Download Cell, Tissue, and Tumor Kinetics in Response to Irradiation Bill

Biologic Targeting in RT
Bill McBride
Dept. Radiation Oncology
David Geffen School Medicine
UCLA, Los Angeles, Ca.
[email protected]
WMcB2008
www.radbiol.ucla.edu
Objectives
• Understand the relationship between molecular carcinogenesis
and radiation response
• Know how to target receptor tyrosine kinases
• Know what agents are in clinical trials and the molecules they
target
• Know the clinical trial data on receptor targeting in combination
with RT
• Understand why some trials fail
• Know what other pathways have and are being targeted, why,
and how
WMcB2008
www.radbiol.ucla.edu
An increased therapeutic ratio can be
achieved only by exploiting some difference
between normal and malignant tissues
Cancer Biology
Radiobiology
• Tumor Oncogenes
• Intrinsic Radiosensitivity
• Tumor Suppressor Genes
• Tumor Cell Proliferation
• Tumor Microenvironment
– Vasculature
– Hypoxia
– Metabolism
– Immunity
• Tumor Cell Death/Survival
• DNA Repair
• Differences between cancer and normal cells are known
• Where is the link between cancer biology and radiobiology?
WMcB2008
www.radbiol.ucla.edu
Features of Carcinogenesis
Mutations with gain in function (oncogenes)
conspire with those conferring loss of function
(tumor suppressor genes) to affect molecular
signaling pathways and cause
•
•
•
•
•
•
•
Unabated, self-sufficient growth factor signaling (overexpression of ligands
or receptors)
Loss of response to anti-proliferative signals
Evasion of cell death programs
Increase in replicative potential (telomeres)
Promotion of tissue invasion and metastasis
Sustained angiogenesis
DNA repair abnormalities and genomic instability
After: Hanahan D, Weinberg RA, Cell 57-70, 2000.
Overall decrease in cell loss factor and tumors grow
www.radbiol.ucla.edu
WMcB2008
Cell Lines Vary in Intrinsic Radiosensitivity
LYMPHOMA
NEUROBLASTOMA
MYELOMA
SMALL CELL LUNG CANCER
MEDULLOBLASTOMA
BREAST CA
SCC
PANCREATIC CA
COLORECTAL CA
NON-SMALL CELL CA
MELANOMA
OSTEOSARCOMA
GLIOBLASTOMA
HYPERNEPHROMA
S.F. 2Gy in vitro
0.2 (0.08 - 0.37)
0.43 (0.14 - 0.75)
0.52 (0.2 - 0.86)
Correlates with histological type and in vivo curability
WMcB2008
www.radbiol.ucla.edu
Oncogenes and Radiation Resistancy
Surviving fraction
1
ras
+
myc
0
2
4
Dose (Gy)
6
8
10
S.F.
0.1
bcr-abl
v-fes
c-myc
Ha-ras
Rat -1/v-mos
0.01
wt-ras
Rat -1
myc
(from McKenna et al, 1990)
Dose (Gy)
0
2
4 Dose (Gy)
6
8
10
1
S.F.
0.1
c- myc
v-abl
0.01
Rat -1
c-myc +v-abl
v-abl+ dn-myc
• Cancer is associated with
deregulation of the same signaling
pathways as determine intrinsic
cellular radiosensitivity
• This is through activation of signal
transduction pathways that alter
intrinsic radioresistancy
• Transformation is not requiredWMcB2008
www.radbiol.ucla.edu
Can you Predict How Mutations will Affect
Response to RT?
•
•
•
•
Activation of cell cycle progression and
survival pathways generally increases
radioresistance
Activation of pro-apoptotic/cell cycle
arrest pathways generally
radiosensitize
The deregulated signaling pathways to
which the cancer becomes “addicted”
will provide the best targets for
modifying radioresistance
McBride, W.H. and G.J. Dougherty, Nature
Medicine, 1995. 1(11): 1215-1217
WMcB2008
www.radbiol.ucla.edu
A Large Number of Small Molecule Kinase
Inhibitors have been Developed
(FDA-approved)
Imatinib (Gleevec) Bcr-Abl, c-kit, PDGFR-a
Gefitinib (Iressa)
EGFR
Erlotinib (Tarceva)
EGFR
Bortezomib (Velcade) Proteasome
Sorafenib (Nexavar) c-Raf, BRA, Kit, EGFR,
CML, GIST80%-CML, 54% GIST
NSLC
10% respond
NSLC, mesothelioma
Median survival 6.7 months
Multiple myeloma
1 year 23% of patients
mRCC
PFS longer
FLT-3, VEGFR, PDGFR-β
Sunitinib (Sutent)
Dasatinib (Sprycel)
Multiple RTKs, VEGF, PDGF
BCR-ABL, SRC family,
GIST and mRCC
CML and Ph+ ALL
GIST: 25.5% MRCC: 36.5%
In trials
c-KIT, EPHA-2, PDGFR-β
WMcB2008
www.radbiol.ucla.edu
A Large Number of Monoclonal Antibodies
that inhibit Signaling Pathways are Available
(FDA-approved)
Bevacizumab (Avastin)
VEGF
Alemtuzumab (Campath) CD52
Cetuximab (Erbitux)
EGFR (HER-1)
Trastuzumab (Herceptin) HER2
Tositumomab (Bexxar)
CD20
Rituximab (Rituxan)
CD20
Ibritumomab tiuxetan (Zevalin) CD20
Gemtuzumab (Mylotarg) CD33
Panitumumab(Vectibix)
EGFR
CRC
B-cell CLL
CRC, pancreatic Ca
Breast cancer
NHL
NHL, CLL,MM, HCL
NHL
AML
mCRC
5 months prolonged survival
9.5 months 30% patients
increased response HNSCC, NSLC
25 months for 26%
57% to 71% respond
3 months in 45% of patients
80% respond
6 months 30% of patients
PFS 96 days
Bevacizumab, cetuximab, and panitumumab each cost about $100,000/ patient.yr
WMcB2008
www.radbiol.ucla.edu
Where is Molecular Targeting Going?
• Most molecular targeting agents are likely to
be more cytostatic than cytotoxic, and are
unlikely to be curative on their own.
• To cure cancer, you need to kill all the cancer
cells !!
• It makes sense to use molecular targeted
therapy to enhance tumor response to RT
(and vice-versa)!
WMcB2008
www.radbiol.ucla.edu
Robert et al., J. Clin Oncol 19:3234-3243, 2001
13 CR and 2PR of 15 evaluable advanced HNSCC cases receiving Cetuximab plus RT
•Volume 354:567-578
February 9, 2006
Radiotherapy plus Cetuximab for Squamous-Cell Carcinoma of the Head and Neck
James A. Bonner, M.D., Paul M. Harari, M.D., Jordi Giralt, M.D., Nozar Azarnia, Ph.D., Dong M. Shin, M.D., Roger B. Cohen, M.D.,
Christopher U. Jones, M.D., Ranjan Sur, M.D., Ph.D., David Raben, M.D., Jacek Jassem, M.D., Ph.D., Roger Ove, M.D., Ph.D.,
Merrill S. Kies, M.D., Jose Baselga, M.D., Hagop Youssoufian, M.D., Nadia Amellal, M.D., Eric K. Rowinsky, M.D., and K. Kian Ang,
M.D., Ph.D.
The median duration of locoregional control was 24.4 months among patients treated with
cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone
(hazard ratio for locoregional progression or death, 0.68; P=0.005). With a median follow-up
of 54.0 months, the median duration of overall survival was 49.0 months among patients
treated with combined therapy and 29.3 months among those treated with radiotherapy
alone (hazard ratio for death, 0.74; P=0.03). Radiotherapy plus cetuximab significantly
prolonged progression-free survival (hazard ratio for disease progression or death, 0.70;
P=0.006).
With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or
greater toxic effects, including mucositis, did not differ significantly between the two groups.
WMcB2008
www.radbiol.ucla.edu
EGFR (ErbB-1)
Also ErbB-2, 3, 4
EGF/TGF-a
The Pathways
Glucose
Amino acids
ATP
GLUT1
sos
Grb2
GDP
P
PIP2
P
P
P
SH2
P
PI-3K
SH2
P110
x
PH
P
Glucose
Akt
PKA
PTEN
Glucose-6-P
sos
GTP
PIP3
SH3
Ras
Raf-1
PIP2
PIP3
LKB1
Glycolysis
a, , d
AMPK
MEK
ERK1
ERK2
Src
MAPK/ERK signaling
Multiple
downstream
targets
P
P
P
MDM2
NF-kB
BAD
P
FKHD
SH3
PH
P
mTOR
p27
FasL
p53
cell death/survival
cell cycle arrest/progression
DNA repair/misrepair
SH2
P
GSK3
cell metabolism
binds phosphotyrosine residues
binds proline-rich sequences
binds lipid ligands (products of PI-3K)
www.radbiol.ucla.edu
WMcB2008
EGFR Targeting Agents in the Clinic
• Monoclonal antibodies
•
•
•
•
Cetuximab (Erbitux) chimeric IgG1
Panitumumab humanized IgG2a
Matuzumab (discontinued)
Trastuzumab (Herceptin directed to
Her2/neu; ErbB-2)
• Small molecule TK inhibitors
•
•
•
•
•
•
Gefitinib (Iressa)
Tarceva (Erlotinib)
PKI-166 (ErbB-1 and -2)
Lapatinib (ErbB-1 and -2)
EKB-569 (ErbB-1, -2, -4)
CI-1033 (ErbB-1, -2, -4)
• Antisense oligonucleotides
• Dominant negative truncated
receptor gene therapy
WMcB2008
www.radbiol.ucla.edu
EGFR Targeting: Rationale
• Many tumors overexpress or activate EGFR and it generally correlates
with outcome
• Increased gene copy
• Gene Mutation
• Domain deletion (EGFRviii in GBM and other cancers)
• EGFR is a strong independent prognostic determinant for overall and
disease-free survival as well as a strong predictor for locoregional
relapse, but not distant metastasis, for patients receiving definitive RT
(Ang et al., Cancer Res, 2002)
• EGFR activation causes radioresistance.
• Blocking EGFR activation radiosensitizes
• RT induces EGFR phosphorylation and tumor cell proliferation
• Sadly, there is little correlation between EGFR expression and response
to EGFR inhibitors….and there are no good in vitro models of cellular
response to EGFR blockade
WMcB2008
www.radbiol.ucla.edu
Preclinical Data: Cetuximab potentiates RT against
tumor growth in mice
Control
C225 x1
C225 x3
14
18 Gy
18 Gy +
C225 x1
Tumor Size (mm)
12
10
18 Gy +
C225 x3
8
6
4
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
Days
Clin Cancer Res 6: 701, 2000
Int J Radiat Oncol Biol Phys 51: 474, 2001
www.radbiol.ucla.edu
(Huang and Harari, 2000)
WMcB2008
Mechanisms of Action of EGFR
Inhibition with RT
•
•
•
•
•
•
•
•
•
•
Blocks ligand binding (MoAb)
Prevents EGFR phosphorylation and downstream signaling
Decreases DNA repair after irradiation
– EGFR nuclear translocation
– Binds to and blocks DNA-Pk?
Increases radiation-induced apoptosis
Cell cycle effects
Decreases tumor cell proliferation
– accelerated repopulation?
Improves reoxygenation
Blocks angiogenesis
– Inhibit VEGF and radiosensitizes vasculature?
Inhibition of tumor cell invasion and metastasis
Kills tumor cells through antibody-dependent cellular cytotoxicity (MoAb)
WMcB2008
www.radbiol.ucla.edu
There are lots of clinical trials ongoing,
planned, or closed like these two
More toxicity with IMRT than non-IMRT
WMcB2008
www.radbiol.ucla.edu
PI3K Inhibitors in the Clinic
Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy.
Nathan T. Ihle and Garth Powis Molecular Cancer Therapeutics 8, 1, January 1, 2009
There are currently 9 PI3K inhibitors in Phase I/II trials and 10 mTOR inhibitors
WMcB2008
www.radbiol.ucla.edu
But not all trials are successful!
Machiels, JP et al Phase I/II study of preoperative
cetuximab, capecitabine (Xeloda), and external beam
radiotherapy in patients with rectal cancer Ann Oncol,
18:738-744, 2007.
Only 5% pathological CR
Rodel, C. et al., Multicenter phase II trial of chemoradiation
with oxiplatin for rectal cancer. J. Clin Oncol 25:110-117,
2007.
Only 9% pathological CR
WMcB2008
www.radbiol.ucla.edu
Why may they fail?
• Need for Biomarkers to identify those who are going
to respond
– Acneiform rash predicts better than most markers
that have been investigated!
One week after Cetuximab and RT - courtesy K. Haustermans
www.radbiol.ucla.edu
WMcB2008
EGFR Mutations in Lung Cancer:
Correlation with Clinical Response to
Gefitinib (Iressa) Therapy
SCIENCE VOL 304 4 JUNE 2004
J. Guillermo Paez,1,2* Pasi A. Janne,1,2* Jeffrey C. Lee,1,3* Sean Tracy,1 Heidi Greulich,1,2 Stacey
Gabriel,4 Paula Herman,1 Frederic J. Kaye,5 Neal Lindeman,6 Titus J. Boggon,1,3 Katsuhiko Naoki,1
Hidefumi Sasaki,7 Yoshitaka Fujii,7 Michael J. Eck,1,3 William R. Sellers,1,2,4 Bruce E.
Johnson,1,2 Matthew Meyerson1,3,4
Receptor tyrosine kinase genes were sequenced in non-small cell lung cancer
(NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth
factor receptor gene EGFR were found in 15 of 58 unselected tumors from Japan
and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor
gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more
frequently in Japan. EGFR mutations were found in additional lung cancer
samples from U.S. patients who responded to gefitinib therapy and in a lung
adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib,
but not in gefitinib-insensitive tumors or cell lines. These results suggest that
EGFR mutations may predict sensitivity to gefitinib.
WMcB2008
www.radbiol.ucla.edu
EGFR (ErbB-1)
Also ErbB-2, 3, 4
EGF/TGF-a
Mutant EGFR
ATP
Mutant PI-3K
Bypass Mutations
Why may they Fail?
PTEN loss
Glucose
Amino acids
Mutant AKT
GLUT1
sos
Mutant Ras
Grb2
GDP
P
PIP2
P
P
P
SH2
P
PI-3K
SH2
P110
x
PH
P
PTEN
Glucose
Akt
PKA
Glucose-6-P
sos
GTP
PIP3
SH3
Ras
Raf-1
PIP2
PIP3
LKB1
Glycolysis
a, , d
AMPK
MEK
ERK1
ERK2
Src
MAPK/ERK signaling
Multiple
downstream
targets
Mutant Src
Mutant
mdm2
Mutant p53
P
P
P
MDM2
NF-kB
BAD
P
FKHD
SH3
PH
P
mTOR
p27
FasL
p53
cell death/survival
cell cycle arrest/progression
DNA repair/misrepair
SH2
P
GSK3
cell metabolism
binds phosphotyrosine residues
binds proline-rich sequences
binds lipid ligands (products of PI-3K)
www.radbiol.ucla.edu
WMcB2008
Panitumumab in mCRC
Radiological Response
mt KRAS + pan
wt KRAS + pan
PFS mutant KRAS
Pantumumab
mt KRAS + BSC
PFS wt KRAS
Pantumumab
wt KRAS + BSC
Overall Survival
Amado, R. G. et al. J Clin Oncol; 26:1626-1634 2008
WMcB2008
Copyright © American Society of Clinical Oncology
www.radbiol.ucla.edu
Why may they fail?
Poor targets?
• Superior targets are probably
– Binding domain of a kinase to which the
tumor is “addicted”
• Imatinib (Gleevac) is very effective in CML and
GIST. Dasatinib binds even better and is even
more effective as an up-front therapy.
• A mutation, rather than an overexpressed
normal protein.
• Don’t forget the
pharmacokinetics/pharmacodynamics
WMcB2008
www.radbiol.ucla.edu
NF-kB (nuclear factor that acts on B
elements)
• Central role in inflammation and immunity
• Virchow (1863) first proposed that chronic irritation
was the cause of cancer
• Inflammatory cytokines activate ROS production
leading to DNA damage, genomic instability, and
cancer
• NF-B is activated which transcribes anti-apoptotic
factors
•
inhibitors of apoptosis (IAPs) like survivin, Bcl-XL, etc
• NF-B is induced by doses of radiation in the
higher dose range
• The majority of cancers have high NF-B levels
WMcB2008
www.radbiol.ucla.edu
Ligands
Signal Transduction
TNF-a
ras
IL-1 a/
Raf
Akt
MEKK1
IL-6
TGF-
ERK
IL-8
HIF-1
IFN-g
HRE
JNK
AP1
NF-IL-6
p38
TRAF VEGF
IKK
bFGF
Angiogenesis
IkB a/
TNF-a
Inflammation
IL-1 a/
Radioprotection
NF-B
Elk1/cEBP
CRE
Effectors
Possible
Outcomes
NF-kB
IL-6
TGF-
bFGF
MMP
Invasion
VEGF
PPAR g/d
Proliferation
EGF
Bcl-2
ErbB2
IAP
Hypoxia
PLA-A2
COX-2
Arachidonic
Acid
5,12,15
LOX
LTA4
B4
C4
www.radbiol.ucla.edu
PGH2
Survival
(survivin)
PGD2
PGE2
PGF2
PGI2
PGJ2
TBX
Transformation
Immunity
WMcB2008
COX Inhibitors
• Non-selective COX I and 2 inhibitors
– NSAIDs - aspirin, ibuprofen, indomethacin
• Selective COX2 inhibitors
– celecoxib, rofecoxib, meloxicam, NS-398,
etc
Note: Anti-tumor action of celecoxib may not
be solely through COX2 inhibition
WMcB2008
www.radbiol.ucla.edu
Tumor Vasculature as a Therapeutic
Target
• Vascular targeting
Blood vessel
– Induction of selective and irreversible damage to
established tumor-associated blood vessels
– normalize the abnormal tumor vasculature, increase tumor
oxygenation, and reduce interstitial fluid pressure (IFP)
– Acute treatment
• Anti-angiogenesis
– Preventing the growth of new tumor-associated blood
vessels
– Chronic treatment
Blood vessel
WMcB2008
www.radbiol.ucla.edu
Advantages of Vascular Targeting
•
•
•
Since many thousands of tumor cells depend upon each
blood vessel for the delivery of oxygen and nutrients,
theoretically even limited damage to tumor vasculature may
occlude a vessel and cause “an avalanche of tumor cell
death”.
Since cells being targeted are in contact with the blood
stream, delivery problems that limit the efficacy of therapies
directed toward tumor cells are not an issue
Since endothelial cells are genetically stable and nontransformed, treatment related resistance is less likely to
emerge
WMcB2008
www.radbiol.ucla.edu
VEGF
• VEGF is a major angiogenic factor
• There is a correlation between VEGF
expression in tumor tissue and microvessel
counts, which generally results in poorer
survival
Mean microvessel
counts (200x)
VEGF
positive
VEGF
negative
102.9*
66.8
*P=0.01.
Imoto H, Osaki T, Taga S, et al. J Thorac Cardiovasc Surg. 1998;115:1007-1014.
WMcB2008
www.radbiol.ucla.edu
Bevacizumab (Avastin)
•
•
•
Monoclonal anti-VEGF
First-line treatment for patients with metastatic carcinoma of the colon or
rectum in combination with intravenous 5-FU-based chemotherapy. Also,
lung and breast cancer trials.
Randomized, phase III trial, with previously untreated metastatic
colorectal cancer.
– bolus-IFL plus placebo – O.S. 15.6 months, PFS 6.4 months
– bolus-IFL plus bevacizumab – O.S. 20.3 months, PFS 10.6 months
– 5-FU/LV plus bevacizumab – 18.3 months, PFS 8.8 months
– Overall response rate = 39%, and median duration of response = 8.5
months.
– Complications - GI perforations and wound dehiscence 2%
WMcB2008
www.radbiol.ucla.edu
• As well as being a growth factor for endothelial cells,
VEGF is vascular permeability factor
• Cancer cells are killed indirectly by damaging tumor blood
vessels (anti-vascular effect)
• VEGF-targeted agents increase the response of tumors to
radiation in preclinical models
• They may sensitize tumors to radiation
• By transiently normalizing the tumor vasculature,
leading to greater tumor oxygenation, and thereby
increasing the cytotoxicity of radiation to cancer cells
• By increasing the radiosensitivity of tumor-associated
endothelial cells.
WMcB2008
www.radbiol.ucla.edu
Bevacizumab (Avastin)
Feasibility of using bevacizumab with radiation therapy and
temozolomide in newly diagnosed high-grade glioma One-year
progression-free survival and overall survival rates were 59.3% and
86.7%, respectively. Int J Radiat Oncol Biol Phys. 72:383, 2008.
RTOG 0417 A PHASE II STUDY OF BEVACIZUMAB IN
COMBINATION WITH DEFINITIVE RADIOTHERAPY AND
CISPLATIN CHEMOTHERAPY IN UNTREATED PATIENTS WITH
LOCALLY ADVANCED CERVICAL CARCINOMA
Phase II: Docetaxel, Cisplatin, Fluorouracil, Bevacizumab, and
Radiation Therapy in Treating Patients With Advanced
Nasopharyngeal Carcinoma
WMcB2008
www.radbiol.ucla.edu
Targeting Loss of Function
Tumor Suppressor Genes
Is tougher than targeting oncogenes
• Replacement Gene therapy
– Requires all tumor cells to be targeted
– Currently, no vector has 100% efficiency of gene
transfer in vivo
– Vectors have associated toxicity that limits dosage
• Targets downstream of the mutation
– E.g. Akt in PTEN deficient tumors
– But it is divorced from the real target
WMcB2008
www.radbiol.ucla.edu
Radiosensitization by Ad-p53
AdVluc+Irrad.
1.4
1.00
SKOV
AdVp53
control
Tumor 1.2
Diameter
(cm) 1.0
S.F.
0.8
0.10
0.6
SKOV/P53
0.4
AdVp53
+irr.
0.2
irrad. irrad.
xxx xxx
0.0
0.01
0
2
DOSE (Gy)
In Vitro
www.radbiol.ucla.edu
4
0
10
20
30
40
50
Time (days)
In Vivo
WMcB2008
•
Current approaches to overcoming vector limitations are
unlikely to greatly improve the situation
• Replicating adenoviruses
• Tissue specific/ hypoxia-induced/radiationinduced promoters
WMcB2008
www.radbiol.ucla.edu
Exploiting Low Tumor Oxygenation
with Hypoxic Cytotoxins
WMcB2008
www.radbiol.ucla.edu
Mechanism of Hypoxic Cytotoxicity of
Tirapazamine
.-
O
N
O
O2
2
O
Hypoxia
N
N
N
O
N
NH
+
2 1e +H
Reductase
TPZ
M. Brown
www.radbiol.ucla.edu
N
NH
2
OH
TPZ Radical
WMcB2008
Tirapazamine is Toxic
for Hypoxic Cells in vitro
100
Surviving Fraction
10-1
HCR
= 300
10-2
10-3
air
hypoxia
10-4
10-5 1
10
100
1000
10000
Tirapazamine Conc (M)
M. Brown
www.radbiol.ucla.edu
WMcB2008
Tirapazamine showed Promise when Combined
with XRT or Chemotherapy in Phase I/II Trials
Lung
Cancer
Cervix
Cancer
Head &
Neck
Cancer
WMcB2008
www.radbiol.ucla.edu
• But failed in several Phase III trials, although
several have yet to report
• In 2007, Sanofi-Aventis sold Tirapazamine to
SRI International
• It is now in trials with Cisplatin and RT in
Treating Patients With Stage IB, Stage II,
Stage III, or Stage IVA Cervical Cancer
• Importantly, it seems to work better in patients
whose tumors have a high hypoxic fraction,
indicating the need for preclinical testing
WMcB2008
www.radbiol.ucla.edu
What will be the role of RT in the postgenomic era?
•
•
•
•
The pathways that are responsible for cancer are often also
the pathways responsible for treatment resistance!
Most molecular targeting agents are likely to be more
cytostatic than cytotoxic, and are unlikely to be curative on
their own.
It makes sense to use molecular targeted therapy to enhance
tumor response to conventional treatments - these will be
largely adjunctive therapies!
They are potentially very powerful, but the pathways they
target are complex
There is an urgent need to co-ordinate treatment so as
to include all the biological factors that are needed for
individualization.
WMcB2008
www.radbiol.ucla.edu
Molecular Profiling
- Proteomics
TMA, SELDI,
MALDI, Immuno
Prognosis
- Genomics
microarrays, SNP
- Epigenomics
Critical Target
Identification
Diagnosis
Molecular Imaging
- Spread
- Metabolism
- Hypoxia
- Proliferation
- Vascularity
Treatment Decision
Treatment Validation
Data
Analysis
Biostatistics
www.radbiol.ucla.edu
Bioinformatics
-Pathway usage
-Biomarker
identification
Molecular Imaging
- Spread
- Metabolism
- Hypoxia
- Proliferation
- Vascularity
Monitoring
Response
Assessment
Biomarker validation
Phosphoprofiling
Repair
Cell cycle
Survival
Angiogenesis
WMcB2008
Questions:
Biologic Modulation of Radiation Delivery
WMcB2008
www.radbiol.ucla.edu
Which of the following has shown Phase III
efficacy in combination with RT.
1. Trastuzumab
2. Gefitinib
3. Bortezomib
4. Cetuximab
5. Avastin
WMcB2008
www.radbiol.ucla.edu
Trastuzumab is a monoclonal antibody that
targets
1. EGFR
2. Her2neu
3. NF-kB
4. TP53
WMcB2008
www.radbiol.ucla.edu
Which of the following has proven to be the
best marker for response to EGFR inhibitors
1. EGFR levels assessed pre-treatment by
immunohistochemistry
2. Acneiform rash during therapy
3. Inhibition of MAP kinase activity in tumor
biopsy during therapy
4. PTEN status
WMcB2008
www.radbiol.ucla.edu
The response to the EGFR inhibitor
Panitumumab in metastatic colorectal
cancer correlates with
1. PTEN loss
2. EGFR over expression
3. Ras mutation
4. TP53 mutation
WMcB2008
www.radbiol.ucla.edu
Bevacizumab is a first-line treatment for patients with
1. Metastatic carcinoma of the colon or rectum in
combination with intravenous 5-FU-based
chemotherapy
2. Glioblastoma in combination with temozolomide
and RT
3. HNSCC with chemoradiation therapy
4. Multiple myeloma that have failed other forms of
therapy
WMcB2008
www.radbiol.ucla.edu
Bortezomib (Velcade) is approved in the US
for the treatment of patients with multiple
myeloma. It targets
1. CD20
2. EGFR
3. Proteasomes
4. VEGF
WMcB2008
www.radbiol.ucla.edu
Answers
1.
2.
3.
4.
5.
6.
7.
NA
4
2
2
3
1
3
WMcB2008
www.radbiol.ucla.edu