Document text
Principal Investigator: Liangliang Hao
Organization: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
Fiscal Year: 2024
Award: $249,000
Funding agency: National Cancer Institute
Summary
More than 90% of all cancer-related deaths are caused by metastasis, the spread of cancer from its origin.
By the time most cancer metastases become clinically visible, the disease has progressed too far to benefit from
early-stage interventions such as surgery or radiation. Thus, new approaches accessing specific diagnostic
biomarkers are highly desired to improve therapeutic outcomes. Microenvironmental signatures such as
extracellular matrix (ECM) alterations, stromal composition, or immune components exhibit critical determinants
of metastatic dissemination broadly across cancers. Herein, the main goal of this proposal is to converge the
disease hall markers and rational design of biomolecular engineering to develop multidisciplinary approaches
towards precision diagnostics of cancer metastasis. As metastases start to invade, they alter the extracellular
matrix through aberrant proteolytic activities that could be leveraged as biomarkers. The applicant set out to
systematically identify proteases expressed in metastatic colorectal cancer (CRC) by transcriptomic and
proteomic analysis. To improve the detection sensitivity, it is proposed to integrate the proteolytic activity to
formulate a library of enzyme activated sensors by reengineering the ECM targeting nanobody with
extraordinarily tumor targeting efficacy for maximal on-target signal generation (Aim 1). To optimize the detection
specificity, the multiplexity of these activity-based sensors will be extensively expanded for disease classification
using CRISPR-Cas-based nucleic acid barcode readout. Preliminary investigation into the in vivo DNA barcodes
revealed that they could be detected noninvasively as a urinary reporter, but could also enable portable detection
on paper (Aim 2). Beyond initial diagnosis, disease stratification and treatment monitoring are critical to
establishing a robust therapy. The novel sensors will thus be evaluated for noninvasive tumor monitoring and
imaging in disease recapitulating metastatic CRC models (Aim 3). Successful completion of these three aims
would offer a tumoral activation responsive, genetically encoded tracking (TARGET) platform can 1) unveil new
biology at the metastasis-specific tumor microenvironment, 2) provide a completely noninvasive way to track
tumor metastasis, and 3) offer a pipeline for validating novel therapies, which are currently unachievable by
single modality agents. This project requires innovative integration across several fields. The candidate has
assembled an exceptional team to help her achieve the goals of technology development and career transition,
including her mentor Dr. Sangeeta Bhatia (MIT, medical engineering) and Drs. Tyler Jacks (MIT, tumor genetics),
Dr. Richard Hynes (MIT, extracellular matrix), Dr. Frank Gertler (MIT, cell motility) and Dr. Shawn Chen (NIH,
theranostics) on the mentoring committee. This training period will allow the candidate to gain experience in
tumor microenvironment network, pre-clinical cancer models and analytical chemistry. In the future, the principles
of this modular platform could apply to other disease areas. The research program here aligns well with the
candidate’s long-term goal to develop multi-scale engineered tools in the context of cancer.
Terms: <Abscission><Address><Analytic Chemistry><Analytical Chemistry><Anatomic Sites><Anatomic structures><Anatomy><Antibody Fragments><Architecture><Area><Assay><Bar Codes><Benchmarking><Best Practice Analysis><Bioassay><Biological><Biological Assay><Biological Markers><Biology><Biosensor><Blood><Blood Reticuloendothelial System><CAT scan><CRC screening><CRISPR><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><CT X Ray><CT Xray><CT imaging><CT scan><Cancer Cause><Cancer Etiology><Cancer Model><CancerModel><Cancers><Career Mobility><Cas nuclease technology><Cause of Death><Cell Communication and Signaling><Cell Locomotion><Cell Migration><Cell Movement><Cell Signaling><Cell-Extracellular Matrix><Cellular Migration><Cellular Motility><Characteristics><Clinic><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Colorectal Cancer><Complement><Complement Proteins><Complex><Computed Tomography><DNA><Deoxyribonucleic Acid><Dependence><Detection><Development><Diagnosis><Diagnostic><Diagnostic Sensitivity><Diagnostic Specificity><Diffuse><Disease><Disease stratification><Disorder><ECM><Early Diagnosis><Engineering><Engineering / Architecture><Enzyme Gene><Enzymes><Esteroproteases><Evaluation><Excision><Exhibits><Extirpation><Extracellular Matrix><Fostering><Future><Generations><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Goals><Homing><Human><Image><Imaging Device><Imaging Instrument><Imaging Procedures><Imaging Technics><Imaging Techniques><Imaging Tool><Immune><Immunes><Immunoglobulin Fragments><Implant><In Vitro><Injectable><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intratumoral heterogeneity><Invaded><Investigation><Lesion><Libraries><Light><Low-resource area><Low-resource community><Low-resource environment><Low-resource region><Low-resource setting><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Medical><Medical Imaging><Mentors><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Modality><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Monitor><Mutation><NIH><National Institutes of Health><Neoplasm Metastasis><Non-Invasive Detection><Noninvasive Detection><Nucleic Acids><Oligo><Oligonucleotides><Oncology><Oncology Cancer><Operative Procedures><Operative Surgical Procedures><PET><PET Scan><PET imaging><PETSCAN><PETT><Paper><Patients><Peptidases><Peptide Hydrolases><Peptides><Personalized medical approach><Photoradiation><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Precision therapeutics><Primary Neoplasm><Primary Tumor><Property><Protease Gene><Proteases><Proteinases><Proteolytic Enzymes><Proteomics><Rad.-PET><Radiation><Recombinants><Removal><Reporter><Reporting><Research><Resource-constrained area><Resource-constrained community><Resource-constrained environment><Resource-constrained region><Resource-constrained setting><Resource-limited area><Resource-limited community><Resource-limited environment><Resource-limited region><Resource-limited setting><Resource-poor area><Resource-poor community><Resource-poor environment><Resource-poor region><Resource-poor setting><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Site><Specificity><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Survival Rate><Testing><Therapeutic><Time><Tomodensitometry><Training><United States National Institutes of Health><Urine><Validation><Visualization><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><barcode><benchmark><bio-markers><biologic><biologic marker><biological sensor><biological signal transduction><biomarker><cancer cell><cancer diagnosis><cancer metastasis><cancer microenvironment><cancer type><career advancement><career transition><catscan><cell motility><colorectal cancer detection><colorectal cancer early detection><colorectal cancer metastasis><colorectal cancer screening><complementation><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><delivery vector><delivery vehicle><design><designing><detect colorectal cancer><detection sensitivity><developmental><diagnostic biomarker><diagnostic marker><diagnostic platform><diagnostic system><disease classification><disorder classification><early detection><efficacy validation><empowerment><experience><genome mutation><heterogeneity in tumors><imaging><improved><in vivo><individualized approach><innovate><innovation><innovative><interdisciplinary approach><interventional strategy><intra-tumoral heterogeneity><intratumor heterogeneity><malignancy><metastatic colo-rectal><metastatic colo-rectal cancer><metastatic colo-rectal carcinoma><metastatic colon cancer><metastatic colorectal><metastatic colorectal cancer><metastatic colorectal carcinoma><molecular imaging><molecular profile><molecular signature><molecule imaging><mortality><multidisciplinary approach><nano-sized sensors><nanobodies><nanobody><nanosensing><nanosensors><neoplasm/cancer><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non-contrast CT><noncontrast CT><noncontrast computed tomography><nosology><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><oligos><organoid transplantation><personalized approach><personalized diagnosis><personalized diagnostics><point-of-care diagnostics><portability><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><pre-clinical><precise diagnostics><precision approach><precision diagnostics><precision medicine><precision therapies><precision treatment><precision-based medicine><preclinical><programs><rational design><resection><response><response to therapy><response to treatment><scaffold><scaffolding><sdAb><sensor><single domain antibodies><surgery><tailored approach><tech development><technology development><theranostics><therapeutic outcome><therapeutic response><therapy outcome><therapy response><tool><trafficking><transcriptomics><translational opportunities><translational potential><transplant model><treatment response><treatment responsiveness><treatment strategy><tumor><tumor cell metastasis><tumor heterogeneity><tumor microenvironment><urinary><validate efficacy><validations>