Browsing by Author "Rhodes, Steven D."

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    An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia
    (Ferrata Storti Foundation, 2017-06) Zhou, Yuan; He, Yongzheng; Xing, Wen; Zhang, Peng; Shi, Hui; Chen, Shi; Shi, Jun; Bai, Jie; Rhodes, Steven D.; Zhang, Fengqui; Yuan, Jin; Yang, Xianlin; Zhu, Xiaofan; Li, Yan; Hanenberg, Helmut; Xu, Mingjiang; Robertson, Kent A.; Yuan, Weiping; Nalepa, Grzegorz; Cheng, Tao; Clapp, D. Wade; Yang, Feng-Chun; Pediatrics, School of Medicine
    Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation.
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    Brain Death Secondary to Rocky Mountain Spotted Fever Encephalitis
    (Hindawi, 2020-05-01) Rhodes, Steven D.; Teagarden, Alicia M.; Graner, Brian; Lutfi, Riad; John, Chandy C.; Pediatrics, School of Medicine
    A two-year-old female presented with acutely altered mental status following eight days of fever and rash. She had been camping at an Indiana campground 11 days prior to the onset of illness and was evaluated twice for her fever and rash prior to admission. Laboratory evaluation on admission revealed thrombocytopenia, hyponatremia, and elevated transaminases. The patient developed diffuse cerebral edema, and despite intensive care, the edema led to brain death from Rocky Mountain spotted fever (RMSF). We present this case to highlight the importance of considering RMSF and other tick-borne illnesses in a child with prolonged fever and rash in a nonendemic area and also the difficulty of diagnosis in early stages of disease. A detailed travel history, evaluation of key laboratory findings (white blood count, platelet count, and transaminases), and close follow-up if rash and fevers persist may help to improve detection of RMSF. If a tick-borne illness such as RMSF is suspected, empiric doxycycline therapy should be started immediately, as lab confirmation may take several days and mortality increases greatly after five days of symptoms.
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    Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial
    (Springer Nature, 2021-01) Fisher, Michael J.; Shih, Chie-Schin; Rhodes, Steven D.; Armstrong, Amy E.; Wolters, Pamela L.; Dombi, Eva; Zhang, Chi; Angus, Steven P.; Johnson, Gary L.; Packer, Roger J.; Allen, Jeffrey C.; Ullrich, Nicole J.; Goldman, Stewart; Gutmann, David H.; Plotkin, Scott R.; Rosser, Tena; Robertson, Kent A.; Widemann, Brigitte C.; Smith, Abbi E.; Bessler, Waylan K.; He, Yongzheng; Park, Su-Jung; Mund, Julie A.; Jiang, Li; Bijangi-Vishehsaraei, Khadijeh; Robinson, Coretta Thomas; Cutter, Gary R.; Korf, Bruce R.; Blakeley, Jaishri O.; Clapp, D. Wade; Pediatrics, School of Medicine
    Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1fl/fl;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.
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    Cdkn2a (Arf) loss drives NF1-associated atypical neurofibroma and malignant transformation
    (Oxford, 2019-08) Rhodes, Steven D.; He, Yongzheng; Smith, Abbi; Jiang, Li; Lu, Qingbo; Mund, Julie; Li, Xiaohong; Bessler, Waylan; Qian, Shaomin; Dyer, William; Sandusky, George E.; Horvai, Andrew E.; Armstrong, Amy E.; Clapp, D. Wade; Pediatrics, School of Medicine
    Plexiform neurofibroma (PN) tumors are a hallmark manifestation of neurofibromatosis type 1 (NF1) that arise in the Schwann cell (SC) lineage. NF1 is a common heritable cancer predisposition syndrome caused by germline mutations in the NF1 tumor suppressor, which encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras proteins. Whereas most PN are clinically indolent, a subset progress to atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) and/or to malignant peripheral nerve sheath tumors (MPNSTs). In small clinical series, loss of 9p21.3, which includes the CDKN2A locus, has been associated with the genesis of ANNUBP. Here we show that the Cdkn2a alternate reading frame (Arf) serves as a gatekeeper tumor suppressor in mice that prevents PN progression by inducing senescence-mediated growth arrest in aberrantly proliferating Nf1−/− SC. Conditional ablation of Nf1 and Arf in the neural crest-derived SC lineage allows escape from senescence, resulting in tumors that accurately phenocopy human ANNUBP and progress to MPNST with high penetrance. This animal model will serve as a platform to study the clonal development of ANNUBP and MPNST and to identify new therapies to treat existing tumors and to prevent disease progression.
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    Combined CDK4/6 and ERK1/2 inhibition enhances anti-tumor activity in NF1-associated plexiform neurofibroma
    (American Association for Cancer Research, 2023) Flint, Alyssa C.; Mitchell, Dana K.; Angus, Steven P.; Smith, Abbi E.; Bessler, Waylan; Jiang, Li; Mang, Henry; Li, Xiaohong; Lu, Qingbo; Rodriguez, Brooke; Sandusky, George E.; Masters, Andi R.; Zhang, Chi; Dang, Pengtao; Koenig, Jenna; Johnson, Gary L.; Shen, Weihua; Liu, Jiangang; Aggarwal, Amit; Donoho, Gregory P.; Willard, Melinda D.; Bhagwat, Shripad V.; Clapp, D. Wade; Rhodes, Steven D.; Pediatrics, School of Medicine
    Purpose: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. Experimental design: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice. Results: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo. Conclusions: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.
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    Correction: Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours
    (Springer Nature, 2022) Gampala, Silpa; Shah, Fenil; Zhang, Chi; Rhodes, Steven D.; Babb, Olivia; Grimard, Michelle; Wireman, Randall S.; Rad, Ellie; Calver, Brian; Bai, Ren-Yuan; Staedtke, Verena; Hulsey, Emily L.; Saadatzadeh, M. Reza; Pollok, Karen E.; Tong, Yan; Smith, Abbi E.; Clapp, D. Wade; Tee, Andrew R.; Kelley, Mark R.; Fishel, Melissa L.; Pediatrics, School of Medicine
    Correction to: British Journal of Cancer 10.1038/s41416-021-01270-8, published online 03 March 2021 The original version of this article unfortunately contained an error in Figure 4, specifically: Figure 4f: the middle cell image was originally a duplicate of the middle cell image from Fig. 4d; the correct image is now used. The corrected figure is displayed below. The correction does not have any effect on the final conclusions of the paper. The original article has been corrected.
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    Dystrophic spinal deformities in a neurofibromatosis type 1 murine model
    (PLoS, 2015-03-18) Rhodes, Steven D.; Zhang, Wei; Yang, Dalong; Yang, Hao; Chen, Shi; Wu, Xiahoua; Yang, Xianlin; Mohammad, Khalid S.; Guise, Theresa A.; Bergner, Amanda L.; Stevenson, David A.; Yang, Feng-Chun; Department of Anatomy and Cell Biology, IU School of Medicine
    Despite the high prevalence and significant morbidity of spinal anomalies in neurofibromatosis type 1 (NF1), the pathogenesis of these defects remains largely unknown. Here, we present two murine models: Nf1flox/-;PeriCre and Nf1flox/-;Col.2.3Cre mice, which recapitulate spinal deformities seen in the human disease. Dynamic histomorphometry and microtomographic studies show recalcitrant bone remodeling and distorted bone microarchitecture within the vertebral spine of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice, with analogous histological features present in a human patient with dystrophic scoliosis. Intriguingly, 36-60% of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice exhibit segmental vertebral fusion anomalies with boney obliteration of the intervertebral disc (IVD). While analogous findings have not yet been reported in the NF1 patient population, we herein present two case reports of IVD defects and interarticular vertebral fusion in patients with NF1. Collectively, these data provide novel insights regarding the pathophysiology of dystrophic spinal anomalies in NF1, and provide impetus for future radiographic analyses of larger patient cohorts to determine whether IVD and vertebral fusion defects may have been previously overlooked or underreported in the NF1 patient population.
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    Early administration of imatinib mesylate reduces plexiform neurofibroma tumor burden with durable results after drug discontinuation in a mouse model of neurofibromatosis type 1
    (Wiley, 2020-05-27) Armstrong, Amy E.; Rhodes, Steven D.; Smith, Abbi; Chen, Shi; Bessler, Waylan; Ferguson, Michael J.; Jiang, Li; Li, Xiaohong; Yuan, Jin; Yang, Xianlin; Yang, Feng-Chun; Robertson, Kent A.; Ingram, David A.; Blakeley, Jaishri O.; Clapp, D. Wade; Pediatrics, School of Medicine
    BACKGROUND Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by plexiform neurofibromas (pNF), which are thought to be congenital tumors that arise in utero and enlarge throughout life. Genetic studies in murine models delineated an indispensable role for the stem cell factor (SCF)/c-kit pathway in pNF initiation and progression. A subsequent phase 2 clinical trial using imatinib mesylate to inhibit SCF/c-kit demonstrated tumor shrinkage in a subset of pre-existing pNF, however imatinib’s role on preventing pNF development has yet to be explored. PROCEDURE We evaluated the effect of imatinib dosed at 10–100 mg/kg/day for 12 weeks to 1-month old Nf1flox/flox;PostnCre(+) mice, prior to onset of pNF formation. To determine durability of response, we then monitored for pNF growth at later time points, comparing imatinib to vehicle treated mice. We assessed gross and histopathological analysis of tumor burden. RESULTS Imatinib administered preventatively led to a significant decrease in pNF number, even at doses as low as 10 mg/kg/day. Tumor development continued to be significantly inhibited after cessation of imatinib dosed at 50 and 100 mg/kg/day. In the cohort of treated mice that underwent prolonged follow-up, the size of residual tumors was significantly reduced as compared to age-matched littermates that received vehicle control. CONCLUSIONS Early administration of imatinib inhibits pNF genesis in vivo and effects are sustained after discontinuation of therapy. These findings may guide clinical use of imatinib in young NF1 patients prior to substantial development of pNF.
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    Efficacy of the Allosteric MEK Inhibitor Trametinib in Relapsed and Refractory Juvenile Myelomonocytic Leukemia
    (American Association for Cancer Research, 2024) Stieglitz, Elliot; Lee, Alex G.; Angus, Steven P.; Davis, Christopher; Barkauskas, Donald A.; Hall, David; Kogan, Scott C.; Meyer, Julia; Rhodes, Steven D.; Tasian, Sarah K.; Xuei, Xiaoling; Shannon, Kevin; Loh, Mignon L.; Fox, Elizabeth; Weigel, Brenda J.; Pediatrics, School of Medicine
    Juvenile myelomonocytic leukemia (JMML) is a hematologic malignancy of young children caused by mutations that increase Ras signaling output. Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment, but patients with relapsed or refractory (advanced) disease have dismal outcomes. This phase II trial evaluated the safety and efficacy of trametinib, an oral MEK1/2 inhibitor, in patients with advanced JMML. Ten infants and children were enrolled, and the objective response rate was 50%. Four patients with refractory disease proceeded to HSCT after receiving trametinib. Three additional patients completed all 12 cycles permitted on study and continue to receive off-protocol trametinib without HSCT. The remaining three patients had progressive disease with two demonstrating molecular evolution by the end of cycle 2. Transcriptomic and proteomic analyses provided novel insights into the mechanisms of response and resistance to trametinib in JMML. ClinicalTrials.gov Identifier: NCT03190915. Significance: Trametinib was safe and effective in young children with relapsed or refractory JMML, a lethal disease with poor survival rates. Seven of 10 patients completed the maximum 12 cycles of therapy or used trametinib as a bridge to HSCT and are alive with a median follow-up of 24 months.
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    Existing and Developing Preclinical Models for Neurofibromatosis Type 1–Related Cutaneous Neurofibromas
    (Elsevier, 2023) Staedtke, Verena; Topilko, Piotr; Le, Lu Q.; Grimes, Kevin; Largaespada, David A.; Cagan, Ross L.; Steensma, Matthew R.; Stemmer-Rachamimov, Anat; Blakeley, Jaishri O.; Rhodes, Steven D.; Ly, Ina; Romo, Carlos G.; Lee, Sang Y.; Serra, Eduard; Pediatrics, School of Medicine
    Neurofibromatosis type 1 (NF1) is caused by a nonfunctional copy of the NF1 tumor suppressor gene that predisposes patients to the development of cutaneous neurofibromas (cNFs), the skin tumor that is the hallmark of this condition. Innumerable benign cNFs, each appearing by an independent somatic inactivation of the remaining functional NF1 allele, form in nearly all patients with NF1. One of the limitations in developing a treatment for cNFs is an incomplete understanding of the underlying pathophysiology and limitations in experimental modeling. Recent advances in preclinical in vitro and in vivo modeling have substantially enhanced our understanding of cNF biology and created unprecedented opportunities for therapeutic discovery. We discuss the current state of cNF preclinical in vitro and in vivo model systems, including two- and three-dimensional cell cultures, organoids, genetically engineered mice, patient-derived xenografts, and porcine models. We highlight the models' relationship to human cNFs and how they can be used to gain insight into cNF development and therapeutic discovery.