GIST The Basics

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GIST - The Basics

• Jerry Call
• David Josephy
• August 2007

Information provided is not intended as a
substitute for your physicians guidance and care.
Jerry
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• Gastro-
• Intestinal
• Stromal
• Tumors

A rare type of cancer- about 5,000 cases/year,
USA A type of Sarcoma 1 of GI cancers are GISTs
Jerry
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Cancer Classification
The organ in which a cancer begins is important,
but the type of cell that forms the cancer is
even more important Major classifications
according to cell type - Carcinoma -
Sarcoma - Leukemia
Jerry
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Sarcomas
Cancers that arise from cells of connective
tissues, blood vessels, cartilage, bone,
etc. much less common than carcinomas, which
arise in epithelial (lining) tissues, such as
skin, lung, bladder, colon, and breast. Because
GISTs are a type of sarcoma, hospitals with
sarcoma centers often have the most experience
with GIST.
Jerry
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Where do GIST cells come from?
GIST tumors probably arise from the Interstitial
Cells of Cajal (ICCs) ICCs are the pacemaker
cells of the GI tract they stimulate GI
peristalsis - the waves of contraction which
force the food through the gut.
Jerry
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All GIST tumors are variations of the same
disease, because they all arise in the same cell
type, regardless of the location of the tumor
along the GI tract
esophagus lt5
stomach 40-70
colon/rectum 5-15
small intestine 20-40
colon/rectum 5-15
Jerry
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Prior to 2000, most GISTs were misclassified (leio
myosarcoma, leiomyoma, leiomyoblastoma,
etc.) Many of these patients have had no
recurrence and may still be misclassified.
Jerry
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Incidence How many new GIST cases?

• Estimated
• 15 new GIST cases per million people per year
• 5-10,000 new GIST cases per year, U.S.A.

Jerry
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What causes GIST?

• GIST can be inherited (runs in families), but
  very rarely. Most GISTs arise for unknown
  reasons.
• NO environmental, occupational, or lifestyle
  causes of GIST are known.

Jerry
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GIST is dangerous for the same reasons that other
cancers are dangerous
1. Local growth of tumor may disrupt function of
a vital organ, cause bleeding, etc. 2.
Metastases can damage vital organs (e.g. liver,
lung, brain)
Jerry
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What is cancer metastasis?
Metastasis is spread of the cancer to new sites
in the body.Cells detach from the original
tumor (the primary), travel through the
circulation (blood, lymph), attach in distant
locations, and seed new tumors. Liver is the
most common site for GIST metastasis also the
peritoneum (lining of the abdominal cavity) and
other sites within the abdomen occasionally the
bone, lung, etc.
Jerry
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Metastasis
Metastases of a tumor have the properties of the
primary tumor, irrespective of the site of the
metatases. GIST metastases in the liver are still
GIST tumors (GIST cell type) and are treated like
GISTs They are not liver cancer (cancers
arising from liver cells).
Jerry
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GIST Diagnosis
Pathology is critical! Microscopic examination
of the tumor cells is key. Immunohistochemistry
(discussed later) is essential. The experience
of the pathologist matters. Biopsy and patient
history aid diagnosis.
Jerry
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Risk Assessment

• Even benign GISTs may have malignant potential.
  
• Pathology should include assessment of the risk
  of recurrence/metastasis medical experience
  counts!
• Two important criteria are tumor size and mitotic
  index (a.k.a. mitotic count).

Jerry
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Mitotic index
Mitosis is cell division.
Using the microscope, the pathologist counts
number of dividing cells per 50 High Powered
Fields - an index of how quickly the tumor is
growing
Jerry
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GIST Risk Assessment

• Using the primary size and mitotic index (and to
  a lesser degree, primary location) a risk
  assessment can be made by the pathologist.
• Very low risk
• Low risk
• Intermediate risk
• High risk
• Not all tumors are high risk!
• Risk proposals
• The GIST workshop (widely used)
• Miettinen et al. proposals for Gastric GIST

Jerry
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C-Kit gene/protein and GIST
80-85 of GISTs show mutations in the KIT gene.

• This discovery (1998) transformed our
  understanding of GIST and its treatment.

David
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Genes and Proteins
Genes (DNA) are the genetic instructions
(blueprints) for the construction of the cells
proteins
human cell has genes for about 30,000 proteins
David
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What are proteins used for?

• Almost everything!
• Cell structure and architecture
• Catalysts of metabolism
• Regulation of cell behaviour
• Transport of molecules within the cell
• Communication within and between cells
• Cell-cell recognition
• Immune function (antibodies)
• etc. etc.

David
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Protein expression
All human cells contain the same complement of
genes. Different cell types express different
genes, i.e., they make different proteins. This
is what makes one cell type different from
another.
David
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KIT
KIT is a protein made by only a few types of
adult cells, including most GIST cells. The most
important step in diagnosing GIST is testing
whether the tumor cells express KIT. This is
done by staining the tissue sample with an
antibody that recognizes KIT Immunohistochemistry
.
David
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Immunohistochemistry

• KIT (a.k.a. c-Kit or CD117) is the most
  important stain for the diagnosis of GIST
• about 95 of GISTs express KIT
• (and few, if any, other cancers do)
• 60-70 of GISTs are also CD34-positive

David
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Immunohistochemistry
Stephan Dirnhofer Institute of Pathology Universit
y of Basel Switzerland (London meeting)
David
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What does KIT do?

• Signal transduction protein
• KIT gene is an Oncogene

An oncogene is a gene which, when mutated,
encodes a protein product that causes the cell to
divide, leading to a tumor a stuck gas pedal
David
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What does KIT do?
KIT plays important roles in regulation of normal
cell functions Blood cell formation Fertility GI
tract contractions (ICC) Skin pigmentation
David
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Cell Signaling (Signal Transduction)
Chemical messages are sent between
cells Receptor proteins receive these
messages Cells respond to these signals by
appropriately changing their metabolism and
behavior, e.g., cell divides
David
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Cell-surface receptors
cell membrane
nucleus
receptor
David
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outside
membrane
inside
Signal is transmitted to intracellular proteins
David
biological effects
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Yuzawa 2007
Structure of KIT/ stem cell factor complex
David
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In normal pacemaker cells A message molecule
(a growth factor) called stem cell factor
binds to KIT (pushes the gas pedal). Two Kit
molecules join together (KIT dimerizes) which
activates KIT A series of metabolic changes
begins in the cell, promoting it to grow and
divide.
David
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In GIST cells An altered form of KIT is
produced. This form is always turned on, even
in the absence of stem cell factor. The GIST
cell keeps dividing, in an uncontrolled
manner. Stuck gas pedal
David
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The KIT mutations in GIST tumors are somatic
not germline - mutations

• - occurring in cells of the body during
  development or adulthood, but not affecting germ
  cells (egg or sperm cells)
• the somatic KIT mutation is inherited by all of
  the tumor cells but cannot be passed on to a
  patients children

David
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10-15 of GISTs do not have kit mutations

• - 5-7 PDGFRA, a closely related gene, is
  mutated
• the remainder are wild-type GISTs mechanism of
  tumor growth unknown

David
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Gleevec (imatinib) is an inhibitor of KIT
(and also of the related proteins Abl and
PDGFR-alpha)
N
H N
O
H3C
N
NH
N
100 mg Gleevec Tablets
N
David
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Gleevec (imatinib) is an inhibitor of KIT
Gleevec prevents KIT from transmitting its signal
to the GIST cell (gas pedal is released).
In the absence of signaling, the GIST cell stops
dividing. The GIST cell undergoes apoptosis
programmed cell death or cell suicide gas
tank is emptied.
David
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Most proteins are composed of sub-structures
called domains, which have specialized
functions.
Actin
David
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Most genes are composed of segments called
exons each exon encodes a protein domain.
gene (DNA)
6
1
2
3
4
5
exons
RNA synthesis and splicing
mRNA (exons only)
protein synthesis
protein
David
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KIT mutation testing (Genotyping)

• DNA testing identifies the exon (in KIT or PDGFRA
  gene) which is mutated

Exon 9
Exon 11
Exon 13
Exon 17
Jerry
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KIT mutations in GIST
ligand-binding domain
extra-cellular environment
Exon 9 13
cell membrane
juxtamembrane domain
Exon 11 71
cytoplasm
Exon 13 4
Exon 17 4
Jerry
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Site of mutation affects response to Drugs

• Gleevec
• KIT exon 11 - favorable response
• KIT exon 9 - intermediate response (higher dose)
• Wild-type lower response
• Sutent (for Gleevec-resistant GIST)
• KIT exon 11 lower response
• KIT exon 9 favorable response
• Wild-type favorable response
• Newer drugs
• ???

Jerry
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From Discovery to a New Standard
1998 Discovery of KIT mutations in GIST

• Before Gleevec, 5 response to traditional
  chemotherapy
• July, 2000 - Phase II Gleevec trials
• 85 response rate to Gleevec
• Dec, 2000 Phase III Gleevec trials
• Feb, 2002 Gleevec approved for GIST

Jerry
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Great responses but . . .

• Durable responses to Gleevec
• Median time to progression 2 years
• But resistance is a problem
• Only about 20 of metastatic patients are
  progression-free after 5 years on Gleevec
• In response to the resistance problem
• The Life Raft Group has initiated a strategic
  research initiative to fund cooperative research
  amongst GIST researchers

Jerry
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Where are We Now?

• GIST is a rare disease
• BUT
• Patient interest in trials is extremely high
• GIST is a model for molecularly targeted cancer
  therapy
• Drug company interest is very high
• New approaches
• Destroy KIT (HSP90 inhibitors)
• Inhibit KIT production (flavopiradol)
• Combination therapies
• Downstream targets

Jerry
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GIST - The Basics

• Further questions
• liferaft_at_liferaftgroup.org