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Evolutionary Dynamics of Cancer

Executive Summary

Workshop Concept and Goals

Dobzhansky famously stated that “nothing in biology makes sense except in the light of evolution.” Since then, others have stated “nothing in evolution makes sense except in the light of genetics” and “nothing in evolution makes sense except in the light of ecology.”

This workshop explored the quantitative expression of these complex, multi-scalar dynamics through application of fitness landscapes that link genotypes and phenotypes to reproductive success (fitness) within the context of local environmental conditions.

Accumulating mutations or changes in pattern of gene expression provide the mechanisms of inheritance for evolution. However, each genotype encodes a reaction norm of often-diverse phenotypic traits that permit acclimation to some changes in environmental conditions. Furthermore, evolutionary convergence can allow many different genotypes to specify a single common phenotype and the fitness of any phenotype depends entirely on its environmental (ecological) context.

For cancer cells, their local microenvironment, and its associated Darwinian selection forces, can vary dramatically over space and time as a function of changes in blood flow and host response or iatrogenic perturbations in the form of therapy. Finally, cancer cells can evolve niche construction adaptive strategies to generate local environmental conditions that maximize their fitness creating both evolutionary (population) and ecological (the persisting niche) modes of inheritance.

By quantitatively framing these complex dynamics, fitness landscapes can provide novel insights into the multi-scalar dynamics in cancer biology and treatment including cellular plasticity, tumor-host interactions, and resistance to therapy.

This workshop highlighted areas of study in evolutionary dynamics of cancer, identified emerging areas of emphasis, assessed the state of the field, and discussed future opportunities and how the field can be moved forward.

Topics for Focused Discussion During Workshop Sessions

Session 1. Initiation and Early Disease

Examined on in situ cancers in which the cells evolve within ducts or on mucosal surface. Discussion topics focused on cell-cell competition that leads to evolution of cellular hallmarks like resistance to growth inhibition, independence of growth factors, resistance to cell death, acquisition of limitless replication, increased mutation rate, etc.

Session 2. Progression and Metastases

Explored tissue-level dynamics that follows transition from in situ to invasive cancers.

Discussion topics focused on macroscopic tumor-host eco-evolutionary interactions like niche construction (e.g., angiogenesis and perhaps chronic inflammation), immune evasion, and colonization of distant sites (i.e., adapting to “foreign tissue adaptive landscapes)

Session 3. Resistance to Cancer Therapy

Discussion topics focused on adaptive strategies that permit survival and proliferation following iatrogenic perturbations.

Agenda

Evolutionary Dynamics of Cancer
NCI Division of Cancer Biology Strategic Workshop

August 9-10, 2018

National Cancer Institute Shady Grove Campus
Rockville, Maryland

Workshop Co-Chairs: Robert A. Gatenby, MD, & Christina Curtis, PhD, MSc

Thursday, August 9, 2018
9:00 am – 9:30 am Welcome and Introductions - Room 2W910/912

Robert A. Gatenby, MD, Moffitt Cancer Center
Christina Curtis, PhD, MSc, Stanford University
Dan Gallahan, PhD, National Cancer Institute
Nastaran Zahir, PhD, National Cancer Institute

9:30 am – 10:30 am

Keynote Opening Talks

9:30 am – 10:00 am Darwinian Dynamics in Cancer Biology and Therapy
Robert A. Gatenby, MD, Moffitt Cancer Center
10:00 am – 10:30 am Towards Quantifying and Forecasting Human Tumor Progression
Christina Curtis, PhD, MSc, Stanford University
10:30 am – 1:00 pm Session 1: Initiation and Early Disease

Session Chair: Carlo Maley, PhD, Arizona State University

10:30 am – 10:35 am Opening by Session Chair
10:35 am – 11:00 am Evolutionary Dynamics of Neoplastic Progression
Carlo Maley, PhD, Arizona State University
11:00 am – 11:25 am Cancer is a Disease of Epigenetic Stochasticity
Andrew P. Feinberg, MD, MPH, Johns Hopkins University
11:25 am – 11:40 am Break
11:40 am – 12:05 pm Virus Density and Infectious Causation of Cancers
Paul W. Ewald, PhD, University of Louisville
12:05 pm – 12:30 pm Highly Multiplex 2D and 3D Optical Imaging Methods for Examining Tumor
Development and Organization
Ronald Germain, MD, PhD, National Institute of Allergy and Infectious Diseases
12:30 pm – 1:00 pm Discussion
1:00 p.m. – 1:45 p.m. Lunch (on own)
1:45 pm – 4:20 pm Session 2: Progression and Metastasis

Session Chair: Christine Iacobuzio-Donahue, MD, PhD, Memorial Sloan Kettering Cancer Center

1:45 pm – 1:50 pm Opening by Session Chair
1:50 pm – 2:15 pm Evolutionary Dynamics of Pancreatic Cancer
Christine Iacobuzio-Donahue, MD, PhD, Memorial Sloan Kettering Cancer Center
2:15 pm – 2:40 pm Therapeutic Eutrophication and its Implications for Cancer Progression
Kenneth J. Pienta, MD, Johns Hopkins University
2:40 pm – 3:00 pm Break
3:00 pm – 3:25 pm Tracing the Evolution of Metastasis with Hypermutable DNA
Kamila Naxerova, PhD, Massachusetts General Hospital
3:25 pm – 3:50 pm Evolved Resistance and Vulnerability to Invasion
Günter Wagner, PhD, Yale University
3:50 pm – 4:20 pm Discussion
4:20 pm – 4:45 pm Recap and Preview of Day 2

Robert A. Gatenby, MD, Moffitt Cancer Center
Christina Curtis, PhD, MSc, Stanford University

4:45 pm Adjourn Day 1
4:45 pm Shuttle service to Sheraton Rockville Hotel
6:00 pm Group dinner (on your own) Thai Farm, 800 King Farm Blvd, Suite 125
Agenda: Friday August 10, 2018
8:00 am Shuttle Departs Sheraton Rockville Hotel for NCI Shady Grove
8:30 am – 9:00 am Security at NCI Shady Grove
9:00 am – 9:25 am Day 2 Opening Remarks - Room 2W910/912

Robert A. Gatenby, MD, Moffitt Cancer Center
Christina Curtis, PhD, MSc, Stanford University

9:25 am – 12:00 pm Session 3: Resistance to Cancer Therapy

Session Chair: Dan Landau, MD, PhD, Weill Cornell/ NY Genome Center

9:25 am – 9:30 am Opening by Session Chair
9:30 am – 9:55 am Genotype-fitness Maps of EGFR Mutant Lung Adenocarcinoma Chart the Evolutionary Landscape of Resistance and Combination Therapy Optimization
Dan Landau, MD, PhD, Weill Cornell/ NY Genome Center
9:55 am – 10:20 am Targeting Collateral Sensitivity in Cancer
Michael T. Hemann, PhD, Massachusetts Institute of Technology
10:20 am – 10:40 am Break
10:40 am – 11:05 am Personalized Adaptive Therapies for Metastatic Melanoma
Alexander (Sandy) Anderson, PhD, Moffitt Cancer Center
11:05 am – 11:30 am Genetic Instability and Dynamic Precision Medicine of Cancer
Robert A Beckman, MD, Georgetown University Medical Center
11:30 am – 12:00 pm Discussion
12:00 pm – 12:45 pm Lunch (on own)
12:45 pm – 2:00 pm Workshop Outcomes, Next Steps, White Paper Planning

Group discussion led by:
Robert A. Gatenby, MD, Moffitt Cancer Center
Christina Curtis, PhD, MSc, Stanford University

2:00 pm – 2:15 pm Closing Remarks

Robert A. Gatenby, MD, Moffitt Cancer Center
Christina Curtis, PhD, MSc, Stanford University
Dan Gallahan, PhD, National Cancer Institute
Nastaran Zahir, PhD, National Cancer Institute

2:15 pm Adjourn

Participant List

First Name

Last Name

Degree

Institution

Alexander (Sandy)

Anderson

PhD

Moffitt Cancer Center

Victoria

Aranda

PhD

Nature Publishing Group

Robert A.

Beckman

MD

Georgetown University Medical Center

Jennifer

Couch

PhD

NCI

Christina

Curtis

PhD, MSc

Stanford University

Paul W.

Ewald

PhD

University of Louisville

Andrew P.

Feinberg

MD, MPH

Johns Hopkins University

Dan

Gallahan

PhD

NCI

Robert

Gatenby

MD

Moffitt Cancer Center

Ronald

Germain

MD, PhD

NIAID

Michael T.

Hemann

PhD

Massachusetts Institute of Technology

Shannon

Hughes

PhD

NCI

Christine

Iacobuzio-Donahue

MD, PhD

MSKCC

Dan

Landau

MD, PhD

Weill Cornell/NY Genome Center

Carlo

Maley

PhD

Arizona State University

Kamila

Naxerova

PhD

Massachusetts General Hospital

Kenneth J.

Pienta

MD

Johns Hopkins University

Dinah

Singer

PhD

NCI

Ruping

Sun

PhD

Stanford University

Gunter

Wagner

PhD

Yale University

Nastaran

Zahir

PhD

NCI

 

Workshop Report

Perspective in Nature Genetics: Characterizing the ecological and evolutionary dynamics of cancer

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