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Biologic Targeting in RT Bill McBride Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles, Ca. [email protected] Objectives. Understand the relationship between molecular carcinogenesis and radiation response Know how to target receptor tyrosine kinases

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Biologic Targeting in RTBill McBrideDept. Radiation OncologyDavid Geffen School MedicineUCLA, Los Angeles, [email protected]


Objectives
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


Cancer Biology

Tumor Oncogenes

Tumor Suppressor Genes

Tumor Microenvironment

Vasculature

Hypoxia

Metabolism

Immunity

Radiobiology

Intrinsic Radiosensitivity

Tumor Cell Proliferation

Tumor Cell Death/Survival

DNA Repair

An increased therapeutic ratio can be achieved only by exploiting some difference between normal and malignant tissues

  • Differences between cancer and normal cells are known

  • Where is the link between cancer biology and radiobiology?


Features of carcinogenesis
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


Cell Lines Vary in Intrinsic Radiosensitivity

S.F. 2Gy in vitro

LYMPHOMA

NEUROBLASTOMA

MYELOMA

SMALL CELL LUNG CANCER

MEDULLOBLASTOMA

BREAST CA

SCC

PANCREATIC CA

COLORECTAL CA

NON-SMALL CELL CA

MELANOMA

OSTEOSARCOMA

GLIOBLASTOMA

HYPERNEPHROMA

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


Oncogenes and radiation resistancy

0

2

4

6

8

10

Dose (Gy)

10

0

2

4

6

8

1

ras

+

myc

S.F.

bcr-abl

v-fes

c-myc

Ha-ras

Rat -1/v-mos

wt-ras

Rat -1

0.1

Surviving fraction

0.01

Dose (Gy)

1

c- myc

S.F.

v-abl

0.1

Rat -1

c-myc +v-abl

myc

0.01

v-abl+ dn-myc

Dose (Gy)

Oncogenes and Radiation Resistancy

(from McKenna et al, 1990)

  • 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 required


Can you predict how mutations will affect response to rt
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


A large number of small molecule kinase inhibitors have been developed fda approved
A Large Number of Small Molecule Kinase Inhibitors have been Developed(FDA-approved)

Imatinib (Gleevec) Bcr-Abl, c-kit, PDGFR-a CML, GIST 80%-CML, 54% GIST

Gefitinib (Iressa) EGFR NSLC 10% respond

Erlotinib (Tarceva) EGFR NSLC, mesothelioma Median survival 6.7 months

Bortezomib (Velcade) Proteasome Multiple myeloma 1 year 23% of patients

Sorafenib (Nexavar) c-Raf, BRA, Kit, EGFR,mRCC PFS longer

FLT-3, VEGFR, PDGFR-β

Sunitinib (Sutent) Multiple RTKs, VEGF, PDGF GIST and mRCC GIST: 25.5% MRCC: 36.5%

Dasatinib (Sprycel) BCR-ABL, SRC family, CML and Ph+ ALL In trials

c-KIT, EPHA-2, PDGFR-β


A large number of monoclonal antibodies that inhibit signaling pathways are available fda approved
A Large Number of Monoclonal Antibodies that inhibit Signaling Pathways are Available(FDA-approved)

Bevacizumab (Avastin) VEGF CRC 5 months prolonged survival

Alemtuzumab (Campath) CD52 B-cell CLL 9.5 months 30% patients

Cetuximab (Erbitux) EGFR (HER-1) CRC, pancreatic Ca increased response HNSCC, NSLC

Trastuzumab (Herceptin) HER2 Breast cancer 25 months for 26%

Tositumomab (Bexxar) CD20 NHL 57% to 71% respond

Rituximab (Rituxan) CD20 NHL, CLL,MM, HCL 3 months in 45% of patients

Ibritumomab tiuxetan (Zevalin) CD20 NHL 80% respond

Gemtuzumab (Mylotarg) CD33 AML 6 months 30% of patients

Panitumumab(Vectibix) EGFR mCRC PFS 96 days

Bevacizumab, cetuximab, and panitumumab each cost about $100,000/ patient.yr


Where is molecular targeting going
Where is Molecular Targeting Going? Signaling Pathways are Available

  • 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)!


Robert et al., J. Clin Oncol 19:3234-3243, 2001 Signaling Pathways are Available

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.


The pathways

P Signaling Pathways are Available

PTEN

P

P

P

P

P

P

P

binds phosphotyrosine residues

SH2

SH3

binds proline-rich sequences

binds lipid ligands (products of PI-3K)

PH

EGFR (ErbB-1)

Also ErbB-2, 3, 4

EGF/TGF-a

The Pathways

ATP

Glucose

Amino acids

GLUT1

PIP2

PIP3

P

P

sos

Akt

Glucose

Glucose-6-P

Glycolysis

SH3

PH

PKA

PI-3K

Grb2

P

SH2

P

GDP

sos

SH2

x

PIP2

PIP3

LKB1

Ras

GTP

P110

a, b, d

Raf-1

AMPK

p110g

MEK

ERK1

ERK2

Src

MAPK/ERK signaling

BAD

NF-kB

FKHD

GSK3

MDM2

mTOR

Multiple

downstream

targets

p27

FasL

p53

cell death/survival

cell cycle arrest/progression

DNA repair/misrepair

cell metabolism


Egfr targeting agents in the clinic
EGFR Targeting Agents in the Clinic Signaling Pathways are Available

  • 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


Egfr targeting rationale
EGFR Targeting: Rationale Signaling Pathways are Available

  • 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


Preclinical data cetuximab potentiates rt against tumor growth in mice
Preclinical Data: Cetuximab potentiates RT against tumor growth in mice

Control

C225 x1

C225 x3

18 Gy

1

4

18 Gy +

C225 x1

1

2

1

0

18 Gy +

C225 x3

Tumor Size (mm)

8

6

4

0

4

8

1

2

1

6

2

0

2

4

2

8

3

2

3

6

4

0

4

4

4

8

5

2

5

6

Days

Clin Cancer Res 6: 701, 2000

(Huang and Harari, 2000)

Int J Radiat Oncol Biol Phys 51: 474, 2001


Mechanisms of action of egfr inhibition with rt
Mechanisms of Action of EGFR Inhibition with RT growth in mice

  • 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)


There are lots of clinical trials ongoing planned or closed like these two
There are growth in micelots of clinical trials ongoing, planned, or closed like these two

More toxicity with IMRT than non-IMRT


Pi3k inhibitors in the clinic
PI3K Inhibitors in the Clinic growth in mice

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


But not all trials are successful
But not all trials are successful! growth in mice

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


Why may they fail
Why may they fail? growth in mice

  • 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


EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib (Iressa) TherapySCIENCE 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.


Bypass mutations

P Response to Gefitinib (Iressa) Therapy

PTEN

P

P

P

P

P

P

P

binds phosphotyrosine residues

SH2

SH3

binds proline-rich sequences

binds lipid ligands (products of PI-3K)

PH

Why may they Fail?

EGFR (ErbB-1)

Also ErbB-2, 3, 4

EGF/TGF-a

Bypass Mutations

ATP

Mutant EGFR

Glucose

Amino acids

Mutant PI-3K

PTEN loss

Mutant AKT

GLUT1

PIP2

PIP3

P

P

sos

Glucose

Glucose-6-P

Glycolysis

SH3

PH

Akt

Mutant Ras

PKA

PI-3K

Grb2

P

SH2

P

GDP

sos

SH2

x

PIP2

PIP3

LKB1

Ras

GTP

P110

a, b, d

Raf-1

AMPK

p110g

MEK

ERK1

ERK2

Src

MAPK/ERK signaling

Mutant mdm2

BAD

NF-kB

FKHD

GSK3

MDM2

mTOR

Multiple

downstream

targets

Mutant Src

p27

FasL

p53

Mutant p53

cell death/survival

cell cycle arrest/progression

DNA repair/misrepair

cell metabolism


Panitumumab in mcrc

Radiological Response Response to Gefitinib (Iressa) Therapy

mt KRAS + pan

wt KRAS + pan

PFS mutant KRAS

Pantumumab

PFS wt KRAS

Pantumumab

mt KRAS + BSC

wt KRAS + BSC

Panitumumab in mCRC

Overall Survival

Amado, R. G. et al. J Clin Oncol; 26:1626-1634 2008


Why may they fail poor targets
Why may they fail? Response to Gefitinib (Iressa) TherapyPoor 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


Nf kb nuclear factor that acts on b elements
NF-kB (nuclear factor that acts on B elements) Response to Gefitinib (Iressa) Therapy

  • 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-kB levels


Possible Outcomes Response to Gefitinib (Iressa) Therapy

Angiogenesis

Inflammation

Radioprotection

Invasion

Proliferation

Survival

Transformation

Immunity

Ligands

TNF-a

IL-1 a/b

IL-6

TGF-b

IL-8

IFN-g

bFGF

VEGF

EGF

ErbB2

Hypoxia

Signal Transduction

ras Akt TRAF

Raf MEKK1 IKK

IkB 

ERK JNK p38 NF-B

HIF-1 AP1 Elk1/cEBP

HRE NF-IL-6 CRE NF-kB

Effectors

VEGF

bFGF

TNF-a

IL-1 a/b

IL-6

TGF-b

MMP

PPAR g/d

Bcl-2

IAP

(survivin)

COX-2

PLA-A2

Arachidonic PGH2 PGD2

Acid PGE2

PGF2

PGI2

PGJ2

TBX

5,12,15

LOX

LTA4

B4 C4


Cox inhibitors
COX Inhibitors Response to Gefitinib (Iressa) Therapy

  • 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


Tumor vasculature as a therapeutic target
Tumor Vasculature as a Therapeutic Target Response to Gefitinib (Iressa) Therapy

  • Vascular targeting

    • 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

Blood vessel


Advantages of vascular targeting
Advantages of Vascular Targeting Response to Gefitinib (Iressa) Therapy

  • 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 non-transformed, treatment related resistance is less likely to emerge


VEGF Response to Gefitinib (Iressa) Therapy

  • 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

*P=0.01.

Imoto H, Osaki T, Taga S, et al. J Thorac Cardiovasc Surg. 1998;115:1007-1014.


Bevacizumab avastin
Bevacizumab (Avastin) Response to Gefitinib (Iressa) Therapy

  • 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%


  • 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.


Bevacizumab avastin1
Bevacizumab (Avastin) is

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


Targeting loss of function tumor suppressor genes
Targeting Loss of Function is 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


Radiosensitization by ad p53

1.4 is

1.2

1.0

0.8

0.6

0.4

0.2

0.0

0

10

20

30

40

50

Radiosensitization by Ad-p53

AdVluc+Irrad.

1.00

AdVp53

control

SKOV

Tumor

Diameter

(cm)

S.F.

0.10

SKOV/P53

AdVp53

+irr.

irrad.

irrad.

xxx

xxx

0.01

4

2

0

Time (days)

DOSE (Gy)

In Vitro

In Vivo



Exploiting low tumor oxygenation with hypoxic cytotoxins

Exploiting Low Tumor Oxygenation with Hypoxic Cytotoxins unlikely to greatly improve the situation


Mechanism of hypoxic cytotoxicity of tirapazamine

. unlikely to greatly improve the situation

O

O

2

-

2

*

Hypoxia

*

TPZ Radical

*

Mechanism of Hypoxic Cytotoxicity of Tirapazamine

O

O

N

N

N

N

-

+

NH

N

NH

N

1 e + H

2

2

Reductase

OH

O

TPZ

M. Brown


0 unlikely to greatly improve the situation

10

HCR

= 300

-1

10

-2

10

Surviving Fraction

-3

air

10

hypoxia

-4

10

-5

10

Tirapazamine Conc (M)

1

10

100

1000

10000

Tirapazamine is Toxic

for Hypoxic Cells in vitro

M. Brown


Tirapazamine showed Promise when Combined with XRT or Chemotherapy in Phase I/II Trials

Lung

Cancer

Cervix

Cancer

Head &

Neck

Cancer


  • 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


What will be the role of rt in the post genomic 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

What will be the role of RT in the post-genomic era?

There is an urgent need to co-ordinate treatment so as to include all the biological factors that are needed for individualization.


  • Molecular Profiling the pathways responsible for treatment resistance!

  • Proteomics

  • TMA, SELDI,

  • MALDI, Immuno

  • Genomics

  • microarrays, SNP

  • Epigenomics

  • Bioinformatics

  • Pathway usage

  • Biomarker

  • identification

Prognosis

Critical Target

Identification

Diagnosis

  • Molecular Imaging

  • Spread

  • Metabolism

  • Hypoxia

  • Proliferation

  • Vascularity

Treatment Decision

Treatment Validation

  • Molecular Imaging

  • Spread

  • Metabolism

  • Hypoxia

  • Proliferation

  • Vascularity

Data

Analysis

Monitoring

Biomarker validation

Phosphoprofiling

Repair

Cell cycle

Survival

Angiogenesis

Response

Assessment

Biostatistics


Questions biologic modulation of radiation delivery
Questions: the pathways responsible for treatment resistance!Biologic Modulation of Radiation Delivery


Which of the following has shown Phase III efficacy in combination with RT.

  • Trastuzumab

  • Gefitinib

  • Bortezomib

  • Cetuximab

  • Avastin


Trastuzumab is a monoclonal antibody that targets combination with RT.

  • EGFR

  • Her2neu

  • NF-kB

  • TP53


Which of the following has proven to be the best marker for response to EGFR inhibitors

  • EGFR levels assessed pre-treatment by immunohistochemistry

  • Acneiform rash during therapy

  • Inhibition of MAP kinase activity in tumor biopsy during therapy

  • PTEN status


The response to the EGFR inhibitor Panitumumab in metastatic colorectal cancer correlates with

  • PTEN loss

  • EGFR over expression

  • Ras mutation

  • TP53 mutation


Bevacizumab is a first-line treatment for patients with metastatic colorectal cancer correlates with

  • Metastatic carcinoma of the colon or rectum in combination with intravenous 5-FU-based chemotherapy

  • Glioblastoma in combination with temozolomide and RT

  • HNSCC with chemoradiation therapy

  • Multiple myeloma that have failed other forms of therapy


Bortezomib (Velcade) is approved in the US for the treatment of patients with multiple myeloma. It targets

  • CD20

  • EGFR

  • Proteasomes

  • VEGF


Answers
Answers treatment of patients with multiple myeloma. It targets

1. NA

2. 4

3. 2

4. 2

5. 3

6. 1

7. 3


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