Michael H Erwin

University of Alabama at Birmingham

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Jerry E. Stewart

University of Alabama at Birmingham

Elizabeth A. Beierle

University of Alabama at Birmingham

Jamie M. Aye

University of Alabama at Birmingham

Michael Ohlmeyer

Princeton Satellite Systems (United States)

Colin H. Quinn

University of Alabama at Birmingham

Swatika Butey

University of Alabama at Birmingham

Janet R. Julson

University of Alabama at Birmingham

Karina J. Yoon

University of Alabama at Birmingham

Laura V. Bownes

University of Alabama at Birmingham

Sara C. Hutchins

University of Alabama at Birmingham

Cooperative Institutions

University of Alabama at Birmingham

Children's of Alabama

University of Alabama

Princeton Satellite Systems (United States)

Icahn School of Medicine at Mount Sinai

Case Western Reserve University

Mount Sinai Hospital

NYU Langone Health

Instituto de Salud Carlos III

New York University

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Inhibition of Pim Kinase Supports the Neural Stem Cell Phenotype in Neuroblastoma

Journal of the American College of Surgeons (2022)

Janet R. Julson Laura V. Bownes Colin H. Quinn Sara C. Hutchins Michael H Erwin

Homeobox protein NANOG

PIM1

Stem cell marker

10.1097/01.xcs.0000894372.75788.77

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Effect of oncolytic herpes simplex virus on fusion-positive rhabdomyosarcoma to radiotherapy.

Journal of Clinical Oncology (2024)

Maryam G. Shaikh Nazia Nazam Swatika Butey Michael H Erwin Jerry E. Stewart

10063 Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite multimodal interventions including surgery, chemotherapy, and radiotherapy, nearly a third of patients with localized disease will experience tumor recurrence. Patients with tumors harboring an oncogenic FOXO1 fusion are at greater risk of relapse and are most in need of novel therapies. Oncolytic viruses are being explored as treatments for pediatric tumors, and data suggest that oncolytic viruses may enhance responses to chemoradiotherapy. M002 is a genetically engineered oncolytic herpes simplex virus (oHSV) that exhibits aneurovirulence in normal cells. M002 selectively replicates in malignant cells, eliminating these cells through cellular burst during the lytic cycle. In the present study, we explored the efficacy of the M002 virus alone and in combination with low-dose ionizing radiotherapy in a human patient-derived xenograft (PDX) model of fusion-positive RMS (FP-RMS). Methods: A human FP-RMS PDX was established and maintained by injection into the quadriceps femoris muscle of athymic nude mice under Institutional Animal Care and Use Committee guidelines (IACUC-09363). Tumors were dissociated and cells were treated with increasing multiplicity of infection (MOI) of either the oHSV, R3659 or its genetically engineered variant, M002. A colorimetric assay evaluated the cytotoxicity of oHSV treatments on the RMS PDX cells after 24, 48, and 72 hours of infection. In separate experiments, cells treated with vehicle (control) or infected with M002 were exposed to irradiation (2 Gy), and viability was determined at 24, 48, 72, and 96 hours. Results: Treatment with M002 or its parent construct, R3659, significantly reduced RMS PDX cell viability in a dose-dependent manner at all time points. M002 showed slightly higher cytotoxicity than R3659 as measured by lethal dose 50% (LD50, 37±1.25 vs 44±0.95 PFU/cell, M002 vs R3659, at 24 hours, p=0.02). When sub-lethal doses of M002 were combined with low-dose irradiation, RMS PDX cell viability was significantly decreased compared to cells treated with either M002 or irradiation alone (26% decrease at 10 PFU/cell). Conclusions: Our preliminary data highlight that M002 exhibits cytotoxicity in a PDX model of FP-RMS. Treatment with M002 further increased the cytotoxicity of ionizing radiation compared to individual treatments, suggesting that oHSV sensitized the cells to radiotherapy. Future studies in vivo may provide more pre-clinical evidence for the radio-sensitizing and therapeutic potential of M002 in FP-RMS.

10.1200/jco.2024.42.16_suppl.10063

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PP2A activation as a new therapeutic strategy in neuroblastoma: Making sense out of senescence.

Journal of Clinical Oncology (2024)

Nazia Nazam Maryam G. Shaikh Swatika Butey Michael H Erwin Jerry E. Stewart

10055 Background: Neuroblastoma (NBL) is the most common extracranial solid tumor in children, accounting for 15% of all pediatric cancer deaths. The five-year survival rate for children with high-risk disease is less than 50%, with the primary reasons for mortality being refractory and relapsed disease. One hypothesis for the poor response to therapy and propensity for recurrent disease in high-risk patients is treatment-induced senescence (TIS). Protein phosphatase 2A (PP2A) is a known tumor suppressor that is downregulated in NBL. PP2A activation has been shown to reverse cellular senescence in non-cancerous pathologies, therefore we hypothesized that reactivation of PP2A using novel small molecule activators would function as a novel senotherapeutic in NBL. Methods: We employed MYCNamplified, SK-N-BE(2), and non-amplified, SK-N-AS, established human NBL cell lines. Topotecan, a common NBL chemotherapeutic, known to induce senescence, and ATUX-1215, a small molecule PP2A activator, were utilized. NBL cells were treated with topotecan and ATUX-1215 alone, as well as in combination. Colorimetric assays detected cell viability and proliferation. Immunoblotting identified proteins of interest including γ-H2AX and CCL2. TIS was detected by S-β galactosidase (Sβgal) assay. Results: We found increased expression of the senescence marker, histone γ-H2AX, and increased Sβgal-positive tumor cells supporting the ability of topotecan to generate TIS in NBL. Following treatment with PP2A activator in combination with topotecan, markers of TIS are decreased in both MYCN amplified and non-amplified NBL cells. Further, and importantly, PP2A activation reversed the effects of topotecan TIS and acted in a synergistic fashion to decrease NBL cell viability. Conclusions: Activation of PP2A with a novel small molecule ameliorates topotecan-induced TIS in NBL cells irrespective of MYCN status. These results are promising, providing a potential novel therapeutic adjunct to children who are most in need of innovative interventions.

Senescence

10.1200/jco.2024.42.16_suppl.10055

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Preclinical Evidence Supporting Novel Protein Phosphatase 2A Activators as Therapeutics in Hepatoblastoma

Journal of the American College of Surgeons (2022)

Laura V. Bownes Janet R. Julson Colin H. Quinn Sara C. Hutchins Michael H Erwin

Hepatoblastoma

Viability assay

10.1097/01.xcs.0000894428.50909.da

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