IU Indianapolis ScholarWorks :: Browsing by Author "Smith, Abbi E."

Browsing by Author "Smith, Abbi E."

Now showing 1 - 9 of 9

Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK
(PLOS, 2021-07-15) Chang, Long-Sheng; Oblinger, Janet L.; Smith, Abbi E.; Ferrer, Marc; Angus, Steven P.; Hawley, Eric; Petrilli, Alejandra M.; Beauchamp, Roberta L.; Riecken, Lars Björn; Erdin, Serkan; Poi, Ming; Huang, Jie; Bessler, Waylan K.; Zhang, Xiaohu; Guha, Rajarshi; Thomas, Craig; Burns, Sarah S.; Gilbert, Thomas S.K.; Jiang, Li; Li, Xiaohong; Lu, Qingbo; Yuan, Jin; He, Yongzheng; Dixon, Shelley A.H.; Masters, Andrea; Jones, David R.; Yates, Charles W.; Haggarty, Stephen J.; La Rosa, Salvatore; Welling, D. Bradley; Stemmer-Rachamimov, Anat O.; Plotkin, Scott R.; Gusella, James F.; Guinney, Justin; Morrison, Helen; Ramesh, Vijaya; Fernandez-Valle, Cristina; Johnson, Gary L.; Blakeley, Jaishri O.; Clapp, D. Wade; Pediatrics, School of Medicine
Neurofibromatosis Type 2 (NF2) is an autosomal dominant genetic syndrome caused by mutations in the NF2 tumor suppressor gene resulting in multiple schwannomas and meningiomas. There are no FDA approved therapies for these tumors and their relentless progression results in high rates of morbidity and mortality. Through a combination of high throughput screens, preclinical in vivo modeling, and evaluation of the kinome en masse, we identified actionable drug targets and efficacious experimental therapeutics for the treatment of NF2 related schwannomas and meningiomas. These efforts identified brigatinib (ALUNBRIG®), an FDA-approved inhibitor of multiple tyrosine kinases including ALK, to be a potent inhibitor of tumor growth in established NF2 deficient xenograft meningiomas and a genetically engineered murine model of spontaneous NF2 schwannomas. Surprisingly, neither meningioma nor schwannoma cells express ALK. Instead, we demonstrate that brigatinib inhibited multiple tyrosine kinases, including EphA2, Fer and focal adhesion kinase 1 (FAK1). These data demonstrate the power of the de novo unbiased approach for drug discovery and represents a major step forward in the advancement of therapeutics for the treatment of NF2 related malignancies.
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.
Chemopreventative celecoxib fails to prevent schwannoma formation or sensorineural hearing loss in genetically engineered murine model of neurofibromatosis type 2
(Impact Journals, 2017-10-24) Wahle, Benjamin M.; Hawley, Eric T.; He, Yongzheng; Smith, Abbi E.; Yuan, Jin; Masters, Andi R.; Jones, David R.; Gehlhausen, Jeffrey R.; Park, Su-Jung; Conway, Simon J.; Clapp, D. Wade; Yates, Charles W.; Otolaryngology -- Head and Neck Surgery, School of Medicine
Mutations in the tumor suppressor gene NF2 lead to Neurofibromatosis type 2 (NF2), a tumor predisposition syndrome characterized by the development of schwannomas, including bilateral vestibular schwannomas with complete penetrance. Recent work has implicated the importance of COX-2 in schwannoma growth. Using a genetically engineered murine model of NF2, we demonstrate that selective inhibition of COX-2 with celecoxib fails to prevent the spontaneous development of schwannomas or sensorineural hearing loss in vivo, despite elevated expression levels of COX-2 in Nf2-deficient tumor tissue. These results suggest that COX-2 is nonessential to schwannomagenesis and that the proposed tumor suppressive effects of NSAIDs on schwannomas may occur through COX-2 independent mechanisms.
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.
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.
Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours
(Springer Nature, 2021) 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
Background: MPNST is a rare soft-tissue sarcoma that can arise from patients with NF1. Existing chemotherapeutic and targeted agents have been unsuccessful in MPNST treatment, and recent findings implicate STAT3 and HIF1-α in driving MPNST. The DNA-binding and transcriptional activity of both STAT3 and HIF1-α is regulated by Redox factor-1 (Ref-1) redox function. A first-generation Ref-1 inhibitor, APX3330, is being tested in cancer clinical trials and could be applied to MPNST. Methods: We characterised Ref-1 and p-STAT3 expression in various MPNST models. Tumour growth, as well as biomarkers of apoptosis and signalling pathways, were measured by qPCR and western blot following treatment with inhibitors of Ref-1 or STAT3. Results: MPNSTs from Nf1-Arfflox/floxPostnCre mice exhibit significantly increased positivity of p-STAT3 and Ref-1 expression when malignant transformation occurs. Inhibition of Ref-1 or STAT3 impairs MPNST growth in vitro and in vivo and induces apoptosis. Genes highly expressed in MPNST patients are downregulated following inhibition of Ref-1 or STAT3. Several biomarkers downstream of Ref-1 or STAT3 were also downregulated following Ref-1 or STAT3 inhibition. Conclusions: Our findings implicate a unique therapeutic approach to target important MPNST signalling nodes in sarcomas using new first-in-class small molecules for potential translation to the clinic.
Genetic disruption of the small GTPase RAC1 prevents plexiform neurofibroma formation in mice with neurofibromatosis type 1
(Elsevier, 2020-07-17) Mund, Julie A.; Park, SuJung; Smith, Abbi E.; He, Yongzheng; Jiang, Li; Hawley, Eric; Roberson, Michelle J.; Mitchell, Dana K.; Abu-Sultanah, Mohannad; Yuan, Jin; Bessler, Waylan K.; Sandusky, George; Chen, Shi; Zhang, Chi; Rhodes, Steven D.; Clapp, D. Wade; Pediatrics, School of Medicine
Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the NF1 tumor suppressor gene. NF1 encodes neurofibromin, a GTPase-activating protein for RAS proto-oncogene GTPase (RAS). Plexiform neurofibromas are a hallmark of NF1 and result from loss of heterozygosity of NF1 in Schwann cells, leading to constitutively activated p21RAS. Given the inability to target p21RAS directly, here we performed an shRNA library screen of all human kinases and Rho-GTPases in a patient-derived NF1-/- Schwann cell line to identify novel therapeutic targets to disrupt PN formation and progression. Rho family members, including Rac family small GTPase 1 (RAC1), were identified as candidates. Corroborating these findings, we observed that shRNA-mediated knockdown of RAC1 reduces cell proliferation and phosphorylation of extracellular signal-regulated kinase (ERK) in NF1-/- Schwann cells. Genetically engineered Nf1flox/flox;PostnCre+ mice, which develop multiple PNs, also exhibited increased RAC1-GTP and phospho-ERK levels compared with Nf1flox/flox;PostnCre- littermates. Notably, mice in which both Nf1 and Rac1 loci were disrupted (Nf1flox/floxRac1flox/flox;PostnCre+) were completely free of tumors and had normal phospho-ERK activity compared with Nf1flox/flox ;PostnCre+ mice. We conclude that the RAC1-GTPase is a key downstream node of RAS and that genetic disruption of the Rac1 allele completely prevents PN tumor formation in vivo in mice.
Irradiation of Nf1 mutant mouse models of spinal plexiform neurofibromas drives pathologic progression and decreases survival
(Oxford University Press, 2021-04-23) Laurent, Danny; Smith, Abbi E.; Bessler, Waylan K.; Mendonca, Marc; Chin-Sinex, Helen; Descovich, Martina; Horvai, Andrew E.; Clapp, D. Wade; Nakamura, Jean L.; Radiation Oncology, School of Medicine
Background: Genetically susceptible individuals can develop malignancies after irradiation of normal tissues. In the context of therapeutic irradiation, it is not known whether irradiating benign neoplasms in susceptible individuals promotes neoplastic transformation and worse clinical outcomes. Individuals with Neurofibromatosis 1 (NF1) are susceptible to both radiation-induced second malignancies and spontaneous progression of plexiform neurofibromas (PNs) to malignant peripheral nerve sheath tumors (MPNSTs). The role of radiotherapy in the treatment of benign neoplasms such as PNs is unclear. Methods: To test whether radiotherapy promotes neoplastic progression of PNs and reduces overall survival, we administered spinal irradiation (SI) to conditional knockout mouse models of NF1-associated PNs in 2 germline contexts: Nf1 fllfl ; PostnCre + and Nf1 fl/- ; PostnCre + . Both genotypes develop extensive Nf1 null spinal PNs, modeling PNs in NF1 patients. A total of 101 mice were randomized to 0 Gy, 15 Gy (3 Gy × 5), or 30 Gy (3 Gy × 10) of spine-focused, fractionated SI and aged until signs of illness. Results: SI decreased survival in both Nf1 fllfl mice and Nf1 fl/- mice, with the worst overall survival occurring in Nf1 fl/- mice receiving 30 Gy. SI was also associated with increasing worrisome histologic features along the PN-MPNST continuum in PNs irradiated to higher radiation doses. Conclusions: This preclinical study provides experimental evidence that irradiation of pre-existing PNs reduces survival and may shift PNs to higher grade neoplasms.
Spatial Gene-Expression Profiling Unveils Immuno-oncogenic Programs of NF1-Associated Peripheral Nerve Sheath Tumor Progression
(American Association for Cancer Research, 2024) Mitchell, Dana K.; Burgess, Breanne; White, Emily E.; Smith, Abbi E.; Potchanant, Elizabeth A. Sierra; Mang, Henry; Hickey, Brooke E.; Lu, Qingbo; Qian, Shaomin; Bessler, Waylan; Li, Xiaohong; Jiang, Li; Brewster, Kylee; Temm, Constance; Horvai, Andrew; Albright, Eric A.; Fishel, Melissa L.; Pratilas, Christine A.; Angus, Steven P.; Clapp, D. Wade; Rhodes, Steven D.; Pediatrics, School of Medicine
Purpose: Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) associated with neurofibromatosis type 1 (NF1). Despite similar histologic appearance, these neoplasms exhibit diverse evolutionary trajectories, with a subset progressing to malignant peripheral nerve sheath tumor (MPNST), the leading cause of premature death in individuals with NF1. Malignant transformation of PNF often occurs through the development of atypical neurofibroma (ANF) precursor lesions characterized by distinct histopathologic features and CDKN2A copy-number loss. Although genomic studies have uncovered key driver events promoting tumor progression, the transcriptional changes preceding malignant transformation remain poorly defined. Experimental design: Here we resolve gene-expression profiles in PNST across the neurofibroma-to-MPNST continuum in NF1 patients and mouse models, revealing early molecular features associated with neurofibroma evolution and transformation. Results: Our findings demonstrate that ANF exhibit enhanced signatures of antigen presentation and immune response, which are suppressed as malignant transformation ensues. MPNST further displayed deregulated survival and mitotic fidelity pathways, and targeting key mediators of these pathways, CENPF and BIRC5, disrupted the growth and viability of human MPNST cell lines and primary murine Nf1-Cdkn2a-mutant Schwann cell precursors. Finally, neurofibromas contiguous with MPNST manifested distinct alterations in core oncogenic and immune surveillance programs, suggesting that early molecular events driving disease progression may precede histopathologic evidence of malignancy. Conclusions: If validated prospectively in future studies, these signatures may serve as molecular diagnostic tools to augment conventional histopathologic diagnosis by identifying neurofibromas at high risk of undergoing malignant transformation, facilitating risk-adapted care.

Browsing by Author "Smith, Abbi E."

Results Per Page

Sort Options