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Targeting Chaperone Dependence in Rhabdomyosarcoma

Targeting Chaperone Dependence in Rhabdomyosarcoma. Amit J. Sabnis MD, Bivona Laboratory UCSF Helen Diller Family Comprehensive Cancer Center UCSF Benioff Children’s Hospital. Two Paradigms for Developing Cancer Therapies. Oncogene Dependence. Non-Oncogene Dependence.

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Targeting Chaperone Dependence in Rhabdomyosarcoma

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  1. Targeting Chaperone Dependence in Rhabdomyosarcoma Amit J. Sabnis MD, Bivona Laboratory UCSF Helen Diller Family Comprehensive Cancer Center UCSF Benioff Children’s Hospital

  2. Two Paradigms for Developing Cancer Therapies Oncogene Dependence Non-Oncogene Dependence LuoJ et al., Cell 2009

  3. HSP70 Chaperones are Cellular Buffers Against Proteotoxic Stress Hypothesis: HSP70 inhibition will engage stress responses in rhabdomyosarcoma cells and lead to cell death.

  4. The HSP70 Inhibitor MAL3-101 Induces Apoptosis in Rhabdomyosarcoma (RMS) Cells • Patient-derived rhabdomyosarcoma cell lines RMS13, Rh41, and Rh18 show micromolar sensitivity to MAL3-101. • MAL3-101 induces apoptosis in sensitive cell lines. RMS13 Cells: 24 Hr Treatment

  5. The Integrated Stress Response (ISR) Links Chaperone Failure to Apoptosis Hypothesis: Activation of the integrated stress response leads to cell death after MAL3-101 treatment.

  6. Probing the Mechanism of Action of MAL3-101 with Derived Isogenic Resistant Cell Lines Parental Line (MAL3-101 Sensitive) Isogenic Resistant Lines (MAL3-101 Resistant) 2 Month MAL3-101 Dose Escalation RMS13 I.R. #1- 4 Treat with MAL3-101 Measure Integrated Stress Response

  7. ISR Activation is a Hallmark of MAL3-101 Sensitivity

  8. ISR Activation is a Hallmark of MAL3-101 Sensitivity

  9. Loss of CHOP Promotes Resistance to MAL3-101 CHOP Knockdown by shRNA Sensitivity to MAL3-101

  10. Conclusions • MAL3-101 is an HSP70 inhibitor that induces apoptosis in rhabdomyosarcoma cells. • Apoptosis is a consequence of engaging the integrated stress response, and is CHOP dependent. • Failure to upregulate CHOP after HSP70 inhibition is a biomarker of resistance to MAL3-101. • Loss of CHOP causes partial resistance to MAL3-101.

  11. Future Directions • Test whether other stress sensors cooperate with the ISR in inducing apoptosis after HSP70 inhibition. • Carry out an unbiased shRNA screen to comprehensively identify mechanisms underlying resistance in I.R. lines. • Test MAL3-101 for activity in explant models of RMS as a prelude to clinical use.

  12. Acknowledgements Support Bivona Lab TreverBivona Jonathan Shue AninSayana LupingLin Collin Blakely EvangelosPazarentzos HCIA Award (T.B.) Damon Runyon-Sohn Pediatric Cancer Fellow (A.J.S.) Collaborators Jeff Brodsky (U. Pittsburgh) Chris Guerriero Peter Walter (UCSF) Diego Acosta-Alvear Carmela Sidrauski Jonathan Weissman (UCSF) Jason Gestwicki (UCSF) St. Baldrick’s Foundation Fellow (A.J.S.)

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