Transcript Presentazione di PowerPoint

Anno accademico 2002-2003
Canale A: Prof. Malavasi
Capitolo 10
La genetica del cancro
Il cancro è una malattia genetica:
1) È il risultato di alterazioni nel DNA che alterano la regolazione
del ciclo cellulare
2) Molte di queste alterazioni sono delle mutazioni
3) Le mutazioni possono essere causate da:
- errori casuali nella replicazione
- esposizione ai carcinogeni (per es. radiazioni o sostanze
chimiche)
- errori nel processo di riparazione del DNA
Cancer is fundamentally genetic, in that it arises from
mutations distorting the information contained in genes. At
the same time, cancer is not genetic--the truly causative
DNA damage is not inherited but acquired.
D.W. Ross, Hospital Practice, 1999
Expanding the Basics
1) Cancer Arises from Damage to DNA. known causes
of gene dysfunction include chemical or irradiational
mutagenesis. Genomic flaws may also arise during
DNA replication as errors that sometimes go
undetected by intracellular repair mechanisms. In
addition, certain viral infections are known to suppress
gene function.
2) The Damage to DNA Is Acquired. Familial cases of
cancer allow use of genetic mapping techniques to
pinpoint cancer-related genes.
3) The Damage Typically Occurs in Multiple Steps.
Epidemiologic data show that the incidence of cancer
increases exponentially with age, but in a small
proportion of cases, the damage happens to come fast,
e.g. some leukemias
The multi-hit hypothesis
The Damage Affects Protooncogenes and Tumor Suppressor Genes.
Our understanding of the molecular basis of cancer is built largely
around evolving concepts of these two types of genes. So far, about
100 human protooncogenes have been discovered, and about 20 tumor
suppressor genes. Both gene types specify proteins related to cell
growth. A protooncogene product promotes such growth; a tumor
suppressor gene product inhibits it.
Oncogenes:
-gain of function mutation: dominant
-not heritable as a germline mutation
Tumor suppressor genes:
-loss of function mutation: recessive
-heritable as germline mutation
The example of follicular lymphoma
Anno accademico 2002-2003
Canale A: Prof. Malavasi
Capitolo 10
La genetica del cancro
The example of chronic myeloid leukemia
CML: clinical features
1) Clonal hematopoietic stem cell disorder
2) 20% of all leukemias (1 – 1,5 cases / 100,000)
3) Clinical course includes a chronic phase (4-5 yrs), an
accelerated phase (6-18 mos) and a blast phase (3-6
mos)
4) Onset at >50 yrs
CML: chronic phase
1)
Characterized by mild hyperplasia with marked leukocytosis
and immature cells of the granulocytic series
2)
Lasts for approximately 4-6 yrs
3)
Thrombocytosis and basophilia are common
4)
Leukemic cells retain the capacity to differentiate normally
5)
50% of patients identified during routine blood tests
6)
Main symptoms include fatigue, night sweats, abdominal
discomfort due to splenomegaly
CML: accelerated and blastic phases
1)
Increasing myeloid immaturity; loss of the ability to
differentiate normally
2)
During the accelerated phase pts show a rising % of blasts
(15-30%) and basophils (> 20%) in the PB and BM;
3)
Blast phase can be either myeloid or lymphoid
CML: molecular basis
1)
1960: Nowell and Hungerford described a consistent
chromosomal abnormality in CML pts.
2)
1973: Rowley clarified that the shortened chr was the product
of a reciprocal translocation
3)
Majority of cases associated with (9; 22) (q34;q11)
traslocation. It is a reciprocal translocation of the long arms of
chromosome 9 and 22, resulting in a shortened chr 22 (the
Philadelphia chr)
4)
The molecular consequences is the fusion of the c-abl
oncogene from chr 9 to sequences from chr 22, the
breakpoint cluster region (bcr), giving rise to the bcr-abl gene.
5)
The length of the fusion protein depends on the site of the
breakpoint in bcr
Why this chromosomal translocation?
1)
Exposure to IR is a risk factor
2)
Bcr and abl are in physical proximity in normal human cells
3)
Bcr-abl transcripts are detectable at low frewuency in the
blood of many healthy individuals
4)
Why do some indivuals develop leukemia while others do
not?
- role of immune responses (HLA)
- stage during which the translocation occurs
CML: molecular features
1)
The two most common fusion proteins are p185 and p210
2)
p210 is seen in >95% of CML pts and 20% of ALL pts
3)
p185 is seen in 10% of adult ALL pts and in the majority of
pediatric Ph+ ALL pts
1)
Ubiquitously expressed 145 kD protein, with 2 isoforms
2)
Human homologue of the v-abl oncogene carried by the
Ableson murine leukemia virus
3)
Nonreceptor tyrosine kinase
4)
Involved in regulation of cell cycle, in the cellular response to
genotoxic stress, in the trasnmission of information
concerning the environment through the integrin signaling
pathway
1)160 kD protein, ubiquitously expressed
2) Serine threonine kinase activity in vitro (Bcr?)
3) Pleckstrin homology domain may activate nuclear factors
4) The true biological relevance remains to be determined
The bcr-abl protein displays a deregulated tyrosine kinase activity
Activation of mitogenic signaling
The example of sqamous cell carcinoma of the cervix
The retinoblastoma example
The example of colon cancer
1) Second most common internal cancer
2) Accounts for 20% of cancer-related deaths in western countries
3) Incidence increases dramatically above age 50
4) Incidence approx equal in men and women
5) 5% is on a hereditary basis
Hereditary colon cancer
The example of breast cancer
1) 180,000 new cases each year in the US
2) 45,000 women die each year in the US because of breast cancer
3) 12% lifetime risk
4) 5-10% hereditary cases
5) Age and family history are the strongest risk factors
Toward molecular cancer therapies
1.
2.
3.
4.
Monoclonal antibodies: the example of anti-CD20
Antisense therapy
Protein therapy
Vaccines
Antibody vs Tumor
Signaling
Apoptosis
Cell cycle arrest
Modulation
Natural effectors
Complement
FcR bearing cells
Induced anti-tumor response
Antigen
Exogenous effects
R-active isotope
toxins
Potential resistance mechanisms to immunotherapy
Lack or decreased expression of targeted antigen
Expression of defensive antigens (CD46, CD55, CD59)
Insufficient mAb delivery
Delivery of apoptotic signals to effector cells
Release of negative immunomodulators
Antibody
Specificity
Target cell
Type
Edrecolomab
(panorex®)
Trastuzumab
(Herceptin®)
a-idiotype abs
17-1A
colon/rectal cancer
Murine IgG2a
HER-2
breast cancer
Humanized murine IgG1
individual B-cell
tumor antigens
CD52
CD20
B-cell lymphomas
Customized human mAb
CLL
NHL
Humanized IgG1
chimeric human/murine IgG1
B1
NHL
Mouse
HLA DR
CD22
NHL
NHL
Murine IgG2a
Murine IgG2a
CD33
AML / CML
humanized murine mAb
CD20
NHL
Chimeric human /murine IgG1
CAMPATH-1
Rituximab
(Rituxan®)
a-B1
(Tositumomab)*
LYM-1*
LL2
(Epratuzumab)*°
a-CD33
(Hu-M195)*
Ibritumomab
* 131I-conjugated
° 90Y-conjugated
Antisense therapy
Gene therapy
Towards molecular therapies