Effect of tumor cell heterogeneity on receptor engagement MPIs: Barroso, Corr and Intes ABSTRACT Precision medicine in oncology has shown great promise in improving patient prognosis and well-being. However, current clinical targeted therapies that act on specific molecular targets associated with cancer have been less effective than anticipated, mainly due to intrinsic and/or relatively rapid acquisition of resistance. Cellular heterogeneity, in particular tumor/stroma compositional heterogeneity and variations in the expression of membrane-bound receptors, has been implicated as an important driver of resistance to anti-cancer treatments. Though, to date, no analytical tool can provide means to replicate these heterogeneities in vitro and can monitor quantitatively the binding of therapeutic antibodies or drug-antibody conjugates to their respective targets, which is critical for drug deliver efficacy. Herein, we propose to integrate a biomanufacturing platform with 3D optical molecular imaging to investigate, for the first time, the influence of tumor cell heterogeneity, namely compositional heterogeneity as well as receptor level expression heterogeneity (i.e., Her2+, EGFR and Tfn), on target-receptor engagement. The unique characteristics of our approach are the ability to manufacture on demand ?histology grade? 3D heterogeneous breast tumor systems and quantify ligand-receptor engagement in these systems beyond the current depth limits of microscopy. To achieve our goals, we have assembled a multidisciplinary research team with established expertise and collaboration track record in all facets on the program. Upon completion of this project, we will have integrated this analytical platform to assess receptor engagement of well-known drug carriers in heterogeneous 3D cancer systems. This platform is expected to advance personalized medicine by providing tools and approaches that can be used to critically assess tailored therapy management strategies.

Public Health Relevance

Effect of tumor cell heterogeneity on receptor engagement MPIs: Barroso, Corr and Intes NARRATIVE An analytic platform to assess mechanistically the influence of tumor heterogeneity on receptor engagement will be integrated. Compared to current approaches, our platform will enable the manufacturing of spatially- precise 3D heterogeneous tumor systems and their fluorescence-based imaging to quantify ligand-target interactions beyond the microscopy depth limit. This new platform will be integrated and optimized using heterogeneous breast tumor systems and well-known clinically relevant receptor targets (i.e., Her2+, EGFR and Tfn). Upon completion of the project, we will have established and demonstrated the utilities of a breakthrough technology for receptor-based targeted therapy biological studies in on-demand bioprinted precise models that could profoundly impact the development of tailored therapy management strategies

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA207725-01A1
Application #
9311733
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Sorg, Brian S
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Rensselaer Polytechnic Institute
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
002430742
City
Troy
State
NY
Country
United States
Zip Code
12180
Rudkouskaya, Alena; Sinsuebphon, Nattawut; Ward, Jamie et al. (2018) Quantitative imaging of receptor-ligand engagement in intact live animals. J Control Release 286:451-459
Angelo, Joseph P; Chen, Sez-Jade; Ochoa, Marien et al. (2018) Review of structured light in diffuse optical imaging. J Biomed Opt 24:1-20
Sinsuebphon, Nattawut; Rudkouskaya, Alena; Barroso, Margarida et al. (2018) Comparison of illumination geometry for lifetime-based measurements in whole-body preclinical imaging. J Biophotonics 11:e201800037
Yao, Ruoyang; Intes, Xavier; Fang, Qianqian (2018) Direct approach to compute Jacobians for diffuse optical tomography using perturbation Monte Carlo-based photon ""replay"". Biomed Opt Express 9:4588-4603
Ochoa, M; Pian, Q; Yao, R et al. (2018) Assessing patterns for compressive fluorescence lifetime imaging. Opt Lett 43:4370-4373
Yang, Fugang; Ozturk, Mehmet S; Yao, Ruoyang et al. (2017) Improving mesoscopic fluorescence molecular tomography through data reduction. Biomed Opt Express 8:3868-3881
Pian, Qi; Yao, Ruoyang; Sinsuebphon, Nattawut et al. (2017) Compressive hyperspectral time-resolved wide-field fluorescence lifetime imaging. Nat Photonics 11:411-414
Long, Feixiao; Intes, Xavier (2017) Dental optical tomography with upconversion nanoparticles-a feasibility study. J Biomed Opt 22:66001