Posts Tagged ‘AACR’

Notes On Tumor Heterogeneity: Targets and Mechanisms, from the 2015 AACR Meeting in Philadelphia PA

Reporter: Stephen J. Williams, Ph.D.

The following contain notes from the Sunday April 19, 2015 AACR Meeting (Pennsylvania Convention Center, Philadelphia PA) 1 PM Major Symposium Session on Tumor Heterogeneity: Targets and Mechanism chaired by Dr. Charles Swanton.

Speakers included: Mark J. Smyth, Charles Swanton, René H. Medema, and Catherine J. Wu

Tumor heterogeneity is a common feature of many malignancies, especially the solid tumors and can drive the evolution and adaptation of the growing tumor, complicating therapy and resulting in therapeutic failure, including resistance. This session at AACR described the mechanisms, both genetic and epigenetic, which precipitate intratumor heterogeneity and how mutational processes and chromosomal instability may impact the tumor progression and the origin of driver events during tumor evolution. Finally the session examined possible therapeutic strategies to take advantage of, and overcome, tumor evolution. The session was chaired by Dr. Charles Swanton. For a more complete description of his work, tumor heterogeneity, and an interview on this site please click on the link below:

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing


Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn


Notes from Charles Swanton, Cancer Research UK; Identifying Drivers of Cancer Diversity

Dr. Swanton’s lecture focused on data from two recent papers from his lab by Franseco Favero and Nicholas McGranahan:

  1. Glioblastoma adaptation Traced Through Decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome (Annals of Oncology, 2015)[1]

This paper described the longitudinal Whole Genome Sequencing (WGS) study of a 35 year old female whose primary glioblastoma (GBM) was followed through temozolomide treatment and ultimately recurrence.

  • In 2008 patient was diagnosed with primary GBM (three biopsies of unrelated sites were Grade II and Grade IV; temozolomide therapy for three years then relapse in 2011
  • WGS of 2 areas of primary tumor showed extensive mutational and copy number heterogeneity; was able to identify clonal TP53 mutations and clonal IDH1 mutation in primary tumor with different patterns of clonality based on grade
  • Amplifications on chromosome 4 and 12 (PDGFRA, KIT, CDK4)
  • After three years of temozolomide multiple translocations found in chromosome 4 and 12 (6 translocations)
  • Clonal IDH1 R132H mutation in primary tumor only at very low frequency in recurrent tumor
  • The WGS on recurrent tumor (sequencing took ONLY 9 days from tumor resection to sequence results) showed mutation cluster in KIT/PDGFRA.PI3K.mTOR axis so patient treated with imatinib
  • However despite rapid sequencing and a personalized approach based on WGS results, tumor progressed and patient died shortly: tumor evolution is HUGE hurdle for personalized medicine

As Dr. Swanton stated:

“we are underestimating the frequency of polyclonal evolution”

  1. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution (Science Translational Medicine, 2015)[2]
  • analyzed nine cancer types to determine the subclonal frequencies of driver events, to time mutational processes during cancer evolution, and to identify drivers of subclonal expansions.
  • identified later subclonal “actionable” mutations, including BRAF (V600E), IDH1 (R132H), PIK3CA (E545K), EGFR (L858R), and KRAS (G12D), which may compromise the efficacy of targeted therapy approaches.
  • > 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K (phosphatidylinositol 3-kinase)–AKT–mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal
  • Mutations in the RAS–MEK (mitogen-activated protein kinase kinase) signaling axis were less likely to be subclonal than mutations in genes associated with PI3K-AKT-mTOR signaling

Branched chain can converge on single resistance mechanism; clonal resistance (for example to PI3K inhibitors can get multiple PTEN mutations in various metastases

Targeting Tumor Heterogeneity

  • Identify high risk occupants (have to know case history)
  • Mutational landscape interferes with anti-PD1 therapies
  • Low frequency mutations affect outcome

Notes from Dr. Catherine J. Wu, Dana-Farber Cancer Institute: The evolutionary landscape of CLL: Therapeutic implications

  • Clonal evolution a key feature of cancer progression and relapse
  • Hypothesis: evolutionary dynamics (heterogeneity) in chronic lymphocytic leukemia (CLL) contributes to variations in response and disease “tempo”
  • Used whole exome sequencing and copy number data of 149 CLL cases to discover early and late cancer drivers: clonal patterns (Landau et. al, Cell 2013); some drivers correspond to poor clinical outcome
  • Methylation studies suggest that there is epigenetic heterogeneity which may drive CLL clonal evolution
  • Developing methodology to integrate WES to determine mutations with immunogenic potential for development of personalized immunotherapy for CLL and other malignancies


  1. Favero F, McGranahan N, Salm M, Birkbak NJ, Sanborn JZ, Benz SC, Becq J, Peden JF, Kingsbury Z, Grocok RJ et al: Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2015, 26(5):880-887.
  2. McGranahan N, Favero F, de Bruin EC, Birkbak NJ, Szallasi Z, Swanton C: Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Science translational medicine 2015, 7(283):283ra254.


Other related articles on Tumor Heterogeneity were published in this Open Access Online Scientific Journal, include the following:


Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

CANCER COMPLEXITY: Heterogeneity in Tumor Progression and Drug Response – 2015 Annual Symposium @Koch Institute for Integrative Cancer Research at MIT – W34, 6/12/2015 9:00 AM EDT – 4:30 PM EDT

My Cancer Genome from Vanderbilt University: Matching Tumor Mutations to Therapies & Clinical Trials

Tumor Imaging and Targeting: Predicting Tumor Response to Treatment: Where we stand?

Mitochondrial Isocitrate Dehydrogenase and Variants

War on Cancer Needs to Refocus to Stay Ahead of Disease Says Cancer Expert


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Upcoming Meetings on Cancer Immunogenetics


Curator: Stephen J. Williams, Ph.D.

Below is a curation of upcoming 2014-15 Cancer Immunogenetics symposia. Some listed have CME credits.

August 2014

Target Discovery for T Cell Therapy Symposium
Next Step to Advance Immunotherapies
August 14, 2014 | Part of ImVacS – The Immunotherapies and Vaccine Summit
Learn more | View Agenda PDF | Register by July 18 & SAVE up to $200


Q&A with Dr. Adrian Bot of Kite Pharma


SITC 2014 Meetings

The Society for Immunotherapy of Cancer (SITC) is a 501 (c)(3) non-profit society of medical professionals. Recent advances in immunology and biology have opened up new horizons in the field of cancer therapy, with an upsurge in the integration of new biologic agents into clinical practice. With several high-caliber scientific meetings with a focus on clinical and translational aspects of biologic approaches to cancer treatment and numerous networking opportunities unique to this organization, the Society for Immunotherapy of Cancer (SITC) has developed into the premier destination for interaction and innovation in the cancer biologics community.

Upcoming SITC Meetings and Activities

sitc banner

Advances in Cancer Immunotherapy™ (ACI™) Regional CME-Certified Programs

  • La Jolla, CA – Friday, August 22, 2014
  • Portland, OR – Friday, October 3, 2014
    Charlotte, NC – Friday, October 3, 2014
  • Tampa, FL – Friday, December 5, 2014


September 2014



  Hematologic Malignancies: Translating Discoveries to Novel Therapies
    September 20-23, 2014 • Sheraton Philadelphia Downtown • Philadelphia, PA

The AACR is proud to announce our conference focused on the blood-based cancers and associated disorders categorized as hematologic malignancies. Sessions will include presentations on leukemia, lymphoma, myeloma, myelodysplastic syndrome, and myeloproliferative neoplasms.


Advances in Melanoma: From Biology to Therapy

Loews Philadelphia • Philadelphia, PA • September 20-23, 2014

With so many recent advances in treating metastatic melanoma, including approaches like immunotherapies, targeted therapies, and combination therapies, melanoma research is at a critical point where it is extremely important for the field to have a continuous exchange of information. Despite the success of various “targeted” inhibitors, therapeutic responses in melanoma patients are often short-lived due to rapidly acquired drug resistance. Therefore, it is essential that melanoma researchers translate the novel understanding of melanoma biology to decipher the mechanisms of innate and acquired drug resistance for the development of improved therapeutic options. To bridge the gap between scientists and clinician-scientists’ professional practice, this conference will provide a platform for discussion and potential collaborations for the discovery of new therapeutic targets.



The 4th Mastering Immunogenicity Summit

September 15-16, 2014

British Consulate-General, Boston MA, USA

Join leaders in the immunogenicity field for a two day conference to learn what constitutes a successful strategy for managing immunogenicity risk, and explore the business case for introducing immunogenicity assessment into your program.

  • Learn about the latest strategies and exciting new technologies
  • Discuss current and developing challenges and exchange new ideas
  • Improve the outcome of your R&D programs

Our 4th Mastering Immunogenicity Conference will continue to have a strong focus on immunogenicity sciences, particularly on what basic research needs to be carried out to improve our understanding of immune regulation to biotherapeutics. We will review progress made in correlating data from pre-clinical predictive tools to clinical outcomes, as well as continuing our discussions surrounding the benefits that Quality by Design has on reduced immunogenicity, considering subsequent patient benefits as well as competitive advantage. Presentations by experts will provide an overview of the wide range of technologies currently used for immunogenicity risk management and how they can be incorporated for a ‘quality by design’ approach.


Immunogenomics 2014

September 29 – October 1, 2014

HudsonAlpha Biotechnology Campus
Huntsville, Alabama, USA

The HudsonAlpha-Science Conference on Immunogenomics will bring together preeminent leaders and thinkers at the intersection of genomics and immunology.

October 2014


Cancer Immunotherapy: Out of the Gate

October 06, 2014 Grand Hyatt New York Hotel at Grand Central, New York, NY

The Cancer Research Institute (CRI) will host its 22nd Annual International Cancer Immunotherapy Symposium October 6-8, 2014 at The Grand Hyatt in New York City. Attracting clinicians, laboratory scientists, postdoctoral fellows, and graduate students, the symposium will feature plenary presentations from leaders in immunology and cancer immunotherapy, a poster session, and numerous networking opportunities.

This year’s CRI symposium, entitled Cancer Immunotherapy: Out of the Gate, will harness the excitement and enthusiasm generated by recent clinical successes to explore new and emerging areas of basic, translational, and clinical research. Topics such as the use of genomic methods to catalogue cancer heterogeneity, mechanistic studies of checkpoint blockage antibodies, new views on immunosurveillance and immunoregulation, and emerging therapies that are altering the landscape of cancer treatment will be discussed.

– See more at:

Cytokines 2014

October 26–29, Melbourne, Australia

EMBO Conference: Innate Lymphoid Cells
September 29–October 1, Paris, France

Recommended reading

Laurie Dempsey


November 2014

SITC 2014 – November 6-9, 2014

  • Gaylord National Hotel & Convention Center, National Harbor, MD
  • SITC 29th Annual Meeting
  • SITC Workshop on Combination Immunotherapy: Where Do We Go From Here?
  • SITC Primer on Tumor Immunology and Cancer Immunotherapy™
  • SITC Hot Topic Symposium – including two topics explored concurrently:
    • Accelerating Tumor Immunity with Agonist Antibodies
    • Engineered T Cell Toxicities
  • Professional Development Session: A Roadmap for Thriving in Your Career

The Fourth International Conference on Regulatory T cells and TH Subsets and Clinical Application in Human Diseases
November 1–4, Shanghai, China

Recommended reading
Olive Leavy





Keystone Symposium: Cell Death Signaling in Cancer and the Immune System
October 28-November 2, Sao Paolo, Brazil

Recommended reading

December 2014

Tumor Immunology and Immunotherapy: A New Chapter
Co-Chairpersons: Robert H. Vonderheide, Nina Bhardwaj, Stanley Riddell, and Cynthia L. Sears
December 1-4, 2014 • Orlando, FL

2015 Conferences

Keystone Symposia on Molecular and Cellular Biology

Tumor Immunology: Multidisciplinary Science Driving Combination Therapy 

February 8—13, 2015

Fairmont Banff Springs, Banff, Alberta, Canada


· March 2015

  1. 8–13, Montreal, Quebec, Canada
  2. 22–27, Banff, Alberta, Canada
  3. 29–3 April, Snowbird, Utah, USA

9th World Immune Regulation Meeting

Keystone Symposium: The Golden Anniversary of B Cell Discovery
Recommended reading

Keystone Symposium: T Cells: Regulation and Effector Function
Recommended reading


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Reporter: Aviva Lev-Ari, PhD, RN

Professor Alexander Levitzki Chosen for American Cancer Research Association Award

April 7, 2013

Jerusalem — The American Association for Cancer Research (AACR) has chosen Professor Alexander Levitzki of The Hebrew University of Jerusalem as the winner of its 2013 Award for Outstanding Achievement in Chemistry in Cancer Research.

The AACR is currently holding its annual meeting through Wednesday in Washington, D.C. Alexander Levitzki, professor of biological chemistry at Hebrew University’Professor Alexander Levitzkis Alexander Silberman Institute of Life Sciences, will deliver his award lecture there on Tuesday afternoon on “Eradicating Tumors by Targeting Nonviral Vectors Carrying PolyIC.”

The AACR said that Professor Levitzki was chosen for the honor in recognition of his contributions to signal transduction therapy and his work on the development of tyrosine kinase inhibitors as effective agents against cancer. 

Professor Levitzki’s concept of targeted cancer therapy using protein tyrosine kinase inhibitors is extensively used by the pharmaceutical industry worldwide to develop anticancer drugs. His studies formed the basis for the development of drugs like imatinib, crizotinib and lapatinib, used for the treatment of patients with chronic myeloid leukemia, lung cancer and breast cancer, respectively. Currently there are more than 200 such inhibitors at various stages of the U.S. Food and Drug Administration’s approval process.

His method of large-scale screening of synthetic compounds tested against a large spectrum of protein kinases for specificity, followed by systematic testing in cell lines and animal studies, became the standard procedure in most of the laboratories working in that field.

Professor Levitzki has received numerous awards throughout his career, including

  • Israel Prize in Biochemistry, the
  • Wolf Prize for Medicine, the
  • Hamilton-Fairley Award from the European Society of Medical Oncology, the
  • Rothschild Prize in Biology and
  • two Prostate Cancer Foundation Research Awards. Last year he received the
  • Nauta Award in Pharmacochemistry, which is the highest award from the European Federation for Medicinal Chemistry.

He is a

He served as

  • President and vice president of the Federation of Israeli Societies of Experimental Biology and received an
  • honorary Ph.D. from Ben-Gurion University in Beersheba.

Professor Levitzki was a member of the scientific advisory board of Teva Pharmaceutical Industries and has served on the editorial board of several journals, including

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