Biology subjects

Finley, S.

Publications and source records attributed to Finley, S..

3 recordsLinked to original sources

bioRxiv2019

ERK activation in CAR T cells is amplified by CD28-mediated increase in CD3ζ phosphorylation

Chimeric antigen receptors (CARs) are engineered receptors that mediate T cell activation. CARs are comprised of activating and costimulatory intracellular signaling domains derived from endogenous T cells that initiate signaling required for T cell activation, including ERK activation through the MAPK pathway. Understanding the mechanisms by which co-stimulatory domains influence signaling can help guide the design of next-generation CARs. Therefore, we constructed an experimentally-validated computational model of anti-CD19 CARs in T cells bearing the CD3{zeta} domain alone or in combination with CD28. We used ensemble modeling to explore different mechanisms of CD28 co-stimulation on the ERK response time. Model simulations show that CD28 primarily influences ERK activation by enhancing the phosphorylation kinetics of CD3{zeta}, predictions that are validated by experimental measurements. Overall, we present a mechanistic mathematical modeling framework that can be used to gain insights into the mechanism of CAR T cell activation and produce new testable hypotheses.

systems biology↗

bioRxiv2018

Computational model of chimeric antigen receptors explains site-specific phosphorylation kinetics

Chimeric antigen receptors (CARs) have recently been approved for the treatment of hematological malignancies, but our lack of understanding of the basic mechanisms that activate these proteins has made it difficult to optimize and control CAR-based therapies. In this study, we use phospho-proteomic mass spectrometry and mechanistic computational modeling to quantify the in vitro kinetics of individual tyrosine phosphorylation on a variety of CARs. We show that each of the ten tyrosine sites on the CD28-CD3{zeta} CAR is phosphorylated by LCK with distinct kinetics. The addition of CD28 at the N-terminal of CD3{zeta} increases the overall rate of CD3{zeta} phosphorylation. Our computational model identifies that LCK phosphorylates CD3{zeta} through a mechanism of competitive inhibition. This model agrees with previously published data in the literature and predicts that phosphatases in this system interact with CD3{zeta} through a similar mechanism of competitive inhibition. This quantitative modeling framework can be used to better understand CAR signaling and T cell activation.

systems biology↗

bioRxiv2017

The impact of tumor receptor heterogeneity on the response to anti-angiogenic cancer treatment

Multiple promoters and inhibitors mediate angiogenesis, the formation of new blood vessels, and these factors represent potential targets for impeding vessel growth in tumors. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor targeted in anti-angiogenic cancer therapies. In addition, thrombospondin-1 (TSP1) is a major endogenous inhibitor of angiogenesis, and TSP1 mimetics are being developed as an alternative type of anti-angiogenic agent. The combination of bevacizumab, an anti-VEGF agent, and ABT-510, a TSP1 mimetic, has been tested in clinical trials to treat advanced solid tumors. However, the patients responses are highly variable and show disappointing outcomes. To obtain mechanistic insight into the effects of this combination anti-angiogenic therapy, we have constructed a novel whole-body systems biology model including the VEGF and TSP1 reaction networks. Using this molecular-detailed model, we investigated how the combination anti-angiogenic therapy changes the amounts of pro-angiogenic and anti-angiogenic complexes in cancer patients. We particularly focus on answering the question of how the effect of the combination therapy is influenced by tumor receptor expression, one aspect of patient-to-patient variability. Overall, this model complements the clinical administration of combination anti-angiogenic therapy, highlights the role of tumor receptor variability in the heterogeneous responses to anti-angiogenic therapy, and identifies the tumor receptor profiles that correlate with a high likelihood of a positive response to the combination therapy. Our model provides novel understanding of the VEGF-TSP1 balance in cancer patients at the systems-level and could be further used to optimize combination anti-angiogenic therapy.

systems biology↗