MIPS Molecular Imaging Program at Stanford
Center for Cancer Nanotechnology Excellence and Translation

Projects

MIPS CCNE-TR Projects

The image above shows scientific structure of our new center (CCNE-T) shows research and clinical focus areas.

Project Interactions

The above figure shows the intersections between the four projects. The interactions between the projects are grouped by project components with similar line patterns.

Project and Core Interaction

Project 1 Interactions: Research Project 1 will design and synthesize the gold-nanorods and other SERS nanoparticles for photoacoustic and Raman molecular imaging and work with P4 to test these in their cultured cancer cell lines in vitro and the mouse cancer models in vivo. We will again work with P4 to test our novel MRI imaging strategy based on intracellularly self-assembling nanoparticles. We will indirectly work with P2 through P4 to utilize cell sorting technologies. As P1, we will provide SERS and other Raman imaging particles to P3 wherein they will be utilized with the cantilever sensors to image specific cell detection ad also utilized for interrogation of cell:cell and cancer cell receptor:ligand interactions, receptor clustering and other imaging applications. We will again work with P3 to use our new nanocrystals for rapid screening and selection of ‘binders’. We will also work with P4 to translate our photoacoustic, Raman and MRI strategies into preclinical cancer studies. P4 will subsequently work with C3 to translate promising candidates for clinical applications. We will utilize C2 to characterize our Raman/Photoacoustic and MR nanoparticles. We will work closely with C1 to provide information about our nanoparticle characteristics and their biological study results for the NCI’s caNanoLab program and provide these to the Cancer Nano Alliance community.

Project 2 Interactions: Projects 2 and 4 (P2 & P4) are two translational research projects in CCNE-T. In particular, P2 will use clinical and mouse samples from P4 and Core 3 to develop and validate the ultrasenstive magneto-nano protein chip platform for monitoring therapeutic response of lung cancer and early diagnosis of ovarian cancer. In addition, P2 will utilize the nanocharacterization and nanofabrication capability in Core 2 to develop magnetic sifter and tunable MNP to harvest circulating tumor cells from lung cancer patients or ovarian cancer stem cells. Rare cells isolated will be interrogated for heterogeneity with the nanotechnologies in Aim 1, as well as by P3, using single cell protein and nucleic acid profiling and secretome analysis to further elucidate cancer pathways and metastasis.    P2 will also leverage the biostatistics expertise in Stanford Cancer Center and nanoinformatics infrastructure in Core 1, through which we will provide data for the NCI’s caNanoLab program and the Cancer Nano Alliance community. Finally, P2 is prepared to capitalize on any novel MNP discovered in P1.

Project 3 Interractions: Project 3 will highly interact with all projects and cores due to its comprehensive analytical platform development missions. We will work with P1 to conjugate antigen-specific cys-diabodies to SERS nanoparticles which will be provided to P1 and P4 for in vitro binding and in vivo imaging studies in later years of the project. We will receive sorted cells from P2 and provide them with our well-characterized ‘binders’ to be used in the magneto-nano sensor chip and also for specific cell capture studies. Again, in collaboration with P2’s cell sorting and concentration devices, we will obtain sorted CTCs from mice orthotopically implanted with the HCC-827 or H1975 cells, and treated with erlotinib in P4. We will obtain clinical samples from our Clinical Core 3 in the later years of the project when our analytical platforms are mature enough for precious clinical samples. We will use Core 1 bioinformatics and biostatistics capabilities to analyze the single cell measurement results from genomics level to proteomics. We will also employ the nanofabrication and nanocharacterization capabilities of Core 2 to design, fabricate and optimize our devices.

Project 4 Interactions: This project (P4) will highly interact with all projects and cores due to its integrative nature. We will work with P1 to test gold nanorods for photoacoustic and molecular imaging. We will also work with P1 to test MRI imaging of self-assembling nanoparticles. We will work with P2 to test the Magneto-Nano sensors with our mouse models. We will work with P3 to test at the single cell level the nanosensors using our mouse models and circulating tumor cells isolated from technologies developed in P2. We will work with the clinical & translation core (C3) to test patient samples from retrospective and prospective studies. We will also work with C3 to translate our photoacoustic and Raman strategies into patient cancer studies. We will utilize C2 to characterize our Raman/photoacoustic nanoparticles. We will work closely with C1 to provide information about our nanoparticle results for the NCI and will work with them on mathematical de-convolution of multiplexed Raman signals.

Core 1 Integration with CCNE-T Projects (Discontinued): CCNE-T research projects are focusing on monitoring and predicting therapeutic response of lung and ovarian cancers using various nanotechnology platforms, with a secondary focus on early detection. Project 1 will be developing several new nanoparticles and nanodevices including nanocrystals and novel nanoparticles as MR contrast agents. We will work with this project to ensure that these new technologies are properly represented within the NanoParticle Ontology (NPO) and that their physical, in vitro, and in vivo characterization data are well-represented in caNanoLab. This will be highly coordinated with the Nanocharacterization and Nanofabrication Core (Core 2). Project 2 will continue to develop their magnetonanosensor platform as well as applying this in clinical work. In addition to ensuring that the nanodevice is properly represented, we will work with this Project 2 to create data model concepts for in vitro, in vivo, and ex vivo characterization such as tissue samples, sample analysis (mutation detection, protein/cell detection, etc.), and circulating tumor cell capture and sorting. Project 3 will develop an integrated platform for cancer related cell detection and analysis using several different nanotechnology platforms. This core will work with this Project 3 in particular on the informatics issues of integrated platforms that marry different nanotechnologies together. This activity will be coordinated with the Clinical Translational and Integration Core ( Core 3).  Project 4 will develop gold nanoparticle- and carbon nanotube-based in vivo imaging strategies for early detection that merge with in vitro measurements as well. This core will continue its work on developing in vivo characterization data models for caNanoLab that would apply to this project as well as work on data models to represent combined in vitro/in vivo approaches such as this one.

Core 2 Integration with CCNE-T Projects:  In support of Core efforts in the previous CCNE-TR award, SNF provided equipment and processing for several projects in this program.  As a result, a broad suite of top-down and bottom-up fabrication methods for direct fabrication of functional nanomagnetic particles was developed13-17 and are now starting to find application in the fabrication of other functionalized nanostructures.   This Core will continue to support direct-fabrication of Nanomagnetic structures in support of Project 2.  In addition, SNF will provide resources and advice for nanoparticle (Project 1) and nanodevice/Lab on a Chip fabrication and integration (Project 3). The optimized and tumor targeted nanorods and other nanoparticles coming from both Project 1 and Project 4 will be characterized and synthesized/fabricated in large batches so that they can be delivered in large quantities for the animal studies of Project 4. We will provide images and nanoscale property information derived from our fabricated structures to Core 1 for integration in their database efforts. We will also provide Nanoscience expertise and advice to Core 1 to improve the quality of their data from the nano perspective.

Core 3 Integration with CCNE-T Projects: Project 1 (Discovery Nanotechnologies, Paul Alivisatos, PhD). This project is primarily a discovery project that feeds novel nanoparticles (e.g., gold nanorods, self-assembling nanoparticles for MRI) into other projects (e.g., P4). As such, it is not expected to directly utilize this core. However, if new nanoparticles are developed that would benefit from access to patient samples, this core will of course help coordinate. Project 2 will have key needs from this core in order to test the cell capture devices with whole blood from patients as well as the magneto-nanosensors for early detection of ovarian cancer and monitoring lung cancer response to Epidermal Growth Factor Receptor (EGFR) therapy using pre and post-therapy blood samples. Project 3 will have key needs from this core in order to test various devices with circulating tumor cells using whole blood from lung cancer patients pre and post-therapy for monitoring response to EGFR therapy. Project 4 will primarily be translating nanoparticles for pilot patient molecular imaging trials in Ovarian Cancer.  This core will help interface CCNE investigators with the NCI Nanocharacterization laboratories (NCL) and with the FDA for IND filing. Core 1 and Core 2 will also significantly interact with the other two cores as needed. When further nanocharacterization is needed, Core 2 will be utilized, and when issues related to data analysis arise, Core 1 will be utilized in conjunction with available biostatistical resources that are a part of the Stanford Cancer Center.

We are highly optimistic that our proposed work will help ongoing efforts to bring nanotechnology into the routine arsenal of cancer biologists and oncologists for improved patient management.


Research Project 1 - Next Generation Smart Nanoparticles
(Jianghong Rao; Brian Rutt; Project Leaders; and Sam Gambhir)

The long-term goal of P1 is to engineer, synthesize, characterize and optimize the next generation nanoparticle platforms that can potentially be translated clinically to develop nanodiagnostics and imaging agents for in vitro and in vivo use for the improved management of cancer. Our primary focus for this CCNE application is to develop and use nanotechnology for monitoring response to anti-cancer therapy and for earlier cancer detection. Our cancer focus in the current proposal is on both lung and ovarian cancers but expect that our strategies will eventually apply to many cancers. Both in vitro nanosensors and in vivo nano-molecular imaging will be utilized to accomplish our long-term goals. The combination of both in vitro and in vivo diagnostic strategies is expected to lead to a much greater accuracy and cost-effectiveness than either strategy alone. To translate our in vitro and in vivo diagnostic strategies we will utilize mouse models that help us to test our approaches prior to clinical translation. The clinical translation will be accomplished through the clinical translation core (Core 3) which links to various clinical trials and leverages on other funding mechanisms already in place in our CCNE. In order to meet the improved nanoparticle needs of our other proposed Research Projects, P1 will be focusing on the development of these newer types of nanoparticles and nano-strategies as described in sections below. We envision that these new types of nanoparticles will have outstanding advantages for biomedical imaging and the development of in vitro diagnostics such as for multimodal imaging, multiplexing, multi-effector functionalities, improved signal amplification via outstanding signal to noise ratio characteristics of the to-be-developed nanocrystals. These advantages are especially valuable with clinical biological fluid samples which always present significant challenges. Thus, the focus of P1 will be the realization of the next generation nanoparticles, their in vitro characterization in cell culture models, and the delivery of these nanoparticles to the other projects for further detailed studies to assess their utility as cancer diagnostics and cancer imaging agents. This project also fulfills the requirement of the CCNE RFA wherein a basic research project with nanotechnology discovery was listed as one of the required projects. Being a fundamental nanoscience discovery project, the proposed P1 meets this condition.

 

Research Project 2 - Magneto-Nano Diagnostic and Analytical Devices for Cancer
(Shan Wang Project Leader; Irving Weissman; Robert Wilson; Alice Fan; and Dean Felsher)

Research Project 2 is centered on the translational research of devising and applying novel and tunable magnetic nanoparticles (MNP), ultrasensitive magnetic sensor chips, and highly efficient magnetic sorters for cancer biomarkers and cells. The resulting magneto-nano protein chip platform will detect protein biomarkers down to attomolar concentrations and will be used for monitoring therapeutic response of lung cancer and early diagnosis of ovarian cancer. The resulting magnetic sifter and tunable MNP will be used to harvest circulating tumor cells from lung cancer patients or ovarian cancer stem cells with unprecedented capture and release efficiencies of >90%, critical for both cancer diagnosis and treatment. These rare cells will be interrogated with the nano-technologies, as well as Project 3, by single cell protein and nucleic acid profiling and secretome analysis to further elucidate cancer pathways and metastasis. The application of these advances in nanotechnology to pre-clinical models and clinical subjects will lead to better understanding and treatment of cancer.

 

Research Project 3 - Nanotechnologies for Comprehensive Single Cancer Cell Analysis
(Stephen Quake Project Leader; Luke Lee; Parag Mallick; Scott Manalis; and David Agus)

Cancer therapeutics targeted against the Epidermal Growth Factor Receptor (EGFR) have demonstrated great potential in lung cancer; however, these agents are effective in only a subset of patients. Furthermore, tumors that are initially responsive frequently acquire resistance over time. Though it is straightforward to measure molecular (DNA, RNA, protein) and biophysical (mass, density, charge) characteristics of tumors in bulk, recent studies have shown wide cell-to-cell variability and the importance of characterizing that variability in estimating patient outcome1,2,3. We hypothesize that molecular and biophysical characterizations of circulating cells can discriminate cells that are responsive to therapy from those that are resistant. When analyzing cells collected from the circulation, or from other bodily fluids (e.g., pleural effusions, ascites), typically only a small number of cells are available. To asses the cell-to-cell heterogeneity of this limited number of cells, we propose to develop and to apply quantitative, comprehensive single-cell analysis devices for assessing the DNA genome (e.g., single nucleotide polymorphisms, fusions, deletions), RNA expression, protein abundance (cell surface, intracellular, and secretome abundance), and biophysical properties of single cells for the dual purposes of predicting a patient’s likely response to EGFR-targeted therapies and for monitoring a patient’s acquisition of resistance to EGFR-targeted therapies. We propose two specific aims for the development, testing, and application of our comprehensive analysis platform.

 

Research Project 4 - Integration of Nano-Molecular Imaging and Nanosensors
(Sam Gambhir Project Leader; and Jonathan Berek)

Our long-term goals are to clinically translate nanodiagnostics (in vitro and in vivo) for the improved management of cancer patients. Our primary focus for this competing CCNE renewal is on developing and using nanotechnology for earlier cancer detection/intervention, and for monitoring response to anti-neoplastic therapy. In the current proposal we focus on both ovarian and non-small cell lung cancers but expect that our strategies will eventually apply to many other cancers. We have made significant progress over the last cycle of this CCNE competing renewal grant including the development of Raman and photoacoustic molecular imaging strategies. In the last year we have also pursued translation of gold based Raman nanoparticles with endoscopic imaging for earlier colorectal cancer detection in patients. Both in vitro nanosensors and in vivo nano-molecular imaging will be utilized to accomplish our long-term goals. The combination of both in vitro and in vivo diagnostic strategies is expected to lead to a much greater accuracy and cost-effectiveness than either strategy alone. To translate our in vitro and in vivo diagnostic strategies we will utilize mouse models of human cancer that help us to test our approaches prior to clinical translation. The clinical translation will be accomplished through the help of the clinical translation core (Core 3) which links to various clinical trials and leverages on other funding mechanisms already in place in our CCNE. Two aims focused on ovarian and non-small cell lung cancer diagnostics will be pursued to accomplish our goals.

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