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WMcB2008 Biologic Targeting in RT Bill McBride Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles, Ca.

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Presentation on theme: "WMcB2008 Biologic Targeting in RT Bill McBride Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles, Ca."— Presentation transcript:

1 WMcB2008 Biologic Targeting in RT Bill McBride Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles, Ca.

2 WMcB2008 Objectives Understand the relationship between molecular carcinogenesis and radiation responseUnderstand the relationship between molecular carcinogenesis and radiation response Know how to target receptor tyrosine kinasesKnow how to target receptor tyrosine kinases Know what agents are in clinical trials and the molecules they targetKnow what agents are in clinical trials and the molecules they target Know the clinical trial data on receptor targeting in combination with RTKnow the clinical trial data on receptor targeting in combination with RT Understand why some trials failUnderstand why some trials fail Know what other pathways have and are being targeted, why, and howKnow what other pathways have and are being targeted, why, and how

3 WMcB2008 Cancer Biology Tumor OncogenesTumor Oncogenes Tumor Suppressor GenesTumor Suppressor Genes Tumor MicroenvironmentTumor Microenvironment –Vasculature –Hypoxia –Metabolism –Immunity An increased therapeutic ratio can be achieved only by exploiting some difference between normal and malignant tissues Radiobiology Intrinsic Radiosensitivity Tumor Cell Proliferation Tumor Cell Death/Survival DNA Repair Differences between cancer and normal cells are knownDifferences between cancer and normal cells are known Where is the link between cancer biology and radiobiology?Where is the link between cancer biology and radiobiology?

4 WMcB2008 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)Unabated, self-sufficient growth factor signaling (overexpression of ligands or receptors) Loss of response to anti-proliferative signalsLoss of response to anti-proliferative signals Evasion of cell death programsEvasion of cell death programs Increase in replicative potential (telomeres)Increase in replicative potential (telomeres) Promotion of tissue invasion and metastasisPromotion of tissue invasion and metastasis Sustained angiogenesisSustained angiogenesis DNA repair abnormalities and genomic instabilityDNA repair abnormalities and genomic instability Overall decrease in cell loss factor and tumors grow After: Hanahan D, Weinberg RA, Cell 57-70, 2000.

5 WMcB2008 Cell Lines Vary in Intrinsic Radiosensitivity LYMPHOMANEUROBLASTOMAMYELOMA SMALL CELL LUNG CANCER MEDULLOBLASTOMA BREAST CA SCC PANCREATIC CA COLORECTAL CA NON-SMALL CELL CA MELANOMAOSTEOSARCOMAGLIOBLASTOMAHYPERNEPHROMA 0.2 ( ) 0.43 ( ) 0.52 ( ) S.F. 2Gy in vitro Correlates with histological type and in vivo curability

6 WMcB2008 Oncogenes and Radiation Resistancy Dose (Gy) S.F. Rat -1 c- myc v-abl c-myc +v-abl v-abl+ dn-myc myc ras+myc Surviving fraction Dose (Gy) (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

7 WMcB2008 Can you Predict How Mutations will Affect Response to RT? Activation of cell cycle progression and survival pathways generally increases radioresistanceActivation of cell cycle progression and survival pathways generally increases radioresistance Activation of pro-apoptotic/cell cycle arrest pathways generally radiosensitizeActivation 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 radioresistanceThe 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, (11):

8 WMcB2008 A Large Number of Small Molecule Kinase Inhibitors have been Developed (FDA-approved) Imatinib (Gleevec) Bcr-Abl, c-kit, PDGFR-  CML, GIST80%-CML, 54% GIST Gefitinib (Iressa) EGFR NSLC10% respond Erlotinib (Tarceva) EGFR NSLC, mesotheliomaMedian survival 6.7 months Bortezomib (Velcade) Proteasome Multiple myeloma1 year 23% of patients Sorafenib (Nexavar) c-Raf, BRA, Kit, EGFR, mRCC PFS longer FLT-3, VEGFR, PDGFR-β FLT-3, VEGFR, PDGFR-β Sunitinib (Sutent) Multiple RTKs, VEGF, PDGF GIST and mRCCGIST: 25.5% MRCC: 36.5% Dasatinib (Sprycel) BCR-ABL, SRC family, CML and Ph+ ALL In trials c-KIT, EPHA-2, PDGFR-β c-KIT, EPHA-2, PDGFR-β

9 WMcB2008 A Large Number of Monoclonal Antibodies that inhibit Signaling Pathways are Available (FDA-approved) Bevacizumab (Avastin)VEGFCRC5 months prolonged survival Alemtuzumab (Campath)CD52B-cell CLL 9.5 months 30% patients Cetuximab (Erbitux) EGFR (HER-1) CRC, pancreatic Ca increased response HNSCC, NSLC Trastuzumab (Herceptin)HER2Breast cancer25 months for 26% Tositumomab (Bexxar)CD20NHL57% to 71% respond Rituximab (Rituxan)CD20NHL, CLL,MM, HCL3 months in 45% of patients Ibritumomab tiuxetan (Zevalin) CD20NHL 80% respond Gemtuzumab (Mylotarg)CD33AML 6 months 30% of patients Panitumumab(Vectibix)EGFRmCRC PFS 96 days Bevacizumab, cetuximab, and panitumumab each cost about $100,000/ patient.yr

10 WMcB2008 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.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 !!To cure cancer, you need to kill all the cancer cells !! I t makes sense to use molecular targeted therapy to enhance tumor response to RT (and vice-versa)!I t makes sense to use molecular targeted therapy to enhance tumor response to RT (and vice-versa)!

11 WMcB2008 Volume 354: February 9, 2006Volume 354: 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. Robert et al., J. Clin Oncol 19: , CR and 2PR of 15 evaluable advanced HNSCC cases receiving Cetuximab plus RT

12 WMcB2008 P P P110 SH2 SH2 SH3 P PIP2 PIP3 PH cell death/survival cell cycle arrest/progression DNA repair/misrepair Akt FKHD p27FasL SH3 binds proline-rich sequences PH binds lipid ligands (products of PI-3K) SH2 binds phosphotyrosine residues sos Ras ERK1ERK2 MEK Raf-1 P P Src Grb2 PI-3K GDP GTP MAPK/ERK sign  PTEN PIP2PIP3 MDM2 NF-kB BAD GSK3  mTORP P PP PP p53 cell metabolism Glucose Amino acids PKA LKB1 AMPK GLUT1 Glucose Glucose-6-P GlycolysisP x ATP EGF/TGF-  EGFR (ErbB-1) Also ErbB-2, 3, 4 Multipledownstreamtargets The Pathways  p110 

13 WMcB2008 EGFR Targeting Agents in the Clinic Monoclonal antibodiesMonoclonal antibodies Cetuximab (Erbitux) chimeric IgG1Cetuximab (Erbitux) chimeric IgG1 Panitumumab humanized IgG2aPanitumumab humanized IgG2a Matuzumab (discontinued)Matuzumab (discontinued) Trastuzumab (Herceptin directed to Her2/neu; ErbB-2)Trastuzumab (Herceptin directed to Her2/neu; ErbB-2) Small molecule TK inhibitorsSmall molecule TK inhibitors Gefitinib (Iressa)Gefitinib (Iressa) Tarceva (Erlotinib)Tarceva (Erlotinib) PKI-166 (ErbB-1 and -2)PKI-166 (ErbB-1 and -2) Lapatinib (ErbB-1 and -2)Lapatinib (ErbB-1 and -2) EKB-569 (ErbB-1, -2, -4)EKB-569 (ErbB-1, -2, -4) CI-1033 (ErbB-1, -2, -4)CI-1033 (ErbB-1, -2, -4) Antisense oligonucleotidesAntisense oligonucleotides Dominant negative truncated receptor gene therapyDominant negative truncated receptor gene therapy

14 WMcB2008 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

15 WMcB2008 Preclinical Data: Cetuximab potentiates RT against tumor growth in mice Tumor Size (mm) Control C225 x1 C225 x1 C225 x3 C225 x3 18 Gy 18 Gy + C225 x1 C225 x1 18 Gy + C225 x3 Days Int J Radiat Oncol Biol Phys 51: 474, 2001 Clin Cancer Res 6: 701, 2000 (Huang and Harari, 2000)

16 WMcB2008 Mechanisms of Action of EGFR Inhibition with RT Blocks ligand binding (MoAb)Blocks ligand binding (MoAb) Prevents EGFR phosphorylation and downstream signalingPrevents EGFR phosphorylation and downstream signaling Decreases DNA repair after irradiationDecreases DNA repair after irradiation –EGFR nuclear translocation –Binds to and blocks DNA-Pk? Increases radiation-induced apoptosisIncreases radiation-induced apoptosis Cell cycle effectsCell cycle effects Decreases tumor cell proliferationDecreases tumor cell proliferation –accelerated repopulation? Improves reoxygenationImproves reoxygenation Blocks angiogenesisBlocks angiogenesis –Inhibit VEGF and radiosensitizes vasculature? Inhibition of tumor cell invasion and metastasisInhibition of tumor cell invasion and metastasis Kills tumor cells through antibody-dependent cellular cytotoxicity (MoAb)Kills tumor cells through antibody-dependent cellular cytotoxicity (MoAb)

17 WMcB2008 There are lots of clinical trials ongoing, planned, or closed like these two More toxicity with IMRT than non-IMRT

18 WMcB2008 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

19 WMcB2008 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: , Only 5% pathological CR Rodel, C. et al., Multicenter phase II trial of chemoradiation with oxiplatin for rectal cancer. J. Clin Oncol 25: , Only 9% pathological CR But not all trials are successful!

20 WMcB2008 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

21 WMcB2008 EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib (Iressa) Therapy SCIENCE VOL 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 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.

22 WMcB2008 P P P110 SH2 SH2 SH3 P PIP2 PIP3 PH cell death/survival cell cycle arrest/progression DNA repair/misrepair Akt FKHD p27FasL SH3 binds proline-rich sequences PH binds lipid ligands (products of PI-3K) SH2 binds phosphotyrosine residues sos Ras ERK1ERK2 MEK Raf-1 P P Src Grb2 PI-3K GDP GTP MAPK/ERK sign  PTEN PIP2PIP3 MDM2 NF-kB BAD GSK3  mTORP P PP PP p53 cell metabolism Glucose Amino acids PKA LKB1 AMPK GLUT1 Glucose Glucose-6-P GlycolysisP x ATP EGF/TGF-  EGFR (ErbB-1) Also ErbB-2, 3, 4 Multipledownstreamtargets Bypass Mutations  p110  Mutant Ras Mutant PI-3KPTEN lossMutant AKT Mutant EGFR Mutant Src Mutant p53 Mutant mdm2 Why may they Fail?

23 WMcB2008 Amado, R. G. et al. J Clin Oncol; 26: Panitumumab in mCRC PFS mutant KRAS Pantumumab PFS wt KRAS Pantumumab mt KRAS + pan Radiological Response wt KRAS + pan wt KRAS + BSCmt KRAS + BSC Overall Survival

24 WMcB2008 FDA Statement on Iressa [12/17/04] FDA today released the following statement regarding the failure of a clinical trial of Iressa (gefitinib) to show an overall survival advantage in treating patients with lung cancer: The FDA learned from AstraZeneca that a large clinical trial comparing Iressa (gefitinib) with placebo in patients with non-small cell lung cancer who had failed other courses of cancer therapy showed no survival benefit from taking Iressa. Patients currently taking Iressa should consult with their physicians as soon as possible; patients should not change their therapy without first consulting with their physicians. Alternative therapies are available. FDA has approved Taxotere (docetaxel) and Tarceva (erlotinib), both of which have been shown in studies to improve survival in patients with non-small cell lung cancer whose cancer has progressed while on previous therapies. …Iressa was approved because the data from clinical trials showed that it caused significant shrinkage in tumors in about 10% of patients, and this was thought likely to increase patients' overall survival time. … After the approval of Iressa in 2003, AstraZeneca conducted a study in approximately 1700 patients. …After FDA has evaluated the recent study results, FDA will determine whether Iressa should be withdrawn from the market or if other regulatory actions are appropriate. [6/2005] FDA has approved new labeling for Iressa that states the medicine should be used only in cancer patients who have already taken the medicine and whose doctor believes it is helping them. New patients should not be given Iressa because in a large study Iressa did not make people live longer. There are other medicines for non-small cell lung cancer (NSCLC) that have shown an ability to make people live longer.

25 WMcB2008 Why may they fail? Bypass Pathways Operate Downstream Need to define the critical vertical and horizontal pathways that might intersect to bypass efficacy.Need to define the critical vertical and horizontal pathways that might intersect to bypass efficacy. Downstream pathways such asDownstream pathways such as –Ras –Src –PI-3Kinase –PTEN –Akt

26 WMcB2008 One of the most commonly mutated genes G12V and Q61L are both involved in GTP binding Both mutations stabilize the GTP-bound form of Ras Both result in constitutive MAPK signaling G12V ED Q61L 32 CAAX Box (prenylation) HVR 40 GTPase GTP binding ERK1ERK2 MEK SrcP EGFR sos Ras Raf-1 P Grb2 GDP GTPP x ERK1ERK2 MEK Downstream Mutations: Ras Tethers Ras to membrane Farnesyl Transferase Inhibitors

27 WMcB2008 Why may they fail? Poor targets? Superior targets are probablySuperior 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.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.A mutation, rather than an overexpressed normal protein. Don’t forget the pharmacokinetics/pharmacodynamicsDon’t forget the pharmacokinetics/pharmacodynamics

28 WMcB2008 NF-kB (nuclear factor that acts on B elements) Central role in inflammation and immunityCentral role in inflammation and immunity Virchow (1863) first proposed that chronic irritation was the cause of cancerVirchow (1863) first proposed that chronic irritation was the cause of cancer Inflammatory cytokines activate ROS production leading to DNA damage, genomic instability, and cancerInflammatory cytokines activate ROS production leading to DNA damage, genomic instability, and cancer NF-  B is activated which transcribes anti-apoptotic factorsNF-  B is activated which transcribes anti-apoptotic factors inhibitors of apoptosis (IAPs) like survivin, Bcl-XL, etcinhibitors of apoptosis (IAPs) like survivin, Bcl-XL, etc NF-  B is induced by doses of radiation in the higher dose rangeNF-  B is induced by doses of radiation in the higher dose range The majority of cancers have high NF-  B levelsThe majority of cancers have high NF-  B levels

29 WMcB2008 Ligands TNF-  IL-1  IL-6 TGF-  IL-8 IFN-  bFGFVEGFEGFErbB2Hypoxia Signal Transduction ras Akt TRAF ras Akt TRAF Raf MEKK1 IKK IkB  IkB  ERK JNK p38 NF-  B HIF-1 AP1 Elk1/cEBP HRE NF-IL-6 CRE NF-kB EffectorsVEGFbFGF TNF-  IL-1  IL-6 TGF-  MMP PPAR  Bcl-2IAP(survivin) Possible Outcomes AngiogenesisInflammationRadioprotectionInvasionProliferationSurvival Transformation Transformation Immunity Immunity Arachidonic PGH2PGD2 AcidPGE2 PGF2PGI2PGJ2TBX LTA4 B4 C4 COX-2 PLA-A2 5,12,15LOX

30 WMcB2008 Responsible for conversion of arachadonic acid to prostaglandins and other eicosanoidsResponsible for conversion of arachadonic acid to prostaglandins and other eicosanoids Role in inflammation, tumor progression, angiogenesis, metastasisRole in inflammation, tumor progression, angiogenesis, metastasis Overexpressed in many cancers: HNSCC, breast, prostate, cervix, bladder, liver, etc.Overexpressed in many cancers: HNSCC, breast, prostate, cervix, bladder, liver, etc. Epidemiological data suggest that NSAIDs and selective COX-2 inhibitors might prevent the development of cancers, including colorectal, oesophageal and lung cancer.Epidemiological data suggest that NSAIDs and selective COX-2 inhibitors might prevent the development of cancers, including colorectal, oesophageal and lung cancer. Selective COX-2 inhibitors enhances tumor response to radiation and chemotherapeutic agentsSelective COX-2 inhibitors enhances tumor response to radiation and chemotherapeutic agents In prostate Ca, independent predictor of distant metastasis and treatment failure. Khor et al Lancet Oncol 8: , 2007In prostate Ca, independent predictor of distant metastasis and treatment failure. Khor et al Lancet Oncol 8: , 2007 In CRC it is less clear but a high level after preoperative RT has been found and associated with distant metastases and poor prognosis. De Heer et al. Clin Cancer Res 13, 2955, 2007In CRC it is less clear but a high level after preoperative RT has been found and associated with distant metastases and poor prognosis. De Heer et al. Clin Cancer Res 13, 2955, 2007 COX-2

31 WMcB2008 COX-2 High expression COX-2 Low expression p value = Overall survival curves of 37 stage IV NPC patients receiving radiotherapy, as a function of COX-2 expression COX-2 Photomicrograph of the undifferentiated carcinoma (WHO type 3) of nasopharynx showing strongly expression of immunoreactively for COX-2 (ABC method X 400). The cells show strongly positive in cytoplasm and surround the nucleus membrane. Chen, W.C. et al. Prediction of poor survival by cyclooxygenase-2 in patients with T4 nasopharyngeal cancer treated by radiation therapy: clinical and in vitro studies. Head Neck, (6):

32 WMcB2008 COX Inhibitors Non-selective COX I and 2 inhibitorsNon-selective COX I and 2 inhibitors –NSAIDs - aspirin, ibuprofen, indomethacin - Selective COX2 inhibitorsSelective COX2 inhibitors –celecoxib, rofecoxib, meloxicam, NS-398, etc Note: Anti-tumor action of celecoxib may not be solely through COX2 inhibition

33 WMcB2008 Tumor Vasculature as a Therapeutic Target Vascular targetingVascular 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-angiogenesisAnti-angiogenesis –Preventing the growth of new tumor-associated blood vessels –Chronic treatment Blood vessel

34 WMcB2008 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 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 issueSince 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 emergeSince endothelial cells are genetically stable and non- transformed, treatment related resistance is less likely to emerge

35 WMcB2008 VEGF is a major angiogenic factorVEGF is a major angiogenic factor There is a correlation between VEGF expression in tumor tissue and microvessel counts, which generally results in poorer survivalThere 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: VEGF positive VEGF negative Mean microvessel counts (200x) 102.9*66.8 VEGF

36 WMcB2008 Bevacizumab (Avastin) Monoclonal anti-VEGFMonoclonal 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.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.Randomized, phase III trial, with previously untreated metastatic colorectal cancer. –bolus-IFL plus placebo – O.S months, PFS 6.4 months –bolus-IFL plus bevacizumab – O.S 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%

37 WMcB2008 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.

38 WMcB2008 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 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, Bevacizumab (Avastin)

39 WMcB2008 Higher VEGF protein expression has been associated with poorer survival Reference: 1. Yuan A, Yu CJ, Chen WJ, et al. Int J Cancer Pred Oncol. 2000;89:

40 WMcB2008 Targeting Loss of Function Tumor Suppressor Genes Is tougher than targeting oncogenes Replacement Gene therapyReplacement 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 mutationTargets downstream of the mutation –E.g. Akt in PTEN deficient tumors –But it is divorced from the real target

41 WMcB2008 AdV-  -galactosidase Injection into Melanoma Tumor: day 2

42 WMcB2008 Radiosensitization by Ad-p53 S.F DOSE (Gy) SKOV SKOV/P Time (days) Tumor TumorDiameter (cm) (cm) control AdVp53 AdVluc+Irrad. AdVp53+irr. irrad. xxx xxx irrad. In Vitro In Vivo

43 WMcB2008 Current approaches to overcoming vector limitations are unlikely to greatly improve the situationCurrent approaches to overcoming vector limitations are unlikely to greatly improve the situation Replicating adenovirusesReplicating adenoviruses Tissue specific/ hypoxia-induced/radiation- induced promotersTissue specific/ hypoxia-induced/radiation- induced promoters

44 WMcB2008 Exploiting Low Tumor Oxygenation with Hypoxic Cytotoxins

45 WMcB2008 Mechanism of Hypoxic Cytotoxicity of Tirapazamine 2 O N N N NH O 1 e + H - + N N N NH O OH 2 Reductase TPZ Hypoxia * * * TPZ Radical. 2 - O O 2 M. Brown

46 WMcB2008 Tirapazamine is Toxic for Hypoxic Cells in vitro Tirapazamine Conc (  M) Surviving Fraction HCR = 300 hypoxia air M. Brown

47 WMcB2008 Lung Cancer Cervix Cancer Head & Neck Cancer Tirapazamine showed Promise when Combined with XRT or Chemotherapy in Phase I/II Trials

48 WMcB2008 But failed in several Phase III trials, although several have yet to reportBut failed in several Phase III trials, although several have yet to report In 2007, Sanofi-Aventis sold Tirapazamine to SRI InternationalIn 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 CancerIt 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 testingImportantly, it seems to work better in patients whose tumors have a high hypoxic fraction, indicating the need for preclinical testing

49 WMcB2008 Capillary 150 O2O2 O2O2 O2O2 Hypoxia Causes Resistance to Radiation and Anticancer Drugs Distance from Capillary (µm). Surviving Fraction Radiation / Chem. Drug Combined Hypoxic Cytotoxin Hypoxic cytotoxins should have an at least additive effect with RT

50 WMcB2008 The pathways that are responsible for cancer are often also the pathways responsible for treatment resistance!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.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!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 complexThey 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.

51 WMcB2008 Treatment Decision Treatment Validation Molecular Imaging - Spread - Metabolism - Hypoxia - Proliferation - Vascularity Molecular Profiling - Proteomics TMA, SELDI, TMA, SELDI, MALDI, Immuno MALDI, Immuno - Genomics microarrays, SNP microarrays, SNP - Epigenomics Bioinformatics -Pathway usage -Biomarker identification identification Biomarker validation PhosphoprofilingRepair Cell cycle SurvivalAngiogenesis Molecular Imaging - Spread - Metabolism - Hypoxia - Proliferation - Vascularity Biostatistics Prognosis Diagnosis ResponseAssessment Monitoring Critical Target Identification DataAnalysis

52 WMcB2008 Prognosis Treat or not treat? Predictive Biomarkers (eg. PTEN) What Treatment? What Dose/Schedule? Pharmacodynamic Biomarkers (eg. Ki67)

53 WMcB2008 DNA copy-number assessment Comparative genome hybridization to DNA microarraysComparative genome hybridization to DNA microarrays Mutation screening DNA sequencingDNA sequencing Mass-spectrometry-based genotypingMass-spectrometry-based genotyping Mutation-specific PCRMutation-specific PCR Gene-expression profiling DNA microarraysDNA microarrays Multiplex PCRMultiplex PCR MicroRNA-expression profiling DNA microarraysDNA microarrays Multiplex PCRMultiplex PCR Proteomic profiling Mass spectrometryMass spectrometry Phosphoproteomic profiling Mass spectrometry using phospho-specific antibodiesMass spectrometry using phospho-specific antibodies Metabolomic profiling Mass spectrometryMass spectrometry

54 WMcB2008 Cy3 Cy5 labeled nucleotides Normal Tumor 40,000 probes for 20,000 genes Compare with common reference sample Tissue Microarray Defined Prognosis Classifier of <100 genes Gene Microarray

55 WMcB2008 Lung Ca 67 tumors, 56 patients Garber et al. PNAS

56 WMcB2008

57 WMcB2008 Questions: Biologic Modulation of Radiation Delivery

58 WMcB2008 Which of the following has shown Phase III efficacy in combination with RT. 1.Trastuzumab 2.Gefitinib 3.Bortezomib 4.Cetuximab 5.Avastin

59 WMcB2008 Trastuzumab is a monoclonal antibody that targets 1.EGFR 2.Her2neu 3.NF-kB 4.TP53

60 WMcB2008 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

61 WMcB2008 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

62 WMcB2008 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

63 WMcB2008 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

64 WMcB2008 Answers 1.NA


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