MEDICA@MUSC (Medical University of South Carolina)
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Simultaneous Inhibition of ErbB3 and Calmodulin-Mediated Signaling Effectively Inhibits Malignant Peripheral Nerve Sheath Tumor Proliferation and Survival
Get PDFPatients with Neurofibromatosis Type 1 have germline mutations in the neurofibromin gene (NF1) and are prone to develop tumors in the nervous system and elsewhere throughout their lifespan. Loss-of-function mutations of the remaining functional copy of the NF1 tumor suppressor gene in the Schwann cell lineage results in development of benign tumors known as dermal and plexiform neurofibromas. Mutations in additional tumor suppressor genes, like p53 and CDKN2A, subsequently transforms plexiform neurofibromas into highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). At present, no effective treatments are available for MPNSTs, in fact some approaches make these tumors more aggressive. Since both neurofibromas and MPNSTs demonstrate Ras hyperactivation, many laboratories have targeted Ras and key downstream effectors of Ras. Unfortunately, all attempts to develop downstream targeted therapies for MPNSTs have failed. However, upstream receptor tyrosine kinases (RTKs) can activate Ras through several mechanisms in MPNSTs. One RTK, erbB3, has yet to be investigated in MPNST pathogenesis. Furthermore, upstream, and parallel Ras activation by intracellular calcium signaling has also been implicated in MPNSTs but has not yet been investigated. We found that erbB3 is expressed and required for the proliferation and survival of MPNST cells and that erbB3 promotes calcium-mediated signaling viii mechanisms. Using genome-wide shRNA screens, NRG1β-erbB3 microarray analyses and in vitro drug kinomics screening, we identified novel erbB3 and calcium regulated signaling pathways as potential druggable targets for MPNSTs. Due to the historical failure of monotherapy drug treatments in MPNST patients, we sought to identify a combinatorial treatment that effectively inhibited MPNST cell proliferation and survival by targeting upstream activators. We discovered that erbB3 signals through both canonical and novel pathways in MPNSTs and that calcium-calmodulin mediated signaling is an MPNST vulnerability. We have identified a novel calmodulin-independent regulation of the calmodulin effector calmodulin-regulated kinase II (CamKII) and have shown that simultaneous inhibition of erbB3 and calcium-calmodulin mediated signaling significantly reduces MPNST cell proliferation and survival. We conclude that erbB3 contributes significantly to MPNST growth and survival as well as calcium-calmodulin mediated signaling and that inhibition of both pathways is more effective than treatment with erbB or calmodulin inhibitors alone
Mapping the Opal Score for Clinical Trials to Coordinator Hours: A Single Site Study
Get PDFWorkload assessments help provide validation to increase staff, evaluate and ensure equal distribution of work, and assist with budget justifications. The Ontario Protocol Assessment Level (OPAL) is one of the most widely used protocol assessment tools. This study mapped an adapted OPAL score for clinical trials to actual coordinator hours from a single site to determine if the adapted OPAL score could predict coordinator hours. The purpose was to project a more accurate capacity estimate when considering new studies. The Morehouse School of Medicine (MSM) clinical trials management system was queried for actively enrolling interventional studies with corresponding coordinator effort tracking from June 1, 2022, to December 1, 2022. Protocols were graded using an adapted OPAL tool. Linear regression analysis was performed to determine whether a linear association exists between the adapted OPAL score and coordinator effort. Seven studies were included in the analysis. The overall regression was statistically significant (R2 = 0.78, p = 0.008), and the adapted OPAL score significantly predicted tracked coordinator hours (β = 77.22, p = 0.008)
PCBP1 Regulates LIFR Through FAM3C to Maintain Breast Cancer Stem Cell Self-Renewal and Invasiveness
Get PDFThe poly(rC) binding protein 1 gene (PCBP1) encodes the heterogenous nuclear ribonucleoprotein E1 (hnRNPE1), a nucleic acid-binding protein that plays a tumor-suppressive role in mammary epithelial cells by regulating phenotypic plasticity and cell fate. Following the loss of PCBP1 function, the FAM3C gene (encoding the Interleukin-like EMT inducer, or “ILEI” protein) and the leukemia inhibitory factor receptor (LIFR) gene are upregulated. Interaction between FAM3C and LIFR in the extracellular space induces phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Overexpression and/or hyperactivity of STAT3 has been detected in 40% of breast cancer cases and is associated with a poor prognosis. Herein, we characterize a “feed-forward” mechanism that regulates the expression of LIFR in response to FAM3C/LIFR/STAT3 signaling in mammary epithelial cells. We show that the loss of PCBP1 expression upregulates LIFR transcription through activity at the LIFR promoter. We also show that LIFR transcription is affected by modulation of FAM3C expression levels. Additionally, our bioinformatic analysis reveals a signature of transcriptional regulation associated with the FAM3C/LIFR interaction and identifies the TWIST1 transcription factor as a downstream effector that participates in the maintenance of LIFR expression. Finally, we characterize the effect of LIFR expression in cell-based experiments using both mouse and human mammary epithelial cells. Our experiments demonstrate the promotion of invasion, migration, and self-renewal of breast cancer stem cells (BCSCs) following increased LIFR expression, which is consistent with previous studies linking LIFR expression to tumor initiation and metastasis in mammary epithelial cells