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Matthew L. Anderson, MD, PhD Department of Obstetrics & Gynecology & Dan L. Duncan Cancer Center

Small Molecule Inhibitors for Polo-Like Kinase 1 (Plk-1) Sensitize Uterine Leiomyosarcoma to Rapamycin. Matthew L. Anderson, MD, PhD Department of Obstetrics & Gynecology & Dan L. Duncan Cancer Center Baylor College of Medicine. Uterine Smooth Muscle Tumors. Leiomyomas (Fibroids)

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Matthew L. Anderson, MD, PhD Department of Obstetrics & Gynecology & Dan L. Duncan Cancer Center

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  1. Small Molecule Inhibitors for Polo-Like Kinase 1 (Plk-1) Sensitize Uterine Leiomyosarcoma to Rapamycin Matthew L. Anderson, MD, PhD Department of Obstetrics & Gynecology & Dan L. Duncan Cancer Center Baylor College of Medicine

  2. Uterine Smooth Muscle Tumors • Leiomyomas (Fibroids) • Found in as many as 70% of women • Frequent cause of vaginal bleeding, • pelvic pain and infertility • Most common indication for hysterectomy • in the United States • Leiomyosarcomas (ULMS) • 0.8/100,000 women in North America.* • Recurrence rates as high as 70% for • early stage disease. • Treatment options limited • Genetically heterogeneous disease *2010 Seer Database;

  3. ULMS and the G2-M Checkpoint Shan, et al, Clin Cancer Res, 2012 Brewer-Savanah, et al, Clin Cancer Res, 2012

  4. Objective Can other gene products involved in regulating the G2-M cell cycle checkpoint be used more effectively to clinically target ULMS/LMS?

  5. Polo-like Kinase-1 and ULMS **P < 0.01

  6. Targeting Plk-1 in Vitro

  7. Plk-1 Inhibitors in Clinical Development

  8. Plk-1 Inhibitors Inhibit ULMS Growth BI 2536 BI 6727

  9. In Vitro Activity of BI-6727 Monotherapy

  10. Does BI-6727 Sensitize ULMS to Rapamycin? BI-6727 BI-6727 BI-6727 Rapamycin Pre-Treatment BI-6727 Pre-Treatment Co-Treatment

  11. Does BI-6727 Sensitize ULMS to Rapamycin? BI-6727 BI-6727 BI-6727 Rapamycin Pre-Treatment BI-6727 Pre-Treatment Co-Treatment

  12. Impact of Combination Therapy on Apoptosis and Colony Formation

  13. CONCLUSIONS • Overexpression of polo-like kinase-1 (Plk-1) is a robust feature of ULMS. • Targeting of Plk-1 by small molecule inhibitors or other strategies (eg. siRNA) may be an effective strategy to improve ULMS/LMS outcomes. • Targeting G2-M cell cycle transition may be an effective strategy for sensitizing LMS to rapamycin.

  14. Grant Support Sarcoma Foundation of America Cancer Prevention and Research Institute of Texas (CPRIT) The Partnership for Baylor College of Medicine Young Texans Against Cancer Gynecologic Cancer Foundation American Cancer Society Acknowledgements Anderson Lab Claire Mach, Pharm.D. Weiwei Shan, Ph.D. Jong Kim, M.S TriparnaGhosh, B.S. Gyoung Eun Kim, B.S. Lev Lab Dina Lev, M.D., Ph.D. Kari Brewer-Savannah, Ph.D.

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