The Center for Systemic Control of Cyto-Networks

University Of California Los Angeles, Los Angeles CA

Investigators

Linked publications, trials & patents

Abstract

In human disease, various cellular signaling and molecular assemblies may behave or interact aberrantly compared to their healthy state counterparts. Often, it is unclear which molecular nano-complex in the complex network is the most important to control for treating a human disease. Recent work in myeloma provides 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 for engineering molecular interventions. The most effective way to treat a problem of this complexity is to attack on many fronts at once, with optimized drug combination treatments exemplifying this approach. CCC developed the feedback system control (FSC) scheme to rapidly and iteratively arrive at an optimized set of drugs 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 complexes that control outcomes. Importantly, PhosphoFlow also is used to exclude candidate molecular assemblies that are minor drivers or not involved in specific system outcomes. With this methodology, key protein complexes were rapidly identified, such as the S6-regulated ribosome translation complex that behaves aberrantly in HSV-1 infection. We have also applied this powerful yet broadly applicable FSC and PhosphoFlow 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 also observed. The goals of CCC is to i) identify and manipulate/engineer interactions between the key molecular assemblies such as S6-regulated ribosome assembly to improve the treatment of representatives of two major disease classes, cancer and infection, ii) apply our newly gained molecular and cell-based knowledge on manipulating the ribosome to small animal model preclinical tests, and iii) further advance our lung cancer clinical tests by applying this new knowledge in manipulating the ribosome and interacting/regulating pathways. RELEVANCE (See instructions): Lung cancer is the deadliest form of cancer in the U.S. and is responsible for more deaths each year than breast, prostate, colon, hepatic, renal, and skin cancers combined. HSV-1 is one ofthe most pervasive infections with as much as 90% of adults having been exposed to HSV in their lifetime. In the first 4-year NDC period, we were able to showed the advantage of a two-drug therapy in mouse model and clinical tests and identify kev mqlectjlar components in inhibiting HSV infection.