In human disease, various cellular signaling and molecular assemblies may behave or interact aberrantlycompared to their healthy state counterparts. Often, it is unclear which molecular nano-complex in thecomplex network is the most important to control for treating a human disease. Recent work in myelomaprovides evidence that multiple myeloma can become addicted to a normal, unmutated cellular components,in contrast to the usual idea that it is only a singular broken cellular component that is a candidate forengineering molecular interventions. The most effective way to treat a problem of this complexity is to attackon many fronts at once, with optimized drug combination treatments exemplifying this approach. CCCdeveloped the feedback system control (FSC) scheme to rapidly and iteratively arrive at an optimized set ofdrugs and dosages that achieves a desired therapeutic outcome. In addition, PhosphoFlow is a multi-parameter, single-cell phosphorylation analysis methodology that CCC use to identify key protein complexesthat control outcomes. Importantly, PhosphoFlow also is used to exclude candidate molecular assembliesthat are minor drivers or not involved in specific system outcomes. With this methodology, key proteincomplexes were rapidly identified, such as the S6-regulated ribosome translation complex that behavesaberrantly in HSV-1 infection. We have also applied this powerful yet broadly applicable FSC andPhosphoFlow two-step approach to investigate another major disease, cancer. In non-small cell lung cancer(NSCLC) and WEHl-231 leukemia cell line tests, high levels of S6 ribosomal complex activity were alsoobserved. The goals of CCC is to i) identify and manipulate/engineer interactions between the key molecularassemblies such as S6-regulated ribosome assembly to improve the treatment of representatives of twomajor disease classes, cancer and infection, ii) apply our newly gained molecular and cell-based knowledgeon manipulating the ribosome to small animal model preclinical tests, and iii) further advance our lung cancerclinical tests by applying this new knowledge in manipulating the ribosome and interacting/regulatingpathways.
Lung cancer is the deadliest form of cancer in the U.S. and is responsible for more deaths each year thanbreast, prostate, colon, hepatic, renal, and skin cancers combined. HSV-1 is one ofthe most pervasiveinfections with as much as 90% of adults having been exposed to HSV in their lifetime. In the first 4-yearNDC period, we were able to showed the advantage of a two-drug therapy in mouse model and clinical testsand identify kev mqlectjlar components in inhibiting HSV infection.
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