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Professor
Co-Leader, Blood Cell Development and Function
The Balachandran lab is interested in how cells die during host innate-immune responses to viruses and bacteria, and in exploiting these mechanisms for the treatment of human disease, whether infectious, inflammatory or malignant. In particular, the lab is interested in a form of programmed cell death termed necroptosis, driven by the kinase RIPK3. Unlike apoptosis, which proceeds via a caspase cascade that results in the ordered disassembly of the cell, necroptosis is caspase independent and driven by the RIPK3 substrate MLKL. Once activated by RIPK3, MLKL translocates to cellular membranes and induces their disruption, resulting in a form of necrotic cell death. Necroptosis is activated by several classes of innate-immune receptor (e.g., TLRs and cytokines such as TNF-α and interferons) and pathogen (e.g., RNA viruses, DNA viruses, certain gram-negative bacteria). The Balachandran lab is interested in how viruses (particularly RNA viruses), gram-negative bacteria, cytokines, and cellular stresses activate the necroptosis machinery, how necroptosis functions during acute viral and microbial infections to control pathogen spread, and how this death modality can be leveraged for immunotherapy.
The Balachandran lab is interested in how cells die during host innate-immune responses to viruses and bacteria, and in exploiting these mechanisms for the treatment of human disease, whether infectious, inflammatory or malignant. In particular, the lab is interested in a form of programmed cell death termed necroptosis, driven by the kinase RIPK3. Unlike apoptosis, which proceeds via a caspase cascade that results in the ordered disassembly of the cell, necroptosis is caspase independent and driven by the RIPK3 substrate MLKL. Once activated by RIPK3, MLKL translocates to cellular membranes and induces their disruption, resulting in a form of necrotic cell death. Necroptosis is activated by several classes of innate-immune receptor (e.g., TLRs and cytokines such as TNF-α and interferons) and pathogen (e.g., RNA viruses, DNA viruses, certain gram-negative bacteria). The Balachandran lab is interested in how viruses (particularly RNA viruses), gram-negative bacteria, cytokines, and cellular stresses activate the necroptosis machinery, how necroptosis functions during acute viral and microbial infections to control pathogen spread, and how this death modality can be leveraged for immunotherapy.
The lab has recently outlined a pathway by which interferons (IFNs), a family of cytokines with well-known antiviral and immunomodulatory properties, activate RIPK1/3 kinases and trigger necroptotic death. The laboratory continues to work on how IFNs activate RIPK1/3 kinases, and the regulatory mechanisms that normally restrain these kinases in unstimulated cells and only license necroptosis in susceptible cells. We have identified two such mechanisms that protect cells from IFNs: the adaptor protein FADD and the transcription factor NF-κB. Current projects in this area are centered on how FADD (and caspases) are disabled to allow IFNs to trigger necroptosis during an active infection. An allied area of interest is to test the feasibility of NF-κB blockade as a combinatorial approach for the treatment of IFN-responsive human cancers.
More recently, the laboratory has identified RIPK3-activated cell death as an important host defense mechanism that limits spread of RNA viruses, including influenza A. Influenza A viruses produce Z-RNAs, which are novel left-handed RNA duplexes previously thought not to exist in nature; these Z-RNAs trigger the host sensor protein ZBP1, which, in turn, activates, RIPK3, and drives the activation of both MLKL-dependent necroptosis as well as a parallel pathway of FADD/caspase 8-mediated apoptosis. Molecular- and animal model-based approaches are being used to identify additional determinants and regulators of virus-induced necroptosis, relevant cell types in vivo that die by RIPK3-dependent mechanisms, and the physiological contribution of discrete cell death pathways to the control of an acute RNA virus infection.
Finally, the Balachandran laboratory is interested in leveraging necroptosis for immunotherapy, by targeting RIPK1/3 kinases in human cancers that respond to IFN therapy, or by activating ZBP1 in the tumor microenvironment by small-molecule approaches. The latter approach is of particular interest because ZBP1 can activate a form of ‘nuclear necroptosis’ that is even more immunogenic that conventional (i.e., cytoplasm-induced) necroptosis. Indeed, a major reason for the non-responsiveness of these so-called ‘cold’ tumors is that they lack an immunogenic tumor microenvironment (TME) and thus escape T-cell killing despite expressing ICB targets. How to selectively intensify the immunogenicity of the TME has been an unmet challenge. Two broad strategies are commonly pursued: the first is to increase the visibility of tumor cells to the immune system, for example, by inducing tumor cells to die by necrotic lysis, which is highly immunogenic. The second is to induce an immunogenic state in cells of the TME. We have developed small molecule approaches that straddle both strategies to directly activate ZBP1 to trigger ‘on-demand’ nuclear necroptosis in tumor cells, as well as in cells of the TME. We are currently evaluating the potential clinical benefit of these approaches in mouse models of melanoma and other solid cancers.
Siddharth.Balachandran@fccc.edu
Office Phone: 215-214-1527
Lab Phone: 215-214-1528
Fax: 215-728-3574
Office: R224
Lab: R224
Siddharth.Balachandran@fccc.edu
Office Phone: 215-214-1527
Lab Phone: 215-214-1528
Fax: 215-728-3574
Office: R224
Lab: R224
Professor
Co-Leader, Blood Cell Development and Function
The Balachandran lab is interested in how cells die during host innate-immune responses to viruses and bacteria, and in exploiting these mechanisms for the treatment of human disease, whether infectious, inflammatory or malignant. In particular, the lab is interested in a form of programmed cell death termed necroptosis, driven by the kinase RIPK3. Unlike apoptosis, which proceeds via a caspase cascade that results in the ordered disassembly of the cell, necroptosis is caspase independent and driven by the RIPK3 substrate MLKL. Once activated by RIPK3, MLKL translocates to cellular membranes and induces their disruption, resulting in a form of necrotic cell death. Necroptosis is activated by several classes of innate-immune receptor (e.g., TLRs and cytokines such as TNF-α and interferons) and pathogen (e.g., RNA viruses, DNA viruses, certain gram-negative bacteria). The Balachandran lab is interested in how viruses (particularly RNA viruses), gram-negative bacteria, cytokines, and cellular stresses activate the necroptosis machinery, how necroptosis functions during acute viral and microbial infections to control pathogen spread, and how this death modality can be leveraged for immunotherapy.
The Balachandran lab is interested in how cells die during host innate-immune responses to viruses and bacteria, and in exploiting these mechanisms for the treatment of human disease, whether infectious, inflammatory or malignant. In particular, the lab is interested in a form of programmed cell death termed necroptosis, driven by the kinase RIPK3. Unlike apoptosis, which proceeds via a caspase cascade that results in the ordered disassembly of the cell, necroptosis is caspase independent and driven by the RIPK3 substrate MLKL. Once activated by RIPK3, MLKL translocates to cellular membranes and induces their disruption, resulting in a form of necrotic cell death. Necroptosis is activated by several classes of innate-immune receptor (e.g., TLRs and cytokines such as TNF-α and interferons) and pathogen (e.g., RNA viruses, DNA viruses, certain gram-negative bacteria). The Balachandran lab is interested in how viruses (particularly RNA viruses), gram-negative bacteria, cytokines, and cellular stresses activate the necroptosis machinery, how necroptosis functions during acute viral and microbial infections to control pathogen spread, and how this death modality can be leveraged for immunotherapy.
The lab has recently outlined a pathway by which interferons (IFNs), a family of cytokines with well-known antiviral and immunomodulatory properties, activate RIPK1/3 kinases and trigger necroptotic death. The laboratory continues to work on how IFNs activate RIPK1/3 kinases, and the regulatory mechanisms that normally restrain these kinases in unstimulated cells and only license necroptosis in susceptible cells. We have identified two such mechanisms that protect cells from IFNs: the adaptor protein FADD and the transcription factor NF-κB. Current projects in this area are centered on how FADD (and caspases) are disabled to allow IFNs to trigger necroptosis during an active infection. An allied area of interest is to test the feasibility of NF-κB blockade as a combinatorial approach for the treatment of IFN-responsive human cancers.
More recently, the laboratory has identified RIPK3-activated cell death as an important host defense mechanism that limits spread of RNA viruses, including influenza A. Influenza A viruses produce Z-RNAs, which are novel left-handed RNA duplexes previously thought not to exist in nature; these Z-RNAs trigger the host sensor protein ZBP1, which, in turn, activates, RIPK3, and drives the activation of both MLKL-dependent necroptosis as well as a parallel pathway of FADD/caspase 8-mediated apoptosis. Molecular- and animal model-based approaches are being used to identify additional determinants and regulators of virus-induced necroptosis, relevant cell types in vivo that die by RIPK3-dependent mechanisms, and the physiological contribution of discrete cell death pathways to the control of an acute RNA virus infection.
Finally, the Balachandran laboratory is interested in leveraging necroptosis for immunotherapy, by targeting RIPK1/3 kinases in human cancers that respond to IFN therapy, or by activating ZBP1 in the tumor microenvironment by small-molecule approaches. The latter approach is of particular interest because ZBP1 can activate a form of ‘nuclear necroptosis’ that is even more immunogenic that conventional (i.e., cytoplasm-induced) necroptosis. Indeed, a major reason for the non-responsiveness of these so-called ‘cold’ tumors is that they lack an immunogenic tumor microenvironment (TME) and thus escape T-cell killing despite expressing ICB targets. How to selectively intensify the immunogenicity of the TME has been an unmet challenge. Two broad strategies are commonly pursued: the first is to increase the visibility of tumor cells to the immune system, for example, by inducing tumor cells to die by necrotic lysis, which is highly immunogenic. The second is to induce an immunogenic state in cells of the TME. We have developed small molecule approaches that straddle both strategies to directly activate ZBP1 to trigger ‘on-demand’ nuclear necroptosis in tumor cells, as well as in cells of the TME. We are currently evaluating the potential clinical benefit of these approaches in mouse models of melanoma and other solid cancers.
This Fox Chase professor participates in the Undergraduate Summer Research Fellowship.
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