Download HM781-36B

cancer
Goal and approach
Why
we’re losing the war on cancer
this was the cover of fortune magazine
, 2004
In our view of cancer.
For the last 50 years, (1950&2001)
we have focused on
, treating the individual gene
, in understanding cancer
, not in controlling cancer.
The death rate in cancer in over 50 years hasn’t changed.
new approach
—that we hope to push forward in terms of treating cancer.
what is the cancer ?
• diagnosis today is by pattern recognition.
Does it look normal? Does it look abnormal?
• the state-of –the –art today in diagnosing cancer
• There’s no molecular test
• there’s no sequencing of genes
• there’s no looking at the chromosomes
Cancer vocabulary
• Symptoms
• Anatomic descriptions – CT scan
• Body part – liver, breast etc.
Dictionary for describing cancer is very poor
New dictionary to describe cancer
Pathogenic lesions
that were involved in causing this individual cancer.
- HER2 amplified , EGFR activated
- Cancer genome
Cancer genome
• Genomics , proteomics
- Understanding and classifying disease
- Identify what we’re up against
- Prevent disease
Molecular test
암의 가장 중요한 발생원인
신호전달경로의 이상
tyrosine kinase 의 변이,증폭
세포분열, 성장, 사멸 사이의 불균형
다중 신호 전달 연속경로 활성화
종양세포
EGFR tyrosine kinase family
(HER family)
EGFR
HER-1
ErbB-1
HER-2
ErbB-2
HER-3
ErbB-3
HER-4
ErbB-4
A SIGNALING NETWORK of Human epidermal growth factor receptor
•Play a crucial role
in regulationg cell proliferation and differentiation in many tissue types
• has been implicated in a variety of cancer
• MAJOR Target of anticancer drugs
•Clinical Tx is limited
by the development of drug resistance resulting
mainly from a gatekeeper mutation (T790M)
EGFR family 의 암세포에서 발현
Tissue
EGFR(%)
HER-2(%)
HER-3(%)
HER-4(%)
Bladder
31-72
9-36
30-56
30
Breast
14-91
25-30
22-56
n/a
Colon
50-80
26-90
89
n/a
Gastric
40-81
26-56
35
n/a
Head & Neck
80-100
n/a
n/a
n/a
NSCLC
40-80
18-37
n/a
n/a
Ovary
35-70
28-65
n/a
n/a
Pancreas
30-50
n/a
n/a
n/a
EGFR family - major target
Dysregulation of the EGFR signaling pathway
caused by genetic alterations in the kinase domain of EGFR
is associated with malignant transformation in NSCLC.
Hyperactivation of the EGFR family
<In particular : her1 and her2>
Observed in several solid tumors
can be caused by overexpression,
mutations resulting in constitutive activation
or autocrine expression of endogenous ligands.
Therefore ,
the EGFR family remains a major target
for the develpopment of anticancer agents.
First generation of EGFR –targeting
- her-1 specific reversible and quinazolinebased adenosine triphosphate (ATP) competitive inhibitor
- gefitinib , erlotinib
- NSCLC Pt.
who have activating mutations in the HER-1 kinase domain.
(L858R in exon 21 and A750 in exon 19)
- Despite good response,
Pt. almost invariably develop resistance to HER-1-specific
inhibitors,
which has been clinically observed after treatment for 1 years.
- Resistance : T790M mutation within HER-1 tyrosine kinase
The second generation
of EGFR-targeting therapeutic agents
- HER1/HER2 reversible dual inhibitor
- Lapatinib
- Breast ca. & AGC with HER-2 amplication
- More effective than just HER-1 inhibition
The third generation
of EGFR-targeting therapeutic agents
(includes the EGFR irreversible inhibitors)
- HKI-272,CI-1033,PF00299804,BIBW2992
- Covalently modify reactive cysteine residues at
their respective active sites.
Several advantages
of Irreversible EGFR inhibitors
- capable of overcoming the acquired resistance
toward HER-1 specific reversible inhibitors
- show a high potency with a broad spectrum
because of their pan-HER inhibitory profiles.
Two classes of drugs
( interfere with EGFR function)
• Monoclonal antibodies
cetuximab
- competitively binds to EGFR
- side effects
- expensive
- IV
, effectiveness
Two classes of drugs
( interfere with EGFR function)
• Tyrosine kinase inhibitors (TKIs)
gefitinib (IRESSA)
erlotinib (TARCEVA)
- inhibit the catalytic kinase function of the HER family
lapatinib(TYKERB)
BIBW-2992( might overcome gefitinib resistance)
- dual reversible inhibitor of EGFR and HER2
TKIs - Resistant
• Protein kinase 암유전자 증폭에 의해 야기된다
• 저항성을 지닌 돌연변이
- kinase 촉매 domain
- gefitinib or erlotinib 으로 치료된 환자의 EGFR
- imatinib로 치료된 환자의 kinase domain
Irreversible pan-HER inhibitors
(= HM781-36B)
Most potent pan-HER inhibitor
Compared with other EGFR tyrosine kinases inhibitor (erlotinib,lapatinib,BIBW2992)
1.Inhibition of EGFR phosphorylation and the subsequent deactivation of downstream
signaling proteins.
2.Excellent efficacy in a variety of EGFR- and HER-2-dependent tumor
- Erlotinib-sensitive NSCLC cell
- Erlotinib-resistant NSCLC cell
- HER-2 Overexpressing NSCLC cell
- NCI-N87 gastric cancer cell
- SK-ov3 ovarian cancer cll
- EGFR-overexpressing A431 epidermoid carcinoma cancer cell
NSCLC including clinical limitation caused by acquired mutation (EGFR T790M)
Breast Ca. HER-2 & HER-4
Gastric Ca.
HM781-36B
• Excellent selectivity of HM781-36B toward EGFR family
(EGFR,HER-2,HER-4)
which have been recognized as attractive targets of anticancer therapy
and subjected for the study on additional effects upon their inhibition.
• Inhibits the cellular proliferation in a panel of cell lines
with various expression levels of EGFR or HER-2
as well as disease-relevant mutations
• Show strong growth inhibitory activities in various cancer cell
• HER-2 overexpressing NSCLC, Breast ca. , gastric ca.
Not
induce growth inhibitory activity in K-ras mutated NSCLC and normal cell.
Induce excellent in vivo anti-tumor activity
with various EGFR-dependent cancer cell line
진행성 고형암 환자에 대한 HM781-36B 의 최대 내약 용량 결정 및
안전성,약동학적 양상 평가를 위한 제 1사 임상시험
31명 등록
0.5mg 부터 증량
MTD – 24mg 으로 결정
12명 등록
GC,BC – 6명 ( HER2 amplication)
NSCLC – 6명 (EGFR mutation)
Common side effect
Daily oral treatment with HM781-36B
- SKIN RASH
- DIARRHEA
Caused by the inhibition of EGFR
- These symptoms have been recovered
after the cessation of administration.
RASH
Adverse
Event
1
Rash/
Macular or
desquamat papular
ion
eruption
or
erythema
without
associated
symptoms
2
3
4
5
Macular or
papular
eruption or
erythema with
pruritus or other
associated
symptoms;
localized
desquamation
or other lesions
covering
<50% of body
surface
area (BSA)
Severe,
generalized
erythroderma or
macular,
papular or
vesicular
eruption;
desquamation
covering ≥50%
BSA
Generalize Death
d
exfoliative,
ulcerative,
or bullous
dermatitis