?????? (Target therapy of cancer)

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????????????????
???????? ???????
???
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??????(Target therapy of cancer)

• ????????????????,???????????????????,?????????????
  ?
• ???????????????????????????????
• ?????????

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??????( Fluorescence in situ hybridization,FISH
)??
4
??

• FISH Fluorescence In Situ Hybridization
• ???????DNA???????????????DNA??
• ??????? ???? ???
• ??????????????????????????????

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(No Transcript)
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FISH???????????????
FISH???????(Translocation)??????????
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??????

• ?????????????????
• ??
• ????????????IHC????????
• ????????,??????????????
• ?????????????????????!!!

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FISH???????????
??? FISH???? ????
?????? IGH/CCND1???? ????
?????? BCL2/IGH???? ?????????
????B????? BCL6?????? ?????????
?????? C-MYC?????? ????
??????????? MALTI???? ????
???????????? API2-MALTI???? ????
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???B?????(DLBCL) ?????????
CD5??DLBCL ????B?????(GCB)?
?????B?????(non-GCB) 3?
???CD10?BCL6?MUM1?????????B???????????B?????? gt30
?????CD10?CD10(-)?BCL-6()?MUM-1(-)???GCB ??????
non-GCB?
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BCL6 ?????????B?????
? BCL6????---????????B?????
????????40?DLBCL??BCL6?????
? BCL6??????----????
????102?DLBCL???BCL6????????????????,BCL6????????3
6???,??????????82,???BCL6??????????
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????
Offit, K. N Engl J Med, 1994. 331(2) p. 74-80.
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IGH/CCND1???????????

• IGH/CCND1????--???????????

IGH/CCND1???????95???????,?????????????????????
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l ??????????,??????? l ??????????,??????,???
????
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API2/MALT1???????
??GLP API2/GLP MALT1
??????2??(apoptosis inhibitor-2,API2),??11???? ??
????????(Mucosa-associated lymphoid tissue 1
,MALT1 ),??18?????
API2???MALT1??????????????,??????????????????
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API2/MALT1????????

• API2/MALT1????????????HP??

?MALT??????????(HP)???????????,MALT1/API2?????
?????HP????,?????HP?????
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l ??????????,??????? l ??????????,??????,???
????
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BCL2/IGH???????????

• BCL2/IGH????-----??????????

BCL2/IGH??????80-85?FL???,??BCL2/IGH??????????FL
?

• BCL2/IGH????-----????

BCL2/IGH???FL??3?????100,??????54
???3???????87.5,??????13?
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l ??????????,??????? l ??????????,??????,???
????
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????-????
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????-????
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C-MYC???????????

• ??????????

?80???????????t(814) (q24q32)
?15???????????t(28)(p11q24)
?5??t(822)(q24q11)? ???????C-MYC?????????
???????????,????????????????????
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(No Transcript)
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????-????
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FISH????????????
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??? Her-2??

• ????Her-2??
• ??17q11.2-q12
• ????????(?
• ????????????)
• 25-30???????HER-2???
• HER-2???????Herceptin?????????????
• HER2?????????????????

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???Her-2???????
Cerb-B-2 3 ????????gt30
2,1 ,- FISH?????????
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????????
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• 1.RNA?A??(RnaseAcleavage)
• 2.????????(DGGE)
• 3. ???????(HA)
• 4. ??????(CCM)
• 5.???????(Carbodiimide,CDI)
• 6.??????(Enzyme Mismatch Cleavage, EMC)
• 7.??????? (Single-Strand Conformation)
• 8.?????????
• 9.DNA??(Sequencing)
• 10.????????(Dideoxy Finger-printing, ddF)
• 11.????????
• 12.??????(protein truncation test)

??
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13.???????????(Denaturing High Performance Liguld
Chromatography DHPLC) 14.DNA????(DNAchip)
15.????????? 16.???????????????(Allele-Specific
Oligonucleotide,ASO) 17.??????(Primer
Extension,PEX) 18.????????(Oligonucleotide
Ligation Assay,OLA) 19.???????(Restriction
Fragment Analysis) 20.?????PCR?(mutant-enriched
PCR) 21.????????????(Scorpions amplification
refractory mutation system)
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????EGFR???????????????
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????

• ?????????????NSCLC????????????
• ??EGFR??????????????????????
• ??EGFR????????????????????????
• ???????EGFR????,??gt1????????????????3,??????????
  ????

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EGFR??????

• FISH??EGFR????
• ??????????(????????)
• ????
• ????????
• ????GLP EGFR / CSP7
• ??PCR??EGFR??????
• ???? 19 exon (2235-2249??)15bp????
• 19 exon
  (2240-2257??)18bp????
• 19 exon
  (2240-2251??)12bp????
• 21 exon
  2573??TgtG??????
• 21 exon
  2582??TgtG??????

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(No Transcript)
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(No Transcript)
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FQ-PCR??????EGFR??

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??EGFR???????????????
71?????????6?????
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FQ-PCR ??15bp????????
???????????????????????,????????????
9??12??13??55??38??33???
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15bp?????DNA????
sense
antisense
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(No Transcript)
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• ??K-RAS????????

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??

• ????
• ?????
• ????????
• PCR-RFLP
• ??
• ??
• Real-Time PCR

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K-ras?????????
???PCR?????
?????? ??DNA
??????????
????????
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????(Direct Sequencing)

• PCR?????????
• ??????????(Sanger?)
• DNA ????????,?????????????????????,??????????,
  ?????????????

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(No Transcript)
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K-ras??????
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???????????????

• ???????
• ??????????????????
• KRAS?????????EGFR?????
• ???????
• ????????????????????????
• 18??????(18q)??
• ?????????????
• ???????(Thymidylate synthase)

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EGFR ?????????

• EGFR expression correlates with poor prognosis

Tumor type Prognosis Survival Risk of metastasis References
Colorectal Poor Poor - Decreased OS Increased - Hemming (1992) Mayer, De Jong (1992)
Head Neck (SCCHN) Poor Poor Decreased DFS Decreased OS - - Grandis (1998)Maurizi (1996)
Lung (NSCLC) Poor Poor Decreased OS - -Increased Ohsaki (2000)Pavelic (1993)
DFS Disease-free survival OS overall survival
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????????????

• Cetuxamab(?????)
• ???????( IgG1 )
• ?????????????(EGFR)
• ??EGF ?TGFa?EGFR ???,?????????????????
• 2004???FDA??????????
• Panitumumab(????)
• ??????????(IgG2)
• ?????????????(EGFR)
• 2005?7???FDA??????????????

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KRAS ??

• KRAS ??????EGFR????,????RAS/MAPK ??
• ??ERBITUX ??
• KRAS ???Erbitux?????????
• KRAS ????????
• KRAS ?????BRAF??,?? CpG ??????(CIMP)1,2??
• KRAS ????? PI3K ??3

Lièvre A, et al. J Clin Oncol 200826374379
MAPK mitogen-activated protein kinase
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?EGFR???K-ras??????
K-ras???EGFR??????

• K-ras???????????????????
• K-ras????????????EGFR?????,???????????????

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????????????

• 2009?7?FDA??????????????????????

??KRAS????????????????????????
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K-ras????

• K-ras???? 20-60????
• K-ras??????????????,????????K-ras????????

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K-ras???????

• NCCN???????????????????????
• ????K-ras?????
• ??????????(ASCO)???K-ras????????
• ????????EGFR??????????
• ???????????cetuximab ?panitumumab
• ??mCRC????,???????K-ras????

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????(CRC)??EGFR????

• ???????????????(mCRC)?????110?????????????
  EGFR????(???18-21)

Khambata-Ford S, et al. J Clin Oncol
20072532303237
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?EGFR?????KRAS???????

• ??????????
• ????????
• ????????????????
• ???????????????

CHMP gave a positive opinion for ERBITUX May 29,
2008 but for patients with wild-type KRAS
tumors
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(No Transcript)
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HER2?????????

• 810??????HER2?????,??????????22
• ????????????Herceptin???????????11.1?????13.8??
• ?????????16??
• ???????26?

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????????ASCO??

• Herceptin???HER2?????????
• ?????
• ??????????????HER2??

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HER???????

• HER2??????????????????
• ?HER2????????????????12.6??,?????????????5.5???
• ??HER2???????????5?????21.4,???????63.0 ?