Biologic Targeting in RT Bill Mc. Bride Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles, Ca. wmcbride@mednet. ucla. edu WMc. B 2008 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 WMc. B 2008 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? WMc. B 2008 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 WMc. B 2008
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. 2 Gy 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 WMc. B 2008 www. radbiol. ucla. edu
Oncogenes and Radiation Resistancy Surviving fraction 1 ras + myc 0 4 Dose (Gy) 6 8 10 S. F. 0. 1 0. 01 myc (from Mc. Kenna et al, 1990) 2 bcr-abl v-fes c-myc Ha-ras Rat -1/v-mos wt-ras Rat -1 Dose (Gy) 1 0 2 4 Dose (Gy) 6 8 10 S. F. 0. 1 c- myc v-abl 0. 01 Rat -1 c-myc +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 required WMc. B 2008 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 Mc. Bride, W. H. and G. J. Dougherty, Nature Medicine, 1995. 1(11): 1215 -1217 WMc. B 2008 www. radbiol. ucla. edu
A Large Number of Small Molecule Kinase Inhibitors have been Developed (FDA-approved) Imatinib (Gleevec) Bcr-Abl, c-kit, PDGFR- CML, GIST Bcr-Abl, c-kit, PDGFR- Gefitinib (Iressa) EGFR NSLC Erlotinib (Tarceva) EGFR NSLC, mesothelioma Bortezomib (Velcade) Proteasome Multiple myeloma Sorafenib (Nexavar) c-Raf, BRA, Kit, EGFR, m. RCC FLT-3, VEGFR, PDGFR-β Sunitinib (Sutent) Multiple RTKs, VEGF, PDGF GIST and m. RCC Dasatinib (Sprycel) BCR-ABL, SRC family, CML and Ph+ ALL c-KIT, EPHA-2, PDGFR-β 80%-CML, 54% GIST 10% respond Median survival 6. 7 months 1 year 23% of patients PFS longer GIST: 25. 5% MRCC: 36. 5% In trials WMc. B 2008 www. radbiol. ucla. edu
A Large Number of Monoclonal Antibodies that inhibit Signaling Pathways are Available (FDA-approved) Bevacizumab (Avastin) VEGF Alemtuzumab (Campath) CD 52 Cetuximab (Erbitux) EGFR (HER-1) Trastuzumab (Herceptin) HER 2 Tositumomab (Bexxar) CD 20 Rituximab (Rituxan) CD 20 Ibritumomab tiuxetan (Zevalin) CD 20 Gemtuzumab (Mylotarg) CD 33 Panitumumab(Vectibix) EGFR CRC B-cell CLL CRC, pancreatic Ca Breast cancer NHL, CLL, MM, HCL NHL AML m. CRC 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 WMc. B 2008 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)! WMc. B 2008 www. radbiol. ucla. edu
Robert et al. , J. Clin Oncol 19: 3234 -3243, 2001 13 CR and 2 PR 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. WMc. B 2008 www. radbiol. ucla. edu
EGFR (Erb. B-1) Also Erb. B-2, 3, 4 EGF/TGF-a The Pathways Glucose Amino acids ATP GLUT 1 sos Grb 2 GDP P SH 2 PI-3 K P SH 2 Ras Raf-1 PIP 3 SH 3 P 110 P PIP 2 P sos x GTP P PH P Glucose Akt PKA PTEN Glucose-6 -P PIP 2 PIP 3 LKB 1 Glycolysis , , d AMPK p 110 g MEK ERK 1 ERK 2 Src MAPK/ERK sign ling Multiple downstream targets SH 2 SH 3 PH binds phosphotyrosine residues P P P MDM 2 NF-k. B BAD P FKHD P GSK 3 P m. TOR p 27 Fas. L p 53 cell death/survival cell cycle arrest/progression DNA repair/misrepair cell metabolism binds proline-rich sequences binds lipid ligands (products of PI-3 K) www. radbiol. ucla. edu WMc. B 2008
EGFR Targeting Agents in the Clinic • Monoclonal antibodies • • Cetuximab (Erbitux) chimeric Ig. G 1 Panitumumab humanized Ig. G 2 a Matuzumab (discontinued) Trastuzumab (Herceptin directed to Her 2/neu; Erb. B-2) • Small molecule TK inhibitors • • • Gefitinib (Iressa) Tarceva (Erlotinib) PKI-166 (Erb. B-1 and -2) Lapatinib (Erb. B-1 and -2) EKB-569 (Erb. B-1, -2, -4) CI-1033 (Erb. B-1, -2, -4) • Antisense oligonucleotides • Dominant negative truncated receptor gene therapy WMc. B 2008 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 WMc. B 2008 www. radbiol. ucla. edu
Preclinical Data: Cetuximab potentiates RT against tumor growth in mice Control C 225 x 1 C 225 x 3 14 18 Gy + C 225 x 1 Tumor Size (mm) 12 10 18 Gy + C 225 x 3 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) WMc. B 2008
Mechanisms of Action of EGFR Inhibition with RT • • • Blocks ligand binding (Mo. Ab) 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 (Mo. Ab) WMc. B 2008 www. radbiol. ucla. edu
There are lots of clinical trials ongoing, planned, or closed like these two More toxicity with IMRT than non-IMRT WMc. B 2008 www. radbiol. ucla. edu
PI 3 K 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 PI 3 K inhibitors in Phase I/II trials and 10 m. TOR inhibitors WMc. B 2008 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 WMc. B 2008 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 WMc. B 2008
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 Meyerson 1, 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. WMc. B 2008 www. radbiol. ucla. edu
EGFR (Erb. B-1) Also Erb. B-2, 3, 4 EGF/TGF-a ATP Mutant EGFR Mutant PI-3 K Bypass Mutations Why may they Fail? PTEN loss Glucose Amino acids Mutant AKT GLUT 1 sos Mutant Ras Grb 2 GDP P SH 2 PI-3 K P SH 2 Ras Raf-1 PIP 3 SH 3 P 110 P PIP 2 P sos x GTP P PH P PTEN Glucose Akt PKA Glucose-6 -P PIP 2 PIP 3 LKB 1 Glycolysis , , d AMPK p 110 g MEK ERK 1 ERK 2 Src MAPK/ERK sign ling Multiple downstream targets SH 2 SH 3 PH Mutant Src binds phosphotyrosine residues Mutant mdm 2 Mutant p 53 P P P MDM 2 NF-k. B BAD P FKHD P GSK 3 P m. TOR p 27 Fas. L p 53 cell death/survival cell cycle arrest/progression DNA repair/misrepair cell metabolism binds proline-rich sequences binds lipid ligands (products of PI-3 K) www. radbiol. ucla. edu WMc. B 2008
Panitumumab in m. CRC Radiological Response mt KRAS + pan wt KRAS + pan PFS mutant KRAS Pantumumab mt KRAS + BSC PFS wt KRAS Pantumumab Amado, R. G. et al. J Clin Oncol; 26: 1626 -1634 2008 www. radbiol. ucla. edu wt KRAS + BSC Overall Survival WMc. B 2008
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 WMc. B 2008 www. radbiol. ucla. edu
NF-k. B (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 WMc. B 2008 www. radbiol. ucla. edu
Ligands Signal Transduction TNF- ras IL-1 Raf Effectors Possible Outcomes Akt TRAF VEGF MEKK 1 IKK b. FGF Angiogenesis Ik. B TNF- Inflammation Radioprotection IL-6 TGF- ERK JNK p 38 NF- B IL-1 IL-8 HIF-1 AP 1 Elk 1/c. EBP IL-6 IFN-g HRE NF-IL-6 CRE NF-k. B TGF- b. FGF MMP Invasion VEGF PPAR g d Proliferation EGF Bcl-2 Erb. B 2 IAP Hypoxia PLA-A 2 5, 12, 15 LOX COX-2 Arachidonic Acid LTA 4 B 4 C 4 www. radbiol. ucla. edu PGH 2 Survival (survivin) PGD 2 PGE 2 PGF 2 PGI 2 PGJ 2 TBX Transformation Immunity WMc. B 2008
COX Inhibitors • Non-selective COX I and 2 inhibitors – NSAIDs - aspirin, ibuprofen, indomethacin • Selective COX 2 inhibitors – celecoxib, rofecoxib, meloxicam, NS-398, etc Note: Anti-tumor action of celecoxib may not be solely through COX 2 inhibition WMc. B 2008 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 WMc. B 2008 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 WMc. B 2008 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 VEGF positive Mean microvessel counts (200 x) 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. WMc. B 2008 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% WMc. B 2008 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. WMc. B 2008 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 WMc. B 2008 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 WMc. B 2008 www. radbiol. ucla. edu
Radiosensitization by Ad-p 53 Ad. Vluc+Irrad. 1. 4 1. 00 SKOV S. F. Ad. Vp 53 control Tumor 1. 2 Diameter (cm) 1. 0 0. 8 0. 10 0. 6 SKOV/P 53 0. 4 Ad. Vp 53 +irr. 0. 2 irrad. xxx 0. 01 0 2 DOSE (Gy) In Vitro www. radbiol. ucla. edu 4 0 10 20 30 40 50 Time (days) In Vivo WMc. B 2008
• Current approaches to overcoming vector limitations are unlikely to greatly improve the situation • Replicating adenoviruses • Tissue specific/ hypoxia-induced/radiationinduced promoters WMc. B 2008 www. radbiol. ucla. edu
Exploiting Low Tumor Oxygenation with Hypoxic Cytotoxins WMc. B 2008 www. radbiol. ucla. edu
Mechanism of Hypoxic Cytotoxicity of Tirapazamine O N N O . O 2 2 O N N NH O + 2 1 e + H Reductase N Hypoxia N NH 2 * * OH * TPZ M. Brown www. radbiol. ucla. edu TPZ Radical WMc. B 2008
Tirapazamine is Toxic for Hypoxic Cells in vitro 0 10 Surviving Fraction -1 10 HCR = 300 -2 10 -3 10 air hypoxia -4 10 -5 10 100 10000 Tirapazamine Conc ( M) M. Brown www. radbiol. ucla. edu WMc. B 2008
Tirapazamine showed Promise when Combined with XRT or Chemotherapy in Phase I/II Trials Lung Cancer Cervix Cancer Head & Neck Cancer WMc. B 2008 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 WMc. B 2008 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. WMc. B 2008 www. radbiol. ucla. edu
Molecular Profiling - Proteomics TMA, SELDI, MALDI, Immuno - Genomics microarrays, SNP - Epigenomics Prognosis 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 WMc. B 2008
Questions: Biologic Modulation of Radiation Delivery WMc. B 2008 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 WMc. B 2008 www. radbiol. ucla. edu
Trastuzumab is a monoclonal antibody that targets 1. EGFR 2. Her 2 neu 3. NF-k. B 4. TP 53 WMc. B 2008 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 WMc. B 2008 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. TP 53 mutation WMc. B 2008 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 WMc. B 2008 www. radbiol. ucla. edu
Bortezomib (Velcade) is approved in the US for the treatment of patients with multiple myeloma. It targets 1. CD 20 2. EGFR 3. Proteasomes 4. VEGF WMc. B 2008 www. radbiol. ucla. edu
Answers 1. 2. 3. 4. 5. 6. 7. NA 4 2 2 3 1 3 WMc. B 2008 www. radbiol. ucla. edu
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