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University of Missouri - Columbia, POSH Inhibitor-Based Cancer Therapy

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POSH Inhibitor-Based Cancer Therapy presented for Whiteboard2Boardroom on December 11, 2018.

Publicado en: Salud y medicina
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University of Missouri - Columbia, POSH Inhibitor-Based Cancer Therapy

  1. 1. POSH Inhibitor-Based Cancer Therapy Presentation by: Brian Buntaine, M.S., M.B.A. Sr. Licensing Associate Office of Tech. Mgmt & Industry Relations Research lead: Mark Daniels, Ph.D. Associate Professor, Molecular Microbiology and Immunology
  2. 2. Cancer is a Global Health Problem • Cancer is a leading cause of death globally • Second only to cardiovascular disease • Current treatments are generally toxic or ineffective: • 5-year survival rates for various metastatic cancers generally range between 5% - 30%* • Certain high-risk leukemia and lymphoma subtypes remain untreatable • New classes of chemotherapeutics are needed; targeted treatment is highly preferred * https://www.cancercenter.com/ctca-results/ This work aims to develop a tumor cell specific, generally non-toxic treatment for hematological and other cancers.
  3. 3. C-Jun N-Terminal Kinases (JNK) are Master Regulators Implicated in Cancer • The JNKs are mitogen activated protein kinases (MAPKs) involved in many cell processes; they are transcribed from 3 genes: • JNK1 & JNK2: Ubiquitously expressed • JNK3: Expressed in brain, heart, and testes JNKs have been shown in numerous studies to play diverse roles in cancer Figures from Bubici et al. (2013). JNK signaling in cancer: in need of new, smarter therapeutic targets. BJP, 171; 24-37
  4. 4. Inhibitor decreases JNK1/JNK2 by blocking association of POSH with JIP-1 POSH Assembles JNK complex Rac1 POSH SH3.3 MAP3K JIP-1 JNK1 MKK7 Rac1 POSH SH3.3 MAP3K JIP-1 JNK1 MKK7 JNK1 signal no JNK1 signal Inhibitor
  5. 5. POSH/JNK1/JNK2 Have Many Cell Type Specific Roles • Plenty of Src homology 3 (SH3) domains (POSH) is a scaffold molecule involved in a variety of cellular roles: • Immune cells: TCR-mediated JNK1 activation (survival) in CD8+ cells1, Tak1-dependent JNK1/2 activation (diffferentiation) in CD4+ cells2 • Neurons: JNK-mediated apoptosis3, epilepsy4 • Synovial fibroblasts: Joint destruction via activated RASF5 • HIV: Viral assembly and release6 • Cancer: POSH inhibition results in apoptosis in a wide range of cancers including: TRAIL/Fas-mediated apoptosis in prostate cancer7, skin, breast, and lung (canine cancers also). 1. Cunningham et al. (2013). The POSH/JIP-1 scaffold network regulates TCR-mediated JNK1 signals and effector function in CD8+ T cells. Eur. J. Immunol. 43: 3361-3371 2. Cunningham et al. (2016). POSH regulates CD4+ T cell differentiation and Survival. J Immunol. 196: 4003-4013 3. Xu et al. (2013). POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis. EMBO J. 22(2) 252-261 4. Wang et al. (2017). POSH participates in epileptogenesis by increasing the surface expression of the NMDA receptor: a promising therapeutic target for epilepsy. Expert Opin Ther Targets. 21(12) 1083-1094 5. Karouzakis et al. (2014). Epigenome analysis reveals TBX5 as a novel transcription factor involved in the activation of rheumatoid arthritis synovial fibroblasts. J Immunol. 193: 4945-4951 6. Alroy er al. (2005). The trans-golgi network-associated human ubiquitin-protein ligase POSH is essential for HIV type-1 production. Proc Natl Acad Sci USA. 102(5): 1478-1483 7. Christian et al. (2011). Possible role of death receptor-mediated apoptosis by the E3 ubiquitin ligases Siah2 and POSH. 10:57, Targeted POSH inhibition as 1) a cancer therapeutic, and 2) a platform therapy for multiple conditions. Rac1 POSH SH3.3 MAP3K JIP-1 JNK1 MKK7
  6. 6. POSH Inhibition Kills Cancer via JNK1/JNK2 POSH inhibitor decreased proliferation and increased apoptosis in a variety of Lymphoma and Leukemia cell lines
  7. 7. POSH Inhibition Kills Cancer (additional data) POSH inhibition increased survival in mice injected with drug resistant leukemic cell lines compared to non-treated controls POSH inhibition effectively kills skin cancer and breast cancer cells Unpublished data also demonstrate efficacy against prostate and lung cancers
  8. 8. POSH Inhibition: Platform Therapeutic Targeted elimination of T-cells may have potential in treating autoimmune disease Applications in autoimmune disease POSH inhibition demonstrates reduced viral release in HIV infected cells Applications in viral infections
  9. 9. Targeted Delivery of POSH Inhibitors Peptide amphiphile Antitail amphiphile Cell-targeting aptamer + + = Dr. Donald Burke Dr. Mark Daniels Cell targeting Basic Oncology Clinical Oncology Dr. Sandra Bechtel, DVM Dr. Bret Ulery Chemical Engineering
  10. 10. Intellectual Property IP includes: • Issued US patent on multiple cell permeable POSH inhibitors • Pending US patent on targeted amphiphilic peptide POSH inhibitors
  11. 11. Partnering Seeking: • Licensing • Sponsored Research • Collaboration Next Steps: • Dose escalation in mice • Targeting agents • Canine toxicology study • Human trials Contact: Jim Baxendale, Director of Whiteboard2Boardroom baxendalej@umkc.edu Brian Buntaine, M.S., M.B.A. Sr. Licensing and Business Development Associate Office of Technology Licensing and Industry Relations University of Missouri-Columbia Phone: 573-882-0470 buntaineb@missouri.edu

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