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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. - PowerPoint PPT Presentation
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Targeting Chaperone Dependence in Rhabdomyosarcoma
Amit J. Sabnis MD, Bivona LaboratoryUCSF Helen Diller Family Comprehensive Cancer Center
UCSF Benioff Children’s Hospital
Two Paradigms for Developing Cancer Therapies
Oncogene Dependence Non-Oncogene Dependence
Luo J et al., Cell 2009
HSP70 Chaperones are Cellular Buffers Against Proteotoxic Stress
Hypothesis: HSP70 inhibition will engage stress responses in rhabdomyosarcoma cells
and lead to cell death.
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
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.
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
Treat with MAL3-101Measure Integrated Stress Response
RMS13 I.R. #1 - 4
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.
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.
Acknowledgements
Bivona LabTrever BivonaJonathan ShueAnin SayanaLuping LinCollin BlakelyEvangelos Pazarentzos
Support
Damon Runyon-Sohn Pediatric Cancer Fellow (A.J.S.)
St. Baldrick’s Foundation Fellow (A.J.S.)
HCIA Award (T.B.)
CollaboratorsJeff Brodsky (U. Pittsburgh)
Chris GuerrieroPeter Walter (UCSF)
Diego Acosta-AlvearCarmela Sidrauski
Jonathan Weissman (UCSF)Jason Gestwicki (UCSF)