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Targeted Therapy Development for Neurofibromatosis Type 2
Title
Targeted Therapy Development for Neurofibromatosis Type 2.
Creator
Fuse, Marisa, Fernandez-Valle, Cristina, Lambert, Stephen, Altomare, Deborah, Khaled, Annette, University of Central Florida
Abstract / Description
Neurofibromatosis type 2 (NF2) is a debilitating disease characterized by the formation of bilateral vestibular schwannomas, which compress the vestibulocochlear nerve and cause deafness. Additional peripheral schwannomas, meningiomas and ependymomas may also form. NF2 is caused by mutations in the NF2 gene, resulting in the loss of function of the merlin tumor suppressor. Merlin functions in multiple signaling pathways and its absence in Schwann cells yields increased cell survival and...
Show moreNeurofibromatosis type 2 (NF2) is a debilitating disease characterized by the formation of bilateral vestibular schwannomas, which compress the vestibulocochlear nerve and cause deafness. Additional peripheral schwannomas, meningiomas and ependymomas may also form. NF2 is caused by mutations in the NF2 gene, resulting in the loss of function of the merlin tumor suppressor. Merlin functions in multiple signaling pathways and its absence in Schwann cells yields increased cell survival and proliferation, thereby causing schwannoma formation. First line treatment for NF2 is watchful waiting and surgical removal of tumors, potentially resulting in facial paralysis and deafness. To date, there are no pharmacological options for patients with NF2. Since the first clinical trials were completed in 2012, only 5 drugs have been investigated in NF2 patients. Few drugs have elicited a measurable radiographic tumor response and most only result in temporary hearing improvement in a small subset of patients. Development of novel therapeutic compounds is a slow, expensive process. However, re-purposing FDA-approved drugs for NF2 accelerates the transfer of efficacious drugs to the clinic. This dissertation used a systematic approach to identify drugs capable of reducing NF2-associated schwannoma growth. An initial screen revealed drugs that reduced viability of mouse and human merlin-deficient Schwann cells. Efficacious drugs were then advanced to an allograft mouse model of NF2 to identify those that reduced tumor growth in vivo. Drug efficacy was also examined in human primary schwannoma cells. We showed that Src, c-MET and MEK inhibitors reduced viability of merlin-deficient Schwann cells both in vitro and in vivo. We also identified a combination treatment of Src and c-MET inhibitors that induced apoptosis, suggesting the potential for preventing tumor recurrence after completion of drug treatment. The work presented here provides valuable pre-clinical evidence for the advancement of several approved drugs to clinical trials for NF2-associated schwannomas.
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Date Issued
2017
Identifier
CFE0006877, ucf:51707
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0006877
Target validation for Neurofibromatosis Type 2 therapeutics.
Title
Target validation for Neurofibromatosis Type 2 therapeutics.
Creator
Petrilli Guinart, Alejandra, Fernandez-Valle, Cristina, Altomare, Deborah, Khaled, Annette, Lambert, Stephen, University of Central Florida
Abstract / Description
Neurofibromatosis type 2 (NF2) is a benign tumor disease of the nervous system. Development of bilateral vestibular schwannomas is characteristic of NF2; however patients frequently present schwannomas on other nerves, as well as meningiomas and ependymomas. Currently, there are no drug therapies for NF2. There is an urgent need for development of NF2 therapeutics and this dissertation presents two independent potential therapeutic targets.The disease is caused by mutations in the NF2 gene...
Show moreNeurofibromatosis type 2 (NF2) is a benign tumor disease of the nervous system. Development of bilateral vestibular schwannomas is characteristic of NF2; however patients frequently present schwannomas on other nerves, as well as meningiomas and ependymomas. Currently, there are no drug therapies for NF2. There is an urgent need for development of NF2 therapeutics and this dissertation presents two independent potential therapeutic targets.The disease is caused by mutations in the NF2 gene that encodes a tumor suppressor called merlin. Loss of merlin function is associated with increased activity of Rac and p21-activated kinases (PAK) and deregulation of cytoskeletal organization. LIM domain kinases (LIMK1 and 2) are substrates for Cdc42/Rac-PAK, and modulate actin dynamics by phosphorylating cofilin, an actin severing and depolymerizing agent. LIMKs also translocate into the nucleus and regulate cell cycle progression. Here we report that mouse Schwann cells (MSCs) in which merlin function is lost as a result of Nf2 exon2 deletion (Nf2 delta Ex2) exhibited increased levels of LIMK1, LIMK2, and active phospho-Thr508/505-LIMK1/2, as well as phospho-Ser3-cofilin, compared to wild-type normal MSCs. Similarly, levels of LIMK1 and 2 total protein and active phosphorylated forms were elevated in human vestibular schwannomas compared to normal human Schwann cells (SCs). Reintroduction of wild-type NF2 into Nf2?delta Ex2 MSC reduced LIMK1 and LIMK2 levels. Pharmacological inhibition of LIMK with BMS-5, decreased the viability of Nf2?delta Ex2 MSCs in a dose-dependent manner, but did not affect viability of control MSCs. Similarly, LIMK knockdown decreased viability of Nf2?delta Ex2 MSCs. The decreased viability of Nf2?delta Ex2 MSCs was due to inhibition of cell cycle progression as evidenced by accumulation of cells in G2/M phase. Inhibition of LIMKs arrest cells in early mitosis by decreasing Aurora A activation and cofilin phosphorylation.To increase the search for NF2 therapeutics, we applied an alternative approach to drug discovery with an unbiased pilot high-throughput screen of the Library of Pharmacologically Active Compounds. We assayed for compounds capable of reducing viability of Nf2?delta Ex2 MSC as a cellular model for human NF2 schwannomas. AGK2, a SIRT2 (sirtuin 2) inhibitor, was identified as a candidate compound. SIRT2, a mammalian sirtuin, is a NAD+-dependent protein deacetylase. We show that Nf2?delta Ex2 MSC have higher expression levels of SIRT2 and lower levels of overall lysine acetylation than wild-type control MSC. Pharmacological inhibition of SIRT2 decreases Nf2?delta Ex2 MSC viability in a dose dependent manner without substantially reducing wild-type MSC viability. Inhibition of SIRT2 activity in Nf2?delta Ex2 MSC causes cell death accompanied by release of the necrotic markers lactate dehydrogenase and high mobility group box 1 protein into the medium in the absence of significant apoptosis, autophagy, or cell cycle arrest.Overall this work uncovered two novel potential therapeutic targets, LIMK and SIRT2 for NF2 and tumors associated with merlin deficiency.
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Date Issued
2013
Identifier
CFE0005398, ucf:50453
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0005398
THE PRESENCE OF PAIN RELATED CYTOKINES AND CHEMOKINES IN SCHWANNOMAS AND THEIR POTENTIAL ASSOCIATION WITH CHRONIC PAIN IN SCHWANNOMATOSIS
Title
THE PRESENCE OF PAIN RELATED CYTOKINES AND CHEMOKINES IN SCHWANNOMAS AND THEIR POTENTIAL ASSOCIATION WITH CHRONIC PAIN IN SCHWANNOMATOSIS.
Creator
Nagamoto, Jackson D, Fernandez-Valle, Cristina, University of Central Florida
Abstract / Description
Schwannomatosis (SWN) is a genetic disorder that predisposes affected individuals to develop multiple Schwannomas anywhere in the peripheral nervous system. This can be due to a mutation in the LZTR1 or SMARCB1 genes on chromosome 22. SWN has the defining clinical symptom of chronic pain and a lack of vestibular schwannomas, which sets it apart from other, related disorders such as Neurofibromatosis Type II (NF2). Currently, it is unknown what causes the chronic pain of SWN patients but it is...
Show moreSchwannomatosis (SWN) is a genetic disorder that predisposes affected individuals to develop multiple Schwannomas anywhere in the peripheral nervous system. This can be due to a mutation in the LZTR1 or SMARCB1 genes on chromosome 22. SWN has the defining clinical symptom of chronic pain and a lack of vestibular schwannomas, which sets it apart from other, related disorders such as Neurofibromatosis Type II (NF2). Currently, it is unknown what causes the chronic pain of SWN patients but it is hypothesized that cytokines may have promote the neuropathic pain experienced by patients. This study investigates the presence of the chemokine CCL2 and the cytokine IL6 in human SWN schwannomas and non-SWN schwannomas to determine if there is a difference in the presence of these cytokines between the two tumor types. It was demonstrated that all of the SWN schwannomas expressed both CCL2 and IL6 whereas the non-SWN schwannomas expressed only one or the other protein if either. These results indicate that the presence of these cytokines within the SWN schwannomas is different from non-SWN schwannomas and could be a potential contributing factor in the occurrence of neuropathic pain experienced by SWN which is part of the differential diagnosis for NF2 and SWN.
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Date Issued
2019
Identifier
CFH2000525, ucf:45627
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFH2000525