2011 Progress Report – Executive Summary
The CCC’s translational pathway (TPath) has been 1) to direct a desired outcome of cells in a disease state using a feedback system control (FSC) scheme, 2) to identify the cellular nanomachines most affected by FSC-optimized treatments using the PhosphoFlow technique, and 3) to translate this new knowledge to preclinical and clinical tests. Using this approach, the CCC has been able to identifying several molecular assemblies and pathways in the cellular signaling and regulatory network behaving aberrantly compared with their behavior in a healthy state. In particular, the CCC has identified the protein translation machineries, specifically the S6-regulated module of the ribosome assembly, as a key protein complex controlling diseases that include HSV-1 infection, non-small cell lung cancer (NSCLC), leukemia, and human embryonic stem cell.
The most effective way to handle a problem of the magnitude and complexity as a human disease is to attack it on many fronts, such as by using combinatorial drug therapies. Two unique technologies were applied for translating knowledge gained in our cell level studies to guide a search for more effective drugs and drug combinations in preclinical and clinical tests. The FSC scheme can rapidly determine the optimal set of drugs and dosages for a desired biological outcome from a very large number of possible combinations (Tsutsui et al., 2011; Sun et al., 2009; Wong et al., 2008). The PhosphoFlow methodology (Kruzik et al., 2008) can provide multi-parameter, single-cell phosphorylation analysis for identifying key protein complexes that control biological outcomes. Equally important, PhosphoFlow also excludes assumed candidate molecular assemblies that are minor drivers or not involve in specific outcomes.
With these technologies, the optimized combinatorial drugs and key protein complexes have been rapidly identified. For example, the S6-regulated ribosome translation complex was shown to behave aberrantly in HSV-1 infection. Subsequent blockade of S6 phosphorylation with a p70rsk inhibitor abrogated viral infection. Combinatorial drug treatments have shown positive results in blocking virus replication in a mouse model of HSV-1 infection.We have also applied this powerful yet broadly applicable FSC and PhosphoFlow two-step approach to investigate cancer. In NSCLC and AML leukemia cell line tests, high levels of S6 ribosomal complex activity were also identified as candidate biological drivers.
Guided by in vitro FSC results, we also have preclinical mouse model and phase 1 dose escalation clinical test results in NSCLC showing that a previously unexamined 2-drug combination inhibits tumor growth much better than single agents with the same FDA-approved compounds.
For our translational path, we have developed a top-down system approach for systematically studying the responses of biological systems to multiple signals. The approach enables prediction of cellular responses to multiple signals by modeling the responses of a relatively small subset of the possible signal combinations. The models enable further optimization of the cellular responses through appropriate selection of the control combinations. Additionally, the models enable studying and characterizing signal interactions at multiple levels based on the specific cellular output signals measured. The approach was developed using a model system of differential lung cancer inhibition with multiple signals relative to normal fibroblast cells. The study used systems of three and four drugs and we showed that a four-drug combination could be more effective in inhibiting lung cancer versus a three-drug or a two drug combination.
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