Audio and slides for this presentation are available on YouTube: http://youtu.be/FyL7sCDc4Zc Mikael Rinne, MD, PhD, of Dana-Farber Cancer Institute's Center for Neuro-Oncology, discusses the science and genetics behind brain tumors. Rinne covers how scientists can discover DNA alterations in cancer, which alterations are found in brain tumors, and what scientists can do about the alterations. This talk was originally given at Dana-Farber's "Living with Brain Tumors" forum on Sept. 7, 2013. For more information, visit the website for Dana-Farber's Center for Neuro-Oncology: http://bit.ly/13nlpEv

1. The “Basic” Science
Mikael Rinne, M.D., Ph.D.
Dana-Farber Cancer Institute
Center for Neuro-Oncology
September 7, 2013
of Brain Tumors

2. What is Cancer?
DNA directs the functions of cells
Adaptedfromwww.scienceprogress.org
Alterations in the DNA can disrupt cellular function
(mutation, amplification, deletion)
Certain specific alterations can cause cells to:
- divide constantly
- divide indefinitely
- ignore signals to stop growing
- resist cell death
- invade / spread to other sites
- recruit blood vessels

3. What is Cancer?
DNA directs the functions of cells
“Hallmarks” of Cancer:
(Cell 2011)
Adaptedfromwww.scienceprogress.org
Alterations in the DNA can disrupt cellular function
(mutation, amplification, deletion)
Certain specific alterations can cause cells to:
- divide constantly
- divide indefinitely
- ignore signals to stop growing
- resist cell death
- invade / spread to other sites
- recruit blood vessels

4. What is Cancer?
DNA directs the functions of cells
“Hallmarks” of Cancer:
(Cell 2011)
Adaptedfromwww.scienceprogress.org
Alterations in the DNA can disrupt cellular function
(mutation, amplification, deletion)
Certain specific alterations can cause cells to:
- divide constantly
- divide indefinitely
- ignore signals to stop growing
- resist cell death
- invade / spread to other sites
- recruit blood vessels
The result is Cancer
Cancer is caused by a series
of DNA alterations

5. What causes these changes in DNA?
DNA alterations occur at random
Most result from normal “everyday” life in the cell:
- errors copying or separating DNA
- cellular by-products reacting with DNA

6. What causes these changes in DNA?
DNA alterations occur at random
Most result from normal “everyday” life in the cell:
- errors copying or separating DNA
- cellular by-products reacting with DNA
DNA alterations can also result from specific exposures:
- tobacco smoke – [lung cancer]
- ultraviolet light – [melanoma]
- radiation – [leukemias]
- chemicals (asbestos) – [mesothelioma]
- oncoviruses (HPV) – [cervical cancer]

7. What causes these changes in DNA?
DNA alterations occur at random
Random accumulation of specific mutations leads to cancer
Most result from normal “everyday” life in the cell:
- errors copying or separating DNA
- cellular by-products reacting with DNA
DNA alterations can also result from specific exposures:
- tobacco smoke – [lung cancer]
- ultraviolet light – [melanoma]
- radiation – [leukemias]
- chemicals (asbestos) – [mesothelioma]
- oncoviruses (HPV) – [cervical cancer]
Majority of DNA changes have no effect on cell function
Most alterations are either corrected or trigger cell death
…and do not cause cancer

8. How can cancer cell growth be stopped?
Chemotherapy & Radiation damage DNA to trigger cell death
Greatest effect seen in rapidly dividing cells (not cancer-specific)
An increasing understanding of alterations “driving” cancer growth

9. How can cancer cell growth be stopped?
(NEJM 2004)
(NEJM 2010)
(NEJM 2010)
Chemotherapy & Radiation damage DNA to trigger cell death
Greatest effect seen in rapidly dividing cells (not cancer-specific)
An increasing understanding of alterations “driving” cancer growth
Recent trials have shown that successfully targeting
cancer “drivers” can lead to significant tumor responses:
- CML with Bcr-Abl fusion: Imatinib
- Breast Cancer with Her-2 amplification: Trastuzumab
- Lung Cancer with EGFR mutation: Gefitinib
- Lung Cancer with EML4-ALK fusion: Crizotinib
- Melanoma with BRAF mutation: Vemurafenib

10. How can cancer cell growth be stopped?
(NEJM 2004)
(NEJM 2010)
(NEJM 2010)
Chemotherapy & Radiation damage DNA to trigger cell death
Greatest effect seen in rapidly dividing cells (not cancer-specific)
An increasing understanding of alterations “driving” cancer growth
Recent trials have shown that successfully targeting
cancer “drivers” can lead to significant tumor responses:
- CML with Bcr-Abl fusion: Imatinib
- Breast Cancer with Her-2 amplification: Trastuzumab
- Lung Cancer with EGFR mutation: Gefitinib
- Lung Cancer with EML4-ALK fusion: Crizotinib
- Melanoma with BRAF mutation: Vemurafenib

11. How can cancer cell growth be stopped?
(NEJM 2004)
(NEJM 2010)
(NEJM 2010)
(JCO 2011)
Significant interest in discovering DNA alterations in cancers
Chemotherapy & Radiation damage DNA to trigger cell death
Greatest effect seen in rapidly dividing cells (not cancer-specific)
An increasing understanding of alterations “driving” cancer growth
Recent trials have shown that successfully targeting
cancer “drivers” can lead to significant tumor responses:
- CML with Bcr-Abl fusion: Imatinib
- Breast Cancer with Her-2 amplification: Trastuzumab
- Lung Cancer with EGFR mutation: Gefitinib
- Lung Cancer with EML4-ALK fusion: Crizotinib
- Melanoma with BRAF mutation: Vemurafenib

12. How can we discover the DNA alterations in Cancer?
Advances in DNA sequencing technology has made it
possible to sequence entire cancer genomes
www.tcga.org
Broad Institute
Large part of this effort carried out in Boston…
The Cancer Genome Atlas (TCGA)
Comprehensive evaluation of 25 Cancer types
Glioblastoma was the 1st tumor studied
Approximately 500 GBMs characterized in depth
Low Grade Glioma project ongoing
Numerous brain tumor types analyzed / being analyzed:
Glioblastoma
Low Grade Glioma
Meningioma
Brain Metastases
Medulloblastoma

14. What about DNA alterations in Individual Tumors?
Every tumor can have different alterations
Potential for different “drivers” of tumor growth
Certain alterations are more common
Revealed by studying many tumors
To translate these findings to individual patients,
we need to know which alterations are present
in an individual patient’s tumor

15. What about DNA alterations in Individual Tumors?
Every tumor can have different alterations
Potential for different “drivers” of tumor growth
www.dana-farber.org
Goal is to personalize treatment: “Precision Medicine”
Certain alterations are more common
Revealed by studying many tumors
To translate these findings to individual patients,
we need to know which alterations are present
in an individual patient’s tumor
Technology pioneered at Dana-Farber Cancer Institute
allows evaluation of individual patient tumors
- OncoMap / OncoPanel
- DFCI/BWH Neuropathology Tissue Bank

16. What are the DNA alterations in Brain Tumors?
Initial results discovered significantly
amplified or deleted genes
(Nature Genetics 2013)
(PNAS 2007)

17. What are the DNA alterations in Brain Tumors?
(MutSigCV v0.9, Broad Institute)
Initial results discovered significantly
amplified or deleted genes
(Nature Genetics 2013)
(PNAS 2007)
(MutSigCV v2.0, Broad Institute)
Ongoing efforts to discover other alterations…
More recent discovery of recurrent mutations

18. What are the implications of these alterations?
Results show frequent common alterations
in several common “pathways”

19. What are the implications of these alterations?
Results show frequent common alterations
in several common “pathways”

20. What are the implications of these alterations?
Results show frequent common alterations
in several common “pathways”
Constant Division
Ignore Stop
Signals
Resist Cell Death
Indefinite Division
∞
Recruit Blood Vessels Invasion
Additional research has revealed
alterations responsible for:
- indefinite division
- invading / spreading to other sites
- recruiting blood vessels
These pathways are responsible for:
- constant division
- ignoring signals to stop growing
- resisting cell death

21. Indefinite Division
∞
Recruit Blood Vessels Invasion
What can we do about these alterations?
Constant Division
Ignore Stop
Signals
Resist Cell Death
A number of drugs have been developed to
target many of these alterations / pathways
Significant ongoing research to:
- Identify targets within these pathways
- Design drugs to inhibit these targets

22. Indefinite Division
∞
Recruit Blood Vessels Invasion
What can we do about these alterations?
Constant Division
Ignore Stop
Signals
Resist Cell Death
A number of drugs have been developed to
target many of these alterations / pathways
Many current clinical trial agents
target these pathways
Significant ongoing research to:
- Identify targets within these pathways
- Design drugs to inhibit these targets

23. Indefinite Division
∞
Recruit Blood Vessels Invasion
What can we do about these alterations?
Constant Division
Ignore Stop
Signals
Resist Cell Death
A number of drugs have been developed to
target many of these alterations / pathways
Continued significant effort to initiate
clinical trials focused on the most
promising targets
Many current clinical trial agents
target these pathways
Significant ongoing research to:
- Identify targets within these pathways
- Design drugs to inhibit these targets