Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Speakers:

o   Sangeeta Bhatia,

• Challenge meet Opportunity – Future Cancer Research Priorities
• Prevention and early detection of Cancer for improved outcomes
• Global cancer burden – Cancer diagnosis in Low-resources settings
• 2000 microchip became nanoscale – other materials in nanoscale: 1994 – Present advancement in material and devices

o   Tyler Jacks

• Nanotech, Diagnostics, Therapeutics, Cancer Care, Cancer Biology
• New Center for NanoMedicine @MIT aka, @MIT.NANO
• Sponsored: J&J, Sanofi, Thermo Scientific

·       Sanjiv Sam Gambhir, MD, PhD, Stanford University

Bubble Based Nanodiagnostics

• Companies involved: Endra Inc, Bracco, Visualsonics
• Canary Center Vision: Imaging: identify, isolate, Intervene
• Value of early cancer detection: Survival is high ONLY in very very early vs tail of the distribution where 90% of funds goes for therapy: Prostate and Breast cancers — ARE detected early
• Technology: Ultrasound Imaging ($1500 – low cost solution, for molecular level
• Bubble based Nanodiognostics: Molecular level, gas pore shell made of lipids or albomin – provide information on location of cancer – molecular events, atomical modelity
• Bubble size nanobubbles vs microbubbles targeted for Vascular Endothilium In vivo
• Angiogenesis: KDR (molecule)/VEGFR2 (receptor)- over expressed only in neovascularized: Molecular targer is KDR – over expressed in ovarian and breast cancers
• ability of bubbles to identify cancer, toxicity monitored , bubble arrive, bind, cleared
• blind to histology – examine the binding, blind pathology
• bubbles well correlated
• histological diagnosis few mm to few cm — correlation of lesions benign
• 1 cm lesion targeted present in KDR, normal tissue clears more rapidly vs in malignant tissue: ductal adenocarcenoma – 11 minutes after injection
• Duration of US Molecular Imaging Signal
• First-in-man – Bubble Transrectal US Photoaccustic detection modality
• Enzyme activation nanobubbles – nano microbubbles to aggregate and create mass impact vs nanobubbles that are weak in signal potential
• Synthesis of PA/US nanosize RF-acoustic imaging  – target Saline nanodroplets

·       Ralph Weissleder Developing Next Generation Diagnostics for Cancer @MGH

• translational diagnostics: Precision oncology (1) Imaging (2) Tumor biopsy (3) Liquid biopsy
• Enable earlier detection
• Visualization for affordable cost
• NEW Technologies at MGH with use of AI

1. Rapid cellular protein profiling – Fine needle aspirates (FNA): DNA Barcode: Epitope – monoclonal antibodies: Sampling, Barcoding, Imaging, Analysis with AI: Pathways in single cells – protein level in different patient:

x axis patient number

y-axis: Protein type

Vesicles from Host vs from Tumor

2, Exosome

surface – Label-free detection and molecualr profiling of exosome : Pancreatic cancer detection – vesicle express  – they are heteroginous micro vesicles

3. POC testing (AI- Defraction Analysis)

Remote diagnosis:

• Molecular diagnosis – 2015 (PNAS) – nano bids defract patterns – smart phone vs proprietary box – BioMed Eng
• Algorithms – identify molecules and decision tree Clinical Trial at MGH: 24 Lymphoma patients, rest no-Lymphoma, higher precision than microspectrometry
• Automated diagnosis – aspirate – subject to dioagnosis in the Box
• From tissue to single cell
• multiplex pathways
• early detection
• affordability
• visualization/connectivity for interpretation

·       Angela Belcher New Approaches for Finding Tiny Tumors: Towards Early Detection and Treatment of Ovarian Cancer

• Nano material and Biomaterial the intersection of
• Genetic control of materials
• Carbon nano tubes – Using Bacteriophage or phage – A virus that infect bacteria
• from DNA to devices
• Lincoln Labs + MGH + MIT – Carbon Nanotubes used in inexpensive diagnostics: Biomedical imaging: MI, PET: Optical imaging in vivo: Trade-fee: Resolution vs Depth
• Ovarian Cancer: Minimal increase in overall survival over 30 years : Fallopian tubesmaximum reduction in tumor better survival rate
• submillimiter detection: Carbon nanotube multiple tubes
• Pre-surgical planning locates hard-to-detect ovarian tumor – find tumors that are hidden
• Detection od Optically Luminescent – RT tracking T-cells in Cancer Immmunotherapy – following injection in mice remain for 2 days

Speakers:

·       Angela Belcher,

·       Sanjiv Sam Gambhir,

·       Ralph Weissleder

·       Mark Davis Designing Nanoparticles to Safely Cross the Blood-Brain Barrier for Treating Brain Cancers

• Engineer particles for treating solid tumors
• Intracellular drug delivery
• 30-50nm
• Improve PK properties
• Limit Toxicity
• Cyclodex
• Interspecies translation – Nanoparticles can function to design in Humans
• Combination of Avastin and nanoparticle component
• PARP Inhibitor + CRLX101 – in clinical trial by AstraZeneka
• PK in human been presicted if PK known in non-humans
• Therapeutic escape from the exosome polymer end group chemistry
• Tumor localization of Nanoparticles
• Nanoparticles can function in Human NOT in the brain
• better clinical trial design and combination drugs in small clinical trials
• Brain primary vs mestasis in th ebrain
• 50% HER2 positive will have metastesis in the brain
• BBB TfP Receptor-mediate Transcytosis : Antibody affinity, monodenriate
• Nanoparticles behave similarity to antibodies in the brain Nanoparticles characteristics: decreased
• Improved Uptake of Nanoparticles  – fast release of NP during transcytosis
• bring nanoparticles in combination therapy to the brain using transcytosis

·       Suzie Pun Modulating Tumor-Associated Macrophage

• TAM – Targeting Tumor-associated macrophages
• blood monocytes, immunosuppression, metastasis, invasion
• Can we potentiated therapeutics delivery using TAM
• wiin tumors, M2pep is internalized by TAMs
• Cytotoxic KLA peptide – reduce inflammatory of the tumor – M2pepKLA reduces tumor growth rate and improves survival
• increase avidity binding
• Immunomodulation – Marophage targeting for
• Targeting TAM for translation to Humans
• improve drug potency
• synthetic Nucleocapsids  —
• Biomaterials for modulating tumor extracellular matrix
• FSP integrates into fibrin, increasing its half-life – delay degradation of FSP-fibrin
• Polymer cross linking – fibrin deposition in brain metastases
• Fibrin stabilization by FSP alters TAM chronic FSP treatment increases brain metastasis

·       Daniel Anderson Nanoparticle Formulations for RNA Therapy and Gene Editing

• can we make drugs to repair our DNA for therapy
• barriers for systemic delivery of nanaoparticles
• RNA THERAPEUTICS sIRNA – interference: Turning Genes Off: Modular Pharmacology: sequence Selection, Chemical Modification, Encapsulation (like artificial viruses)
• What material can be used for RNA delivery? – How can we increase diversity?
• combinatorial synthesis of lipid-like materials
• RNA Interference – RNA Tx for Liver: Transthyretin-(TTR)
• TTR in primates, in Humans – Delivery of sRNAi – new class of machines
• Chylomicron metabolism: The rate of dietary : Mechanism of APoE mediated iLNP delivery
• sRNAi are not limited for hypatocytes
• One injection – 5 genes silencing in lung endothelial cells
• IMMUNE CELLS AS A TARGET FOR siRNA
• Repaired liver cells in mouth: repopulation of the liver
• How do we deliver Cas9 in vivo?
• Modular Pharmacology: Deliver mRNA to inside cells? using nanoparticles
• chemistry of nanoparticles will delivery to lungs not to liver or to liver not to lungs
• inhaled nanoparticles for mRNA delivery
• Cas9 – for gene editing – – Inject AAV-Virus — >> AAV +Cas( mRNA
• Chemical modification for siRNA: guiding siRNA delivery
• Guide RNA improve Genome editing
• Full modification abolishes the function of sgRNA: Cas9-sgRNA
• e-sgRNA – edited
• PCKS9- hyperlipidemia — Nanoparticle for in vivo  Genome Editing
• RNA NANOTHERAPEUTICS AND CANCER
• Delivery to Immune system – Genome editing in vivo of CAR-Ts

Speakers:

·       Daniel Anderson,

·       Mark Davis,

·       Suzie Pun

Noubar Afeyan, John Maraganore, Bob Langer, Paula Hammond, Michelle Bradbury, Cristianne Rijcken

Moderated by Rebecca Spalding

Noubar Afeyan,

John Maraganore,

Bob Langer,

Paula Hammond,

Michelle Bradbury,

Cristianne Rijcken

Sangeeta Bhatia Activity-based biomarkers for non invasive Cancer Detection, Classification and Monitoring

• • Biomarker paradigm for clinical decisions – Endogenous, singular, blood
  • Synthetic Biomarker paradigm for clinical decisions – Exogenous, multiples, urine
  • Endoprotease in Cancer: MMP9, MMP4
  • Synthetic Biomarkers: Sensitivity
  • Enzyme-responsive nanosensors and PK switch [acitvation fluorescence]
  • Benchmarking synthetic biomarkers against a blood biomarker: Urinary synthetic biomarkers outperform CEA
  • multi-compartment modeling for predicting PK
  • Enhancing sensitivity by nanosensor engineering for ovarian cancer detection
  • Mass barcodes enable multiplexing
  • Mass encoded synthetic biomarkers
  • Differentiating similar diseases with protease activity
  • Paper-based microfluidics in urine biomarker
  • synthetic breath biomarkers for lung disease
  • Protease-Responsive Imaging Sensor for Metastasis (PRISM) – localization of Tumor
  • In vivo Enzyme Profiling by Syntahtic Biomarkers

Rashid Bashir Micro and Nanotechnologies for Analysis of Tissues and Molecules

• liquid biopsy, molecualar analysis of the tumor
• spatial map of nuclei acids in tissue – Intra tumor heterogeniety
• subclonal genetic diversity is important
• laser capture microdissection
• fluoresence in situ hybridization
• Cryo-section on microwell array, pixelate and fix tissue inside wells amplification reagents loaded on chip – amplification reaction: Advantages over PCR
• procees flow on chip
• On-chip RT-LAMP: Spatial fluorescence analysis
• ON CHIP RT-LAMP CONTROL: CANCER (red) VS NON-CANCER (blue)  – FTIR control same section
• Single cell spatial RNA Seq
• Hematology Analyzer – complete blood celll count  vs FLow cytometry
• Cells and Proteins from a Drop of Blood

Convergence : The Future of Health – Cancer Center at Illinois

• • Medical Schools MUST Change  CurrentCurriculum vs Future Curriculum
  • NOW: Yr 1: Basic Science Yr 2: Basic Science Yr 3: Clinical Science +  Required rotation Yr 4: Clinical Science +  elective rotation
  • FUTURE: ALL GENOMICS +BIOENGINEERING to be integrated

Jim Heath A Molecular View of Immuno-Oncology, Institute of System Biology

• Analytical Chemistry challenge:
• Fundamental Immunology
• Challenge CRISPR knocking out genes not for knocking in genes
• Mutated proteins and NEO antiagens: mostly a computational task

Speakers:

·       Rashid Bashir,

·       Sangeeta Bhatia,

·       James Heath

• Personalized Immuno-Oncology

Speakers:

·       Vladimir Bulović

• • MIT.nano
  • color depend on the size of the molecule
  • Drugs & Vitamins are nano-sized:
  • Scents are nano-sized – a fraction of an atom – ethylene – plant hormone – Pheromones – are nanosized
  • Nanoscale will define many future discoveries
  • 51% of the recently tenured SOS faculty – use nano
  • 67% of the recently tenured SOE faculty with benefits – use nano

Speakers:

·       Sangeeta Bhatia