics approach to quantitatively measure functional kinome dynamics in response to lorlatinib and crizotinib in clinically relevant ALK-driven neuroblastoma PDX models. Lorlatinib was a markedly more potent inhibitor of ALK and preferentially downregulated several kinases implicated in G2/M cell cycle transition compared to crizotinib. Lorlatinib treatment also led to the repression of MYCN expression and its occupancy at promoters of the same G2/M kinases. These data providing mechanistic insight into the superior efficacy of lorlatinib over crizotinib for the treatment of ALK-driven neuroblastoma.
2025-09-02
articleOpen accessSenior author<p>Supplementary Table S1 shows catalogue numbers of Taqman probes.</p>
2025-09-02
articleOpen accessSenior author<p>Supplementary Table S4 shows RNA-seq fold changes of differentially expressed genes shared between crizotinib vs vehicle and lorlatinib vs vehicle contrasts for non kinase genes.</p>
2025-09-02
articleOpen accessSenior author<p>Supplementary Figure S8 show inhibition of FAK and FER does not increase sensitivity of crizotinib to neuroblastoma cell lines in 2D and 3D culture.</p>
2025-09-02
articleOpen accessSenior author<p>Supplementary Figure S11 shows Lorlatinib downregulates AURKA expression.</p>
2025-09-02
articleOpen accessSenior author<p>Supplementary Figure S2 shows MIB/MS profiling in neuroblastoma models upon treatment with lorlatinib.</p>
Recent grants
Targeting Oncogenic ALK Signaling in Neuroblastoma
NIH · $5.6M · 2009–2025
NIH · $682k · 2010
Tumor microenvironment-dependent therapy resistance
NIH · $36.6M · 2017–2029
Frequent coauthors
- 510 shared
John M. Maris
- 134 shared
Edward F. Attiyeh
Children's Hospital of Philadelphia
- 133 shared
Sharon J. Diskin
Children's Hospital of Philadelphia
- 114 shared
Kateryna Krytska
Children's Hospital of Philadelphia
- 99 shared
Kristina A. Cole
University of Pennsylvania
- 94 shared
Susan M. Blaney
Children's Cancer Center
- 89 shared
Brenda J. Weigel
University of Minnesota Children's Hospital
- 88 shared
Elizabeth Fox
Labs
Yael P Mosse LabPI
Awards & honors
- Full Member, Abramson Cancer Center at the University of Pen…
- Fellow of the American Association for Cancer Research (AACR…
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