COMBINATION DRUG THERAPIES WITH THE NOVEL RNA POLYMERASE I INHIBITOR CX-5461 IMPROVE EFFICACY IN THE TREATMENT OF MULTIPLE MYELOMA
(Abstract release date: 05/19/16)
EHA Library. Maclachlan K. 06/09/16; 132789; E1240
Dr. Kylee Maclachlan
Contributions
Contributions
Abstract
Abstract: E1240
Type: Eposter Presentation
Background
Ribosome biogenesis is dysregulated in malignancy, which is thought to contribute to cellular transformation and proliferation. Selective targeting of RNA polymerase I (Pol I), the enzyme responsible for transcribing the ribosomal RNA genes, with the novel small molecule inhibitor CX-5461 (Drygin et al., Cancer Res 2011) induces cell death using both p53-dependent and –independent pathways in both haematological and solid tumours. In a murine model of B-cell lymphoma, treatment with CX-5461 significantly increased survival (Bywater et al., Cancer Cell) and the drug is now in early stage clinical trials.
Aims
To determine the efficacy of CX-5461 in the treatment of multiple myeloma (MM), both alone and in combination with standard and emerging MM therapies.
Methods
A panel of human myeloma cell lines (HMCLs) were treated with CX-5461 prior to measuring proliferation, cell death and cell cycle distribution. Western blots were performed at serial time points for markers of DNA damage signalling and cell cycle control. CX-5461 was tested in combination with a variety of therapeutic agents that have demonstrated clinical or preclinical efficacy against MM.
Results
Testing CX-5461 against our panel of HMCLs reveals a wide range of sensitivity to Pol I inhibition. Our data show that sensitivity to CX-5461 is not solely dependent on proliferation rate or p53 status. Treatment of HMCLs with CX-5461 leads to a rapid increase in total and serine-15-phosphorylated p53 protein levels, in line with published data in other malignancies. Interestingly, CX-5461 induced phosphorylation of the checkpoint proteins Chk1 and Chk2, even in mutant p53 expressing cell lines, suggesting activation of p53-independent cell cycle checkpoints.The combination of CX-5461 with drugs having differing mechanisms of action shows increased inhibition of proliferation and induction of cell death compared to single agents alone. Increased efficacy is seen in combination with dexamethasone, everolimus, JQ1, ABT-199 and dinaciclib, with the most dramatic results being seen when CX-5461 is combined with bortezomib, carfilzomib or panobinostat.
Conclusion
Combination drug therapy is necessary to delay acquired drug resistance to single therapeutic agents and increase overall survival. Our data suggest that the novel Pol I inhibitor CX-5461 can be combined with a broad spectrum of agents, with bortezomib, carfilzomib and panobinostat showing the most promise.
Session topic: E-poster
Keyword(s): Multiple myeloma, P53, Treatment
Type: Eposter Presentation
Background
Ribosome biogenesis is dysregulated in malignancy, which is thought to contribute to cellular transformation and proliferation. Selective targeting of RNA polymerase I (Pol I), the enzyme responsible for transcribing the ribosomal RNA genes, with the novel small molecule inhibitor CX-5461 (Drygin et al., Cancer Res 2011) induces cell death using both p53-dependent and –independent pathways in both haematological and solid tumours. In a murine model of B-cell lymphoma, treatment with CX-5461 significantly increased survival (Bywater et al., Cancer Cell) and the drug is now in early stage clinical trials.
Aims
To determine the efficacy of CX-5461 in the treatment of multiple myeloma (MM), both alone and in combination with standard and emerging MM therapies.
Methods
A panel of human myeloma cell lines (HMCLs) were treated with CX-5461 prior to measuring proliferation, cell death and cell cycle distribution. Western blots were performed at serial time points for markers of DNA damage signalling and cell cycle control. CX-5461 was tested in combination with a variety of therapeutic agents that have demonstrated clinical or preclinical efficacy against MM.
Results
Testing CX-5461 against our panel of HMCLs reveals a wide range of sensitivity to Pol I inhibition. Our data show that sensitivity to CX-5461 is not solely dependent on proliferation rate or p53 status. Treatment of HMCLs with CX-5461 leads to a rapid increase in total and serine-15-phosphorylated p53 protein levels, in line with published data in other malignancies. Interestingly, CX-5461 induced phosphorylation of the checkpoint proteins Chk1 and Chk2, even in mutant p53 expressing cell lines, suggesting activation of p53-independent cell cycle checkpoints.The combination of CX-5461 with drugs having differing mechanisms of action shows increased inhibition of proliferation and induction of cell death compared to single agents alone. Increased efficacy is seen in combination with dexamethasone, everolimus, JQ1, ABT-199 and dinaciclib, with the most dramatic results being seen when CX-5461 is combined with bortezomib, carfilzomib or panobinostat.
Conclusion
Combination drug therapy is necessary to delay acquired drug resistance to single therapeutic agents and increase overall survival. Our data suggest that the novel Pol I inhibitor CX-5461 can be combined with a broad spectrum of agents, with bortezomib, carfilzomib and panobinostat showing the most promise.
Session topic: E-poster
Keyword(s): Multiple myeloma, P53, Treatment
Abstract: E1240
Type: Eposter Presentation
Background
Ribosome biogenesis is dysregulated in malignancy, which is thought to contribute to cellular transformation and proliferation. Selective targeting of RNA polymerase I (Pol I), the enzyme responsible for transcribing the ribosomal RNA genes, with the novel small molecule inhibitor CX-5461 (Drygin et al., Cancer Res 2011) induces cell death using both p53-dependent and –independent pathways in both haematological and solid tumours. In a murine model of B-cell lymphoma, treatment with CX-5461 significantly increased survival (Bywater et al., Cancer Cell) and the drug is now in early stage clinical trials.
Aims
To determine the efficacy of CX-5461 in the treatment of multiple myeloma (MM), both alone and in combination with standard and emerging MM therapies.
Methods
A panel of human myeloma cell lines (HMCLs) were treated with CX-5461 prior to measuring proliferation, cell death and cell cycle distribution. Western blots were performed at serial time points for markers of DNA damage signalling and cell cycle control. CX-5461 was tested in combination with a variety of therapeutic agents that have demonstrated clinical or preclinical efficacy against MM.
Results
Testing CX-5461 against our panel of HMCLs reveals a wide range of sensitivity to Pol I inhibition. Our data show that sensitivity to CX-5461 is not solely dependent on proliferation rate or p53 status. Treatment of HMCLs with CX-5461 leads to a rapid increase in total and serine-15-phosphorylated p53 protein levels, in line with published data in other malignancies. Interestingly, CX-5461 induced phosphorylation of the checkpoint proteins Chk1 and Chk2, even in mutant p53 expressing cell lines, suggesting activation of p53-independent cell cycle checkpoints.The combination of CX-5461 with drugs having differing mechanisms of action shows increased inhibition of proliferation and induction of cell death compared to single agents alone. Increased efficacy is seen in combination with dexamethasone, everolimus, JQ1, ABT-199 and dinaciclib, with the most dramatic results being seen when CX-5461 is combined with bortezomib, carfilzomib or panobinostat.
Conclusion
Combination drug therapy is necessary to delay acquired drug resistance to single therapeutic agents and increase overall survival. Our data suggest that the novel Pol I inhibitor CX-5461 can be combined with a broad spectrum of agents, with bortezomib, carfilzomib and panobinostat showing the most promise.
Session topic: E-poster
Keyword(s): Multiple myeloma, P53, Treatment
Type: Eposter Presentation
Background
Ribosome biogenesis is dysregulated in malignancy, which is thought to contribute to cellular transformation and proliferation. Selective targeting of RNA polymerase I (Pol I), the enzyme responsible for transcribing the ribosomal RNA genes, with the novel small molecule inhibitor CX-5461 (Drygin et al., Cancer Res 2011) induces cell death using both p53-dependent and –independent pathways in both haematological and solid tumours. In a murine model of B-cell lymphoma, treatment with CX-5461 significantly increased survival (Bywater et al., Cancer Cell) and the drug is now in early stage clinical trials.
Aims
To determine the efficacy of CX-5461 in the treatment of multiple myeloma (MM), both alone and in combination with standard and emerging MM therapies.
Methods
A panel of human myeloma cell lines (HMCLs) were treated with CX-5461 prior to measuring proliferation, cell death and cell cycle distribution. Western blots were performed at serial time points for markers of DNA damage signalling and cell cycle control. CX-5461 was tested in combination with a variety of therapeutic agents that have demonstrated clinical or preclinical efficacy against MM.
Results
Testing CX-5461 against our panel of HMCLs reveals a wide range of sensitivity to Pol I inhibition. Our data show that sensitivity to CX-5461 is not solely dependent on proliferation rate or p53 status. Treatment of HMCLs with CX-5461 leads to a rapid increase in total and serine-15-phosphorylated p53 protein levels, in line with published data in other malignancies. Interestingly, CX-5461 induced phosphorylation of the checkpoint proteins Chk1 and Chk2, even in mutant p53 expressing cell lines, suggesting activation of p53-independent cell cycle checkpoints.The combination of CX-5461 with drugs having differing mechanisms of action shows increased inhibition of proliferation and induction of cell death compared to single agents alone. Increased efficacy is seen in combination with dexamethasone, everolimus, JQ1, ABT-199 and dinaciclib, with the most dramatic results being seen when CX-5461 is combined with bortezomib, carfilzomib or panobinostat.
Conclusion
Combination drug therapy is necessary to delay acquired drug resistance to single therapeutic agents and increase overall survival. Our data suggest that the novel Pol I inhibitor CX-5461 can be combined with a broad spectrum of agents, with bortezomib, carfilzomib and panobinostat showing the most promise.
Session topic: E-poster
Keyword(s): Multiple myeloma, P53, Treatment
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