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Radiation-associated and sporadic UPS/MFH : Searching for novel therapeutic strategies

Sarcoma Research Laboratory University of Texas, MD Anderson Cancer Center . Radiation-associated and sporadic UPS/MFH : Searching for novel therapeutic strategies. Keila Enitt Torres. UPS/MFH. Pleomorphic malignant fibrous histiocytoma (MFH )  unclassified pleomorphic sarcoma

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Radiation-associated and sporadic UPS/MFH : Searching for novel therapeutic strategies

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  1. Sarcoma Research Laboratory University of Texas, MD Anderson Cancer Center Radiation-associated and sporadic UPS/MFH: Searching for novel therapeutic strategies Keila Enitt Torres

  2. UPS/MFH Pleomorphic malignant fibrous histiocytoma (MFH) unclassified pleomorphic sarcoma Current technology  ? definable line of differentiation

  3. UPS Peak incidence in the 6th and 7th decades of life Typically large, deep, aggressive tumors 5% - metastases at presentation (lung) <3% radiation-associated

  4. UPS Treatment Radical excision with negative margins Neo-Adjuvant RT is offered widely negative margins is not possible. Chemotherapy  Unresectable disease/metastatic disease

  5. 5-year disease-specific survival 44- 66%*

  6. Approach • Low throughput: PI3K/AKT signaling pathway • Determine if AKT/mTOR axis is a relevant target for UPS therapy • High throughput: genomic/proteomic analysis • Understand genetic and molecular de-regulations  UPS progression

  7. PI3K/AKT pathway

  8. Nature Medicine 13, 748 - 753 (2007)

  9. c-Met HGF p-c-Met p-MEK p-AKT

  10. Goal #1 • Confirm whether the AKT/mTOR axis is a potential target for UPS/MFH therapy • Determine whether this pathway is differentially activated in radiation-associated versus sporadic UPS

  11. Radiation-associated sarcoma • Diagnosis of RAS based on the criteria published by Cahan, et al. in 1948.* • Previous radiation tx for different tumor • Development of the sarcoma - radiation field • Histologically different from the primary cancer • Minimum latent period of 5 years between the radiation and development of the sarcoma • Arlen et al. 1971- modified definition • Latency period of 3 years *Cahan et al. Cancer 1948;1:3-29.

  12. Bioresources in the laboratory • Cell lines • Animal models • Human Tissue • Frozen • FFPE

  13. Cell strain/cell line bank > 60 human tumors 6 Radiation-associated UPS cell strains 13 Sporadic UPS cell strains UPS-060 UPS-485 UPS-186 RIS-819.1 RIS-023

  14. UPS-060

  15. AKT/mTOR pathway is activated in UPS Radiation-associated Sporadic RIS-DL618 RIS-DL620 RIS-819 UPS-356 UPS-060 UPS-DL511 hMSC RIS-023 UPS-186 pAKT AKT p4EBP1 4EBP1 pS6K S6K b-actin

  16. UPS-060 UPS-485 RIS -023 RIS -819 Rapamycin Radiation-associated Sporadic 0 10 100 0 10 100 0 10 100 0 10 100 p4EBP1 4EBP1 pS6K S6K pAKT AKT b-actin

  17. Rapamycin Radiation-associated 0 0.05 0.1 0.5 1 5 0 0.05 0.1 0.5 1 5 Concentration (mM) Concentration (mM) Sporadic Concentration (mM) Concentration (mM)

  18. PI103 RIS-819 UPS-060 0 0.05 0.1 mM/4hr 0 0.05 0.1 pAKT AKT p4EBP1 4EBP1 pS6K S6K b-actin

  19. PI103 Radiation-associated Concentration (mM) Concentration (mM) Sporadic Concentration (mM) Concentration (mM)

  20. Cell Cycle UPS-060 Control PI103 RIS-819 Control PI103

  21. Migration Control PI103 UPS-060 RIS-819

  22. Invasion Control PI103 UPS-060 RIS-819

  23. In vivo studies OrthotopicXenograft Model 1-2mm pieces of tumor

  24. RIS-819 tumor growth * *

  25. RIS-819 Immunohistochemistry H&E pAKT p4EBP1 pS6RP Ki67 Control PI103

  26. UPS-060.1 tumor growth * Control PI103

  27. UPS-060.1 Immunohistochemistry H&E pAKT p4EBP1 pS6RP Ki67 Control PI103

  28. Summary PI3K/AKT pathway is activated in radiation-associated and sporadic UPS RA-UPS and sporadic UPS are sensitive to PI103 Effects in vivo model => Cell death

  29. Current studies miRNAanalysis Array-comparative genomic hybridization Sequenome RPPA TMA Exon Sequencing

  30. Reverse-phase protein lysate array for cell signaling analysis

  31. (Log 2) -3.5058 5.1031 Unsupervised hierarchical clustering EIF4E Mesenchymal cells UPS HER-2 Signaling ERK/MAPK PI3K/AKT/mTOR ErbB AMPK HGF signaling IL-15 Signaling 29 molecules differentially expressed >50% P value <0.01

  32. (Log 2) -3.5058 5.1031 Unsupervised hierarchical clusteringRA-UPS versus sporadic UPS RA-UPS Sporadic-UPS

  33. Sarcoma Research Laboratory University of Texas, MD Anderson Cancer Center Acknowledgments • Dina Lev • Raphael E. Pollock • Billy Wang • Alexander J. Lazar • Vinod Ravi • SARC (Sarcoma Alliance for Research through Collaboration)

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