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Tayyaba Hasan PhD
2006 Estimated US Cancer Cases*
Prostate Lung & bronchus Colon & rectum Urinary bladder Melanoma of skin Non-Hodgkin4% lymphoma Kidney Oral cavity Leukemia Pancreas All Other Sites 3% 3% 3% 2% 18% 33% 13% 10% 6% 5%
31% 12% 11% 6% 4% 4% 3% 3% 2% 2% 22% Breast Lung & bronchus Colon & rectum Uterine corpus Non-Hodgkin lymphoma Melanoma of skin Thyroid Ovary Urinary bladder Pancreas All Other Sites
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2006.
2006 Estimated US Cancer Deaths*
Lung & bronchus Colon & rectum Prostate Pancreas Leukemia Liver & intrahepatic bile duct Esophagus Non-Hodgkin lymphoma Urinary bladder Kidney All other sites
31% 10% 9% 6% 4% 4% 4% 3% 3% 3% 23%
26% 15% 10% 6% 6% 4% 3% 3% 2% 2% 23%
Lung & bronchus Breast Colon & rectum Pancreas Ovary Leukemia Non-Hodgkin lymphoma Uterine corpus Multiple myeloma Brain/ONS All other sites
ONS=Other nervous system. Source: American Cancer Society, 2006.
and End Results Program.Five-year Relative Survival (%)* during Three Time Periods By Cancer Site Site • All sites • • • • • • • • • • • Breast (female) Colon Leukemia Lung and bronchus Melanoma Non-Hodgkin lymphoma Ovary Pancreas Prostate Rectum Urinary bladder 1974-1976 50 75 50 34 12 80 47 37 3 67 49 73 1983-1985 53 78 58 41 14 85 54 41 3 75 55 78 1995-2001 65 88 64 48 15 92 60 45† 5 100 65 82 *5-year relative survival rates based on follow up of patients through 2002. . Source: Surveillance. Epidemiology. 1975-2002. 2005. National Cancer Institute. Division of Cancer Control and Population Sciences. †Recent changes in classification of ovarian cancer have affected 1995-2001 survival rates.
What does the pancreas do? Exocrine (85-90%) Endocrine (10-15%) Gray’s Anatomy of the Human Body .
clintoncc. Gray’s Anatomy of the Human Body Robbins Basic Pathology http://faculty.Gregory/default. Digestive gland that secretes digestive enzymes into the duodenum through the pancreatic duct.Exocrine Pancreas (85-90%) Exocrine glands have ducts that carry their secretions to specific locations.suny.htm .edu/faculty/Michael.
clintoncc. Glucagon The effects are opposite of insulin Raises the level of glucose in the blood Normally secreted between meals to maintain the concentration of blood.Gregory/default.com/medical.bigeye.suny.edu/faculty/Michael.htm Insulin promotes the removal of glucose from the blood for storage: glycogen (muscle. glucose NATURE REVIEWS | CANCER VOLUME 2 | DECEMBER 2002 http://faculty. liver) fats (fat cells) protein Promotes the buildup of fats and proteins and inhibits their use as an energy source.htm .Endocrine Pancreas (10-15%) Endocrine glands do not have ducts to carry secretions Islets of Langerhans Secrete insulin and glucagon Ductless Circulatory system carries their hormones to target cells http://www.
Tumors of the Pancreas – Usually Exocrine 60-70% 5-10% 10-15% No histological difference between sites Carcinoma of the head Obstructs bile duct Ulcerates duodenal mucosa Head Neck/Body 20% Tail Diffuse tumors involving entire gland Carcinoma of the tail Remains silent longer Large & widely disseminated Robbins Basic Pathology NATURE REVIEWS | CANCER VOLUME 2 | DECEMBER 2002 .
Bioch et Biophy Acta 97-101 (2005) Cancer Statistics 2006 .Adenocarcinoma of the Pancreas •Over 95% of pancreatic tumors •Average 5-year survival 5% •Extremely resistant to current therapies •Chemotherapy •Radiotherapy •15-20% eligible for surgery •Whipple (pancreaticoduodenectomy) •5-year survival 20% •Management of most patients = Palliation Robbins Basic Pathology NATURE REVIEWS CANCER VOL 2 | DECEMBER 2002 Rustgi. AK.
Mutant Kras • >90% of Panc Ca • “Rite of passage” • Autocrine EGF signaling • Increased MAPK & PI3K • Increased EGFR & ErbB2 • Increased prolif. hypermethylation •Loss of INK4A and ARF • Disrupt Rb and p53 tumor suppression pathways NATURE REVIEWS | CANCER VOLUME 2 | DECEMBER 2002 . deletion. survival. invasion Mutant CDKN2A (p16) KRAS + CDKN2A •80-95% of sporadic Panc Ca • Not seen in other tumors •Tumor-suppressor gene • “Molecular fingerprint” •Mutation.
Metastatic Pattern •Liver •Lungs •Bones •Peripancreatic nodes •Gastric nodes •Mesenteric nodes •Omental nodes •Portohepatic nodes •Spleen •Adrenal glands •Vertebral column •Transverse colon •Stomach •Extend through retroperitoneal spaces •Infiltrate adjacent nerves Robbins Basic Pathology Gray’s Anatomy of the Human Body .
Aim 3: Establish toxicology of PDT-dose in mouse models for pancreatic cancer. Aim 2: Establish biodistribution pattern of the photosensitizer in mouse models of pancreatic cancer.Aims Aim 1: Evaluate responsiveness of pancreatic cell lines to PDT and investigate PDT-based combination regimens in biologically relevant cultures. Aim 4: Determine PDT dose-response of pancreatic tumors in mouse models. Aim 5: Establish the minimum combination PDT and chemotherapy doses required to achieve optimal therapeutic outcome in mouse models Aim 6: Test combination regimen determined from Aim 5 on fresh patient tissue samples ex vivo Aim 7: Strategies for targeted-PDT?? .
. Hypothesis: PDT leads to a more cytotoxic effect than current standard chemotherapies such as Gemcitabine and 5-Fluorouracil in pancreatic cancer cells in monolayer. Three-dimensional cell cultures will provide a more biologically relevant system than monolayers to investigate the efficacy of PDT-based combination regimens.Aim 1: Evaluate responsiveness of pancreatic cell lines to PDT and investigate PDT-based combination regimens in biologically relevant cultures.
Aim 1 10 pancreatic cell lines in monolayer * .
PDT response 3 cell lines in 3D cultures Should be included as prelim data instead of as Aim I? •PS imaging •LCM •In vitro invasion & metastasis model •VEGF (?) imaging Aim 2: PDT efficacy in vivo . ALA(?) •Gemcit efficacy vs.Aim 1 PDT combined with other therapies •PDT + C225 •PDT + Gefitinib •PDT + Erlotinib •PDT + Gemcitabine 10 pancreatic cell lines in monolayer •PDT dose response •BPD vs. PDT response •5-FU efficacy vs.
Hypothesis: Discrete incubation times will lead to differences in photosensitizer localization and concentrations within the tumor compartments. . and between tumor and surrounding normal tissue.Aim 2: Establish biodistribution pattern of the photosensitizer in mouse models of pancreatic cancer.
laproscope.Aim 2 Biodistribution studies •Extraction studies (?) •Aurora (?) •Intravital fluorescence microscopy (develop an endoscopic system:CORE) •Confocal microscopy (?) Establish pancreatic cancer animal models Determine photosensitizer biodistribution and tumor to normal ratios DEPTH-SELECTIVE FIBER OPTIC PROBE FOR AURORA •Establish correlation between aurora & extraction data (CORE will generate the correlation) •Determine time-dependent compartmental distribution of PS •Determine the effect of varying initial PS dose on concentrations in the tumor and surrounding tissue Aim 3: Toxicology Studies Non-invasive PS monitoring: ultrasound. OCT? .
.targeted PDT will be different.Aim 3: Establish toxicology of PDT-dose in mouse models for pancreatic cancer Hypothesis: Maximum tolerated PDT dose between vascular.and extravascular.
DELIVERY LIGHT TOPICALLY) Toxicology •PDT total dose (light x [PS]) •Vascular-targeted PDT •Extravascular PDTC •Establish maximum tolerated PDT dose in vascular-targeted PDT •Establish maximum tolerated PDT dose in extravascular PDT Aim 4: Dose-dependent PDT efficacy . topical ?) (FOR SIMPLICITY.Aim 3 Toxicology studies Maximum Tolerated PDT Dose •Aurora-based modification of light dose to maintain constant PDT dose (1 PS dose ?) •Toxicology studies based on compartmentalization of PS •Light delivery methods (interstitial vs.
Aim 4: Determine PDT dose-response of pancreatic tumors in mouse models Hypothesis: Dose-dependent photodynamic destruction of pancreatic tumors will affect local tumor control and survival in mice. which can be monitored by PET. .
•Correlate PDT dose with tumoricidal efficacy. survival and metastases •Verify that PET can reliably measure acute treatment response •Establish a molecular imaging modality to monitor PDT response in real-time and in vivo Aim 5: Efficacy of PDT-based combination regimens .(molecular marker?) PDT tumoricidal dose response Investigate whether PDT alone upregulates any molecular pathways that are relevant with the candidates for chemotherapy agents.Aim 4 PDT Dose Response •Correlation of PET with tumor burden •PDT dose = light x [PS] (Aurora) •Monitor dose-dependent response of tumors to PDT •Acute (PET) (find out why PET might not be feasible for pancreas) •Long-term •survival •Metastases •Tumor burden •Develop a molecular imaging modality that can reliably predict treatment response.
Aim 5: Establish the minimum combination PDT and chemotherapy doses required to achieve optimal therapeutic outcome in mouse models Hypothesis: PDT-based combination regimens will provide more effective and well tolerated tumor destruction than individual monotherapies. .
Aim 5 Efficacy of combination regimen •PDT + Gemcitabine (consider whether to keep gemcitabine as combination agent considering projects should look beyond current clinical practices) & PDT + ? •Dose-dependence of combination therapy on acute tumor destruction? (PET/molecular imaging?) •Compare treatment effect of combination regimens and individual monotherapies •Acute (PET) •Molecular imaging •Long-term •survival •Metastases •Tolerance to treatment (weight loss?) Tumoricidal response of PDT-based combination regimens 1.Sequence of PDT and chemo? 2.which additional chemo agent (in addition to Gemcitabine)? 3. •Determine the most effective combination regimen in vivo •Establish the minimum dose required to achieve therapeutic efficacy? Chemo Dose Tumor Kill PDT Chemo Dose PDT Dose Aim 6: Efficacy of combination regimen in patient tissue .need to look at cellular molecules that are regulated post-PDT and find appropriate intervention mechanisms.
Aim 6: Test combination regimen determined from Aim 5 on fresh patient tissue samples ex vivo Hypothesis: Pancreatic tumor samples resected from patients are responsive to the combination regimen determined in aim 5 .
a single tissue sample will be cut into 4) •No treatment •PDT alone •Second monotherapy •Combination treatment •MTT/MTS as viability assay •Molecular markers •IHC •LCM •PCR/gene array •ELISA .Aim 6 Tumoricidal response of PDT-based combination regimens What is size of tissue sample? Will they all be treated with PDT prior to resection? Do we want to treat only the samples that were non-responsive to PDT? Efficacy of combination regimen •PDT + combination agent •Evaluate treatment response in 4 groups (if size permits.
nanoparticles or polymers bearing molecules that selectively bind to pancreatic cancer cell surface components such as EGFR C225 antibody carrier EGFR binding Nanoparticle carrier photosensitizer Polymer carrier photosensitizer .??Aim 7: Strategies for targeted-PDT?? Targeted PDT treatments involve photosensitizer-loaded C225 antibodies.
Enzyme-mediated PS activation on tumor surface Conjugation quenching peptide H N Protease activation + H2N Proximity quenching peptide Protease activation peptide .
• Aim 2: development of PDT-based combination regimens in in vitro 3-D cultures based on molecular studies (Aim 1) [chemotherapy agent.New specific aims • Aim 1: molecular signatures affecting response to PDT in in vitro 3-D cultures to form a basis of developing combinations regimens. Biodistribution. sequence] • Aim 3: Establishment of PDT parameters for mouse models of pancreatic cancer (ie. pharmacology) • Aim 4: test PDT-based combination regimens in mouse models of pancreatic cancer and evaluate molecular response and molecular signature (therapeutic arm) [dose response] • Aim 5: novel interventions(aptamer.c225. targeted PDT and bioinformatics Ex vivo fresh samples from patients -> deal in core (in conjunction with Ed’s project and possibly bioinformatics) .other).
Riely GJ. thus providing signaling downstream of EGFR Pao W. 2006 Mar 11 Activated Src and Ras induce gefitantib resistance by activation of Activated Src and Ras induce gefitinib resistance by activation of signaling pathways downstream Baoli Qin. . Pan Q.Resistance to Gefitinib Cancer Chemother Pharmacol. PLoS Med 2(1): e17 Gefitinib resistance in KRAS mutation however EGFR mutants only some were resistant. et al Results suggest that activated Ras and Src could induce gefitinib resistance by activating either or both of Akt and Erk signaling pathways. Wang TY. (2005) KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib. et al. Miller VA.
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