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Notes from Opening Plenary Session – The Genome and Beyond from the 2015 AACR Meeting in Philadelphia PA; Sunday April 19, 2015

 

Reporter: Stephen J. Williams, Ph.D.

The following contain notes from the Sunday April 19, 2015 AACR Meeting (Pennsylvania Convention Center, Philadelphia PA) 9:30 AM Opening Plenary Session

The Genome and Beyond

Session Chairperson: Lewis C. Cantley, Ph.D.

Speakers: Michael R. Stratton, Tyler Jacks, Stephen B. Baylin, Robert D. Schreiber, Williams R. Sellers

  1. A) Insights From Cancer Genomes: Michael R. Stratton, Ph.D.; Director of the Wellcome Trust Sanger Institute
  • How do we correlate mutations with causative factors of carcinogenesis and exposure?
  • Cancer was thought as a disease of somatic mutations
  • UV skin exposure – see C>T transversion in TP53 while tobacco exposure and lung cancer see more C>A transversion; Is it possible to determine EXPOSURE SIGNATURES?
  • Use a method called non negative matrix factorization (like face pattern recognition but a mutation pattern recognition)
  • Performed sequence analysis producing 12,000 mutation catalogs with 8,000 somatic mutation signatures
  • Found more mutations than expected; some mutation signatures found in all cancers, while some signatures in half of cancers, and some signatures not found in cancer
  • For example found 3 mutation signatures in ovarian cancer but 13 for breast cancers (80,000 mutations); his signatures are actually spectrums of mutations
  • kataegis: defined as localized hypermutation; an example is a signature he found related to AID/APOBEC family (involved in IgG variability); kataegis is more prone in hematologic cancers than solid cancers
  • recurrent tumors show a difference in mutation signatures than primary tumor before drug treatment

 

  1. B) Engineering Cancer Genomes: Tyler Jacks, Ph.D.; Director, Koch Institute for Integrative Cancer Research
  • Cancer GEM’s (genetically engineered mouse models of cancer) had moved from transgenics to defined oncogenes
  • Observation that p53 -/- mice develop spontaneous tumors (lymphomas)
  • then GEMs moved to Cre/Lox systems to generate mice with deletions however these tumor models require lots of animals, much time to create, expensive to keep;
  • figured can use CRSPR/Cas9 as rapid, inexpensive way to generate engineered mice and tumor models
  • he used CRSPR/Cas9 vectors targeting PTEN to introduce PTEN mutations in-vivo to hepatocytes; when they also introduced p53 mutations produced hemangiosarcomas; took ONLY THREE months to produce detectable tumors
  • also produced liver tumors by using CRSPR/Cas9 to introduce gain of function mutation in β-catenin

 

See an article describing this study by MIT News “A New Way To Model Cancer: New gene-editing technique allows scientists to more rapidly study the role of mutations in tumor development.”

The original research article can be found in the August 6, 2014 issue of Nature[1]

And see also on the Jacks Lab site under Research

  1. C) Above the Genome; The Epigenome and its Biology: Stephen B. Baylin
  • Baylin feels epigenetic therapy could be used for cancer cell reprogramming
  • Interplay between Histone (Movers) and epigenetic marks (Writers, Readers) important for developing epigenetic therapy
  • Difference between stem cells and cancer: cancer keeps multiple methylation marks whereas stem cells either keep one on or turn off marks in lineage
  • Corepressor drugs are a new exciting class in chemotherapeutic development
  • (Histone Demythylase {LSD1} inhibitors in clinical trials)
  • Bromodomain (Brd4) enhancers in clinical trials
  1. D) Using Genomes to Personalize Immunotherapy: Robert D. Schreiber, Ph.D.,
  • The three “E’s” of cancer immunoediting: Elimination, Equilibrium, and Escape
  • First evidence for immunoediting came from mice that were immunocompetent resistant to 3 methylcholanthrene (3mca)-induced tumorigenesis but RAG2 -/- form 3mca-induced tumors
  • RAG2-/- unedited (retain immunogenicity); tumors rejected by wild type mice
  • Edited tumors (aren’t immunogenic) led to tolerization of tumors
  • Can use genomic studies to identify mutant proteins which could be cancer specific immunoepitopes
  • MHC (major histocompatibility complex) tetramers: can develop vaccines against epitope and personalize therapy but only good as checkpoint block (anti-PD1 and anti CTLA4) but personalized vaccines can increase therapeutic window so don’t need to start PD1 therapy right away
  • For more details see references Schreiker 2011 Science and Shankaran 2001 in Nature
  1. E) Report on the Melanoma Keynote 006 Trial comparing pembrolizumab and ipilimumab (PD1 inhibitors)

Results of this trial were published the morning of the meeting in the New England Journal of Medicine and can be found here.

A few notes:

From the paper: The anti–PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.)

And from Twitter:

Robert Cade, PharmD @VTOncologyPharm

KEYNOTE-006 was presented at this week’s #AACR15 conference. Pembrolizumab blew away ipilimumab as 1st-line therapy for metastatic melanoma.

2:02 PM – 21 Apr 2015

Jeb Keiper @JebKeiper

KEYNOTE-006 at #AACR15 has pembro HR 0.63 in OS over ipi. Issue is ipi is dosed only 4 times over 2 years (per label) vs Q2W for pembro. Hmm

11:55 AM – 19 Apr 2015

OncLive.com @OncLive

Dr Antoni Ribas presenting data from KEYNOTE-006 at #AACR15 – Read more about the findings, at http://ow.ly/LMG6T 

11:25 AM – 19 Apr 2015

Joe @GantosJ

$MRK on 03/24 KEYNOTE-006 vs Yervoy Ph3 stopped early for meeting goals of PFS, OS & full data @ #AACR15 now back to weekend & family

9:05 AM – 19 Apr 2015

Kristen Slangerup @medwritekristen

Keytruda OS benefit over Yervoy in frontline #melanoma $MRK stops Ph3 early & data to come @ #AACR15 #immunotherapy http://yhoo.it/1EYwwq8 

2:40 PM – 26 Mar 2015

Yahoo Finance @YahooFinance

Merck’s Pivotal KEYNOTE-006 Study in First-Line Treatment for…

Merck , known as MSD outside the United States and Canada, today announced that the randomized, pivotal Phase 3 study investigating KEYTRUDA® compared to ipilimumab in the first-line treatment of…

View on web

 

Stephen J Williams @StephenJWillia2

Progression free survival better for pembrolzumab over ipilimumab by 2.5 months #AACR15 @Pharma_BI #Cancer #Immunotherapy

11:56 AM – 19 Apr 2015

 

Stephen J Williams @StephenJWillia2

Melanoma Keynote 006 trial PD1 inhibitor #Immunotherapy 80% responders after 1 year @Pharma_BI #AACR15

 

References

  1. Xue W, Chen S, Yin H, Tammela T, Papagiannakopoulos T, Joshi NS, Cai W, Yang G, Bronson R, Crowley DG et al: CRISPR-mediated direct mutation of cancer genes in the mouse liver. Nature 2014, 514(7522):380-384.

 

Other related articles on Cancer Genomics and Social Media Coverage were published in this Open Access Online Scientific Journal, include the following:

Cancer Biology and Genomics for Disease Diagnosis

Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

Methodology for Conference Coverage using Social Media: 2014 MassBio Annual Meeting 4/3 – 4/4 2014, Royal Sonesta Hotel, Cambridge, MA

List of Breakthroughs in Cancer Research and Oncology Drug Development by Awardees of The Israel Cancer Research Fund

2013 American Cancer Research Association Award for Outstanding Achievement in Chemistry in Cancer Research: Professor Alexander Levitzki

Genomics and Epigenetics: Genetic Errors and Methodologies – Cancer and Other Diseases

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Genomics and Metabolomics Advances in Cancer

Pancreatic Cancer: Genetics, Genomics and Immunotherapy

Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

 

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