Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Speakers
All speakers are affiliated with Harvard Medical School
Cyril Benes, PhD, MGH, Modeling Cancer Therapeutic Response In Vitro; Personalized Therapies and Potential of Functional Diagnostics to Complement Molecular Profiling of Tumors

Successful Clinical Trials:

• BCR-ABL CML
• BRAF – Melanoma
• EGFR – Lung cancer

Acquired Resistance

• sensitive
• response
• resistant

Mechanism of resistance

• Biopsy and culture: Genetic Test
• effect of drug on cancer cells
• faster method to grow the cells
• use only few drugs
• proof of concept  of the genetic information on drug selection

Priscilla Brastianos, MD, MGH, Shifting Clinical Paradigms in Primary and Metastatic Brain Tumors: Unleashing the Power of Genomics to Clinical Care

• Genomics of Brain Tumors – not understood: Meningiomas vs Craniopharyngiomas
• Targeting oncogenes
• Genome profiling; inhibitors in Meningiomas SMO, AKT, NF2 <<< genetic mutations – first NATIONAL study
• Craniopharyngiomas – single driver mutations – NCI trial open this year
• Brain metastesis vs primary tumors: Renal cell carcinoma
• 100 Brain metastesis vs primary tumors study
• Germline (MTOR) — Brain mestasis (onocgenic alteration only in the brain) CDK inhibitors — Primary (MTOR)
• Genomics transforms clinical and drug therapy

Mark Cobbold, MD, PhD, MGH, Tumor Antigens in Cancer and How to Manipulate Antigens to Stimulate Immunity

[MOST IMPORTANT TALK]

• challenges for immuno-oncology (IO)
• Posttranslational NeoAntigens
• tumor — SUrfacre MHC
• PTM peptidomr — MS
• CRC SUrface Phosphopeptides – antigenicity increasing in metastasis
• Re-arming Existing Antibodies
• Re-arming Existing Antibodies for ANtigen Modulation
• T cell activation
• Redirecting CMV- specific T cells

Ryan Corcoran, MD, PhD, MGH, Tumor Heterogeneity and Acquired Resistance to Targeted Therapy

• Pre-treatment Melanoma  — Vemurafenib 15 weeks — Vemurafenib 23 weeks <<< RESISTENCE>>>>
• Tumor heterogeineity, intra lesion heterogeniety
• diagnostically — tolerable therapy for all
• Liquid biopsy: Bool, circulation cells,
• Tumor Biosy vs liquid biopsy to guide therapy: 1.5 MEK1 mutation in the liver for an original colonolrectal cancer
• Blood tumor markers: CEA, TP53p.E171
• MAP2K1 (MEK1) pK57T vs KRAS p.
• Convergent inhibition to overcome heterogeneity of resistance
• BRAF mutant CRC: dabrafenib, trametinib, panitumumab
• Pre-treatment, Response, Progression
• Pretreatment
• Post Treatment

Shawn Demehri, MD, PhD, MGH,  Tumor Immunity against Early Stages of Cancer Development

• Immune system is a potent therapeutic agent against cancer
• potentiate the immune system: CD8+T: cytotoxic T lymphocytes
• carcinoma
• Checkpoints
• Viral infected cells
• immune system promote the immune system
• TSLP – Thymic stromal lymphopoietin supptesses the early stage od skin cancer development: SKin – TSLP CD4-T – clearance of tumor of skin efficacy by TSLP Induction in Pre-Cancer SKin lesion — achieved: CD4, CD8
• BRCA; Adaptive immuneity, Innate Immunity Normal Brain  Glande – CD4, CD3 – cytokeratin

Daniela Dinulescu, PhD, BWH, Opportunities and Challenges for a New Era in Translational Cancer Research

• Global Epigenetics regulators for stem cells in epithelial Ovarian Cancer
• biomarkers platin chemo resistant
• Ovarian cancer
• Epigenetic Hallmark in Melanoma: 5-Hydroxymethylcytosine (5-hmC) – loss of – link between melanoma ansd potential precursors via atypical junctional melanomacytes with 5hmC loss
• Genetic / epigenetic
• PROPOSING Epigenetics adjevants to restore platinon resistance tumor

Ritu Gill, MD, BWH not present
Wilhelm Haas, PhD, MGH, Defining Functional Protein Networks with High-Throughput Proteomics

Fast diagnosis for new treatments. Proteomics for High-Throughput mapping of Protein:Protein Association

• Human Proteome in 5 hrs
• Protein co-expression analysis
• Global Mapping the deregulation of Protein:Protein Association in less than 5 hr
• sample specific Protein:Protein Association deregulation
• # of deregulations Protein:Protein Association correlates with the number of Cancer-specific essential genes
• defining deregulated Protein:Protein Association to identify cancer vulnerabilities
• average fold enrichment = 4

Lida Hariri, MD, PhD, MGH, High Resolution Optical Imaging for Early Detection and Diagnosis of Cancer

• insufficient biopsy yield in lung cancer is a huge poblem
• need enough tumor matter
• optical biopsy guidance in Lung Nodules: needle position, feedback on placement site
• OCT – High-resolution vs( x4) and Large volume
• Invivo response to guidance OCT
• 95% sensitivity and specifivity in parachymal
• Increase Tumor Yield with OCT for tumor fibrosis vs tumor
• Diagnosis criteria: OCT interpretation alone
• virtual 3D optical biopsy
• Guidance vs non guidance
• small tissue biopsy
• fibrosis distinguished samples for research and Biobanking

Aditi Hazra, PhD, BWH, Precision Prevention of Invasive Breast Cancer

• Germline Genome-wide Association studies
• Transcriptome-wide Gene expression studies
• chromosone 22, 1, 6
• chromsome 17 – estrogene – ER negative tripla negative association
• DCIS: stratification and Progression risks
• 1 in 5 diagnosed with DCIS
• Epidemiology + Genomics
• DNA + RNA cross cancer insights
• Data sharing

Jayender Jagadeesan, PhD, BWH, Image-guided Surgery in the Advanced Multimodality Image-guided Operating (AMIGO) Suite

• Poor visualization of common practice
• improve outcomes of surgery by improved IMAGIN technology – BWH – state of the art OR
• Wedge with Tumor resection
• Entire lobe with tumor resection
• INTRA-OPERATIVE leasion finding imaging technology
• Preservation of as much as possible health organ
• Nearly 35% positive margin rate in BCS –
• MR-guided BCS procedural steps – avoid 2nd and 3rd surgeries in the future
• Segmentation algorihtm
• Parathyroid adenoma: nerves around the adenoma – intra-operative image guide by MR
• Virtual reality for surgical applications

Hakho Lee, PhD, MGH, New diagnostic platforms with wide-reaching applications in medicine and life sciences, including biosensors, particularly optimized for on-site, near-patient operation

• Cancer detection
• microelectronics — microfluidics — distributed networks — analytics on Big data
• sensors
• multiplexed detection
• Real- Time liquid Biopsy: Exosomes for Cancer detection and treatment monitoring
• miniaturized devices for exosome analysis
• validation with GBM and Ovarian cancer
• device: Magfnet — electrodes — USB
• beads used in counting cells: Totla 28 malignant cells 16

Alexander Lin, PhD, BWH, Making the Virtual Biopsy a Reality: Advances in MR Spectroscopy of Cancer

Neuroglioma, Non-invasive quantification: Genetic mutauion frequency vs Brain Tumor Spectrum, Normal vs Brain Tumor. Range of diseases with brain involvement: Parkinson, Tumors, Epilapsy, AD, Stroke, HIV. VIRTUAL BIOPSY A REALITY. Major SW development effort
Sandra McAllister, PhD, BWH, The Systemic Nature of Breast Cancer: New Diagnostic and Therapeutic Opportunities

• Breast cancer spread throughout the body (mestastasizes) is incurable
• breast leasion spread into circulation cells that spread to distant organs
• Factors: Cytokines in plasma – OSTEOPONTIN – Pro-Tumerogenic Bone marraw cell GRANULIN induce secretion of factors of proliferetion of tumor cells: IL8, IL6, IL1beta, Cox2, L2, alphSMA
• EGF IGF1
• ER + BRCA
• VEGFR2+, VEGFR2 +BMDCs CD24 recruits pro-angiogenic platelets
• BRCA –
• New paradigma for disease progression
• New biomarker

Mikael Pittet, PhD, MGH, Manipulating Cancer/Immune Cell Interactions

• why some patient respond and other do not
• new approches for non-responders
• hoe immune cells respond to drug
• origins of immune cells
• lang range signals between Tumor and immune cells
• Translational development
• sensitize tumors to immunotherapy
• screen drugs that will trigger tumor to secrete immunogenic phenotypes to change the microenvironment
• New Combination: Oxaliplatin/Cyclophosphamide vs conventional Chemotherapy
• checkpoint blockers –>> durabable Cancer Control
• combine drug therapies
• imaging drug actions in vivo
• Targets: T cells, myyeloid cells, microbiome
• strategic partnerships – clinical trials
• rational selection od drug combination
• widening drug screening

C.P. Raut, BWH, Dana Farber

Miguel Rivera, MD, MGH, In-situ RNA Diagnostics

• RNA as a biomarker for clinical practice
• paraffin embedded tissue
• DNA: stable limited mutations and variants
• Protein: Unmasking (iHC) – limited antibody – needs multiple antigens
• Biomarkers: DNA looking for mutations; RNA – celllines used to detects genes: Markers – RNA probes are difficult
• RNA: Branched DNA amplification: affymetrix ViewRNA
• Powerfulldetection technology for RNA detection: Short not long
• RNA Biomarkers: Albumin
• HPV infected Cancer
• LINE-1 RNA immune=response to Cancer
• RNA Biomarker DIscovery Lab: non-coding RNA

Sandro Santagata, MD, PhD, BWH, What’s In That Tissue? Powerful New Tools Allow Tissue Molecular Imaging

• MR and neuronavigation techniques
• Intraoperative Mass SPectrometry – Glioblastoma  – Ambient Ionization
• Navigation optical sensors mass  spectometry interface
• no laser, no vacuum,
• Metabolite, lipid, Hormone, Drug, Guided Brain Surgery – 2-hydroxyglutarate
• Autopcy od hupothulmuse: Vesopressin, ACTH, Growth Hormone  – molecule present
• heme map the vasculture in the brain in relation to the location of the tumor: Drug distribution vs. location of Tumor — in separate location, tumor did not got the drug
• Stimulated Raman Imaging (SRI): Biomolecular energies
• WHITE MATTER VS GRAY MATTER ZONES, VS GLIOMA disrupting axons

Shiladitya Sengupta, PhD, BWH, Supramolecular Therapeutics: Next-generation Technology for Focal Modulation of the Tumor Immune Contexture

• drugs precise and safe
• cytotoxic T cells
• A NIR dye into tumor vs nano particles into tumors
• assembly of molecular subunits via weak interactions – altered biological effects
• use quantum-mechanically atomistic simulations to design supra molecular therapeutics
• Modulating tumoral innate immunity
• Sustained CSF1R inhibition vs Best in Class anti-tumor efficacy
• p-CSF/t-CSF-1
• platform to extend to Biologics

Paul Shyn, MD, BWH, Costs of Managing Bleeding Risks Before and After Image-guided Biopsies: An Inexpensive Solution?

• MDs dilema when biopsy need be performed, anticoagulants need be stopped
• Cirrosis — diagnosis by imaging ONLY, biopsy of liver may lead to tumor near the biopsy site by cells tumors in circulation
• catherization to stop bleeding
• no needle is small as needed

Matthew Steinhauser, MD, BWH, Multi-isotope Imaging Mass (MIMS) Spectrometry: Leveraging Metabolic Interrogation of Tumors at Subcellular Resolution for Precision Medicine

• measures cellular metabolism with subcellular resolution, including in humans
• fibroblast nucleus N-thymidine-labeled
• N-thymidine-labeled perivascular cells
• Human fat biopsy: Tissue needed – Cancer impacts tissue,
• New methodologies for tumor heterogeniety studies  – not image and histology
• MIMS metabolic imaging of murine histocarcinoma : sarcoma cell adapted to use glucose, not glutamine
• cancer cells identified by MIMS: Tx selects for glutamine avid cells in malignant peripheral nerve sheat
• Pathology vs Radiology

Shannon Stott, PhD, MGH, Microfluidic Technology for Isolation of Exosomes From Cancer Patients

• Exosome isolation device: HB-ExoChip – Cancer cell releasing vesicles
• Microfluidic capture – antibodies place on the surface of the device
• Tumor Exosomes: RNA, DNA
• HB-ExoChip Tunable Biomaterial
• Tumor Specific Enrichment: Microfluidic vs magnetic beads vs serum
• Tumor specific: IgG, EGFR, Cocktail (Tumor Specific Enrichment)
• CLinical Data: Glioblastoma Patients: Patients vs Cohort
• EGFRvIII copy number

Mario Suva, MD, PhD, MGH, Redefining the Cellular Architecture of Human Gliomas Through Large-scale Single-cell Analyses

• Brain tumor by single cell
• Evolution of the Cancer Stem Cell Model
• cancer is heterogenious disease. Cancer complexity can be uncovered by single cell RNA sequencing technologies
• RNA capture transcripts, thus, one cell is a justified unit of analysis as entity
• Resected patient tumor — dissected: Tumor, glia
• Identification of a developmental hierarchy in oligodendroglioma
• Proliferation is restricted to the stem/progenitor cell compartment
• identify supclones: single cell RNA-seq – cnv inference – single cell cnvs
• Clone 1 vs clone 2 all cells vs cycling cells
• phenotype wild type vs mutant type

David Ting, MD, MGH, Disrupting Endogenous Retroviruses as Novel Anti-Cancer Therapeutics