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TRAnslational research in Clinical Oncology (TRACO). Program Director. Terry W. Moody, Ph.D. (301)451-9451 FAX(301)480-4323 Bldg. 31, Rm. 4A48. Organizing Committee. Irwin Arias Terry Moody Lyuba Vartikovski Jonathan Wiest Farah Zia. SYLLABUS. DATE TOPIC SPEAKERS

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TRAnslational research in Clinical Oncology (TRACO)

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Translational research in clinical oncology traco

TRAnslational research in Clinical Oncology (TRACO)


Program director

Program Director

Terry W. Moody, Ph.D.

(301)451-9451

FAX(301)480-4323

Bldg. 31, Rm. 4A48


Organizing committee

Organizing Committee

Irwin Arias

Terry Moody

Lyuba Vartikovski

Jonathan Wiest

Farah Zia


Syllabus

SYLLABUS

DATETOPICSPEAKERS

Sept. 12Introduction, Lung CancerMoody, Giaccone

Sept. 19Metastasis, AngiogenesisHunter, Zudaire

Sept. 26Topoisomerases, Lymphoma

Pommier, Wilson

Oct. 3HIV, EpigeneticsMaldarelli, Verma

Oct. 12Breast Cancer, Health Disparities

Zia, Ambs


Syllabus continued

SYLLABUS, continued

DATETOPICSPEAKERS

Oct. 17Small molecules, Radiation OncologyAustin, Camphausen

Oct. 24Cancer Stem Cells, Epidemiology Bussard, Caporaso

Oct. 31Ovarian Cancer, GenomicsAnnunziata, Khan

Nov. 7RNAi, Cervical CancerCaplen, Schiller

Nov. 14 Lung Cancer, TGFβ

Szabo, Jakowlew


Syllabus continued1

SYLLABUS, continued

DATETOPICSPEAKERS

Nov. 21Colon cancer, ImagingYoung, Choyke

Nov. 28Inflammation, Case Report Harris, Olaku

Dec. 5Nanotechnology, TBA Hall, TBA


Registration

REGISTRATION

The course is open to all interested personnel without charge. Registration is available at the NCI CCR Web site (http://ccr.cancer.gov/careers/courses/traco/)


Ccr component

CCR component

Registrants can attend tumorboards, grand rounds, visit technology and/or core facilities. Please contact Dr. Moody, if interested to make appropriate reservations.


Course certification

COURSE CERTIFICATION

Registrants can obtain a course certificate upon passing a computer graded final examination.


Lung colon breast and prostate cancer account for half of the u s cancer mortalities

Lung, colon, breast and prostate cancer account for half of the U.S. cancer mortalities.

TYPEINCIDENCE(MORTALITY)

Lung171,900(157,200)

Colon/Rectum147,500 (57,100)

Breast211,300 (39,800)

Prostate220,900 (28,900)

Others582,500 (273,500)

Total1,334,100(556,500)

Jemal, Ward and Thun, “Cancer: Principles & Practice of Oncology.” Edited by DeVita, Hellman and Rosenberg. (2006), pp. 226-241


Cancers which kill 10 000 30 000 u s patients annually include

Cancers which kill 10,000-30,000 U.S. patients annually include:

  • Pancreatic cancer

  • Non-Hodgkin’s Lymphoma

  • Leukemia

  • Stomach cancer

  • Ovarian cancer

  • Brain cancer

  • Liver cancer

  • Bladder cancer

  • Esophageal cancer

  • Kidney cancer


Cancer risks include

Cancer risks include:

  • Alcohol

  • Asbestos

  • Diet

  • Familial

  • Hormones


Cancer risks continued

Cancer risks (continued)

  • Obesity

  • Ion Radiation

  • Tobacco

  • U.V. Radiation

  • Viral


Lung cancer kills over 150 000 patients in the u s annually

Lung Cancer kills over 150,000 patients in the U.S. annually.

  • There are 45 Million current smokers and 45 Million ex-smokers in the U.S.

  • It is difficult to quit smoking due to nicotine addiction.


Carcinogens which have been identified in cigarette smoke include

Carcinogens which have been identified in cigarette smoke include:

  • Polyaeromatic hydrocarbons (PAH),

  • aza-arenes,

  • 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK),

  • 1,3 butadiene,

  • ethyl carbamate,

  • ethylene oxide,

  • nickel, chromium, cadmium,

  • polonium, arsenic

  • hydrazine


Translational research in clinical oncology traco

The process by which unreactive carcinogen converts to a form which binds DNA is known as metabolic activation.

  • Bay region diol epoxides are the principal PAH metabolites involved in DNA adduct formation. For Benz[a]pyrene (BaP), BaP-7,8-diol-9,10-epoxide (BPDE) forms adducts with DNA leading to G:C>T:A mutations in pulmonary DNA. The genes for p53 and k-ras are frequently mutated.


Benz a pyrene the chemical structure of bap is shown

BENZ(a)Pyrene●The chemical structure of BaP is shown.


Bap is metabolized by enzymes to bpde

BaP is metabolized by enzymes to BPDE.

BaPP450sBap-7,8-oxideEpoxide hydrolaseBaP-7,8-diolP450sBPDEDNABPDE-N2-dGAcid hydrolysisBP-tetraolBoysen and Hecht, Mutation Res. 543:17(2003).


Carcinogens can be detoxified and excreted prior to dna damage

Carcinogens can be detoxified and excreted prior to DNA damage.

  • Cytochrome p450 enzymes catalyze addition

    of an oxygen to the carcinogen, increasing

    its water solubility.

    ● Phase 2 enzymes convert the oxygenated

    carcinogen to a form that is highly soluble in

    water, converting it to a form that can be

    excreted.


Translational research in clinical oncology traco

DNA is mutated if the rate of carcinogen activation exceeds the rate of carcinogen detoxification and/or DNA repair.

  • DNA adducts as well as intra- and

    interstrand DNA crosslinks are removed by nucleotide excision repair.


P53 a tumor suppressor gene

P53, a tumor suppressor gene:

●mediates the G1 to S-phase checkpoint of the cell cycle,

●drives programmed cell death or apoptosis after DNA damage,

●is increased along with p21 after DNA damage.


P53 mutations are detected in most of the lung cancer patients

P53 mutations are detected in most of the lung cancer patients.

  • G to T transversions occur at the CpG rich codons including 153-158 (exon 5), 248 and 249 (exon7) and 273 (exon 8) of the p53 gene. There is an excess of G to T transversions in smokers relative to non-smokers.


P53 mutations

P53 mutations


Cell cycle phases

Cell cycle phases.


P53 mediates the g 1 to s phase checkpoint of the cell cycle

p53 mediates the G1 to S-phase checkpoint of the cell cycle

●DNAdamage increases p21 and p53.

●P53 drives programmed cell death or apoptosis after DNA damage


Cell cycle enzymes

Cell cycle enzymes


Genotoxicity of tobacco smoke

Genotoxicity of tobacco smoke.

●After 10 years of chronic cigarette smoking, normal lung tissue can undergo hyperplasia and metaplasia.

●After 15 years, dysplasia can result.

●After 20 years, a carcinoma in situ can form.

●After 25 years, a malignant cancer can form.


Carcinogenesis cancer progression occurs over a period of decades

Carcinogenesis●Cancer progression occurs over a period of decades.


Normal lung carbon dioxide is exhaled from the lung whereas oxygen is inhaled

Normal lung●Carbon dioxide is exhaled from the lung whereas oxygen is inhaled.


Hyperplasia after exposure to tobacco smoke hyperplasia can result

Hyperplasia●After exposure to tobacco smoke, hyperplasia can result.


Dysplasia continued exposure to tobacco smoke leads to dysplasia

DysplasiaContinued exposure to tobacco smoke leads to dysplasia.


Adenoma continued exposure to carcinogens leads to benign tumors such as adenomas

Adenoma●Continued exposure to carcinogens leads to benign tumors such as adenomas.


Adenocarcinoma chronic exposure to tobacco leads to malignant tumors such as adenocarcinoma

Adenocarcinoma●Chronic exposure to tobacco leads to malignant tumors such as adenocarcinoma.


Tumor formation growth factors promote carcinogenesis progression factors lead to malignant tumors

Tumor formation ●Growth factors promote carcinogenesis. Progression factors lead to malignant tumors.


Tumors the primary cancer can undergo metastasis to distant organs

Tumors●The primary cancer can undergo metastasis to distant organs.

Carcinoma

Angiogenesis

Migration, Invasion and Metastasis.


Genetic abnormalities in lung cancer include

Genetic abnormalities in lung cancer include:

  • Mutation of tumor suppressor genes such as p53

  • Silencing of tumor suppressor genes such as p16, Rb

  • Amplification of oncogenes such as

    c-myc, cyclin D1, EGF receptor, erbB-2


Types of lung cancer

Types of Lung Cancer.

SCLC (small cell lung cancer)

NSCLC

  • adenocarcinoma

  • large cell carcinoma

  • squamous cell carcinoma


Sclc or oat cell carcinoma

SCLC or oat cell carcinoma

  • Kills approximately 20,000 patients in the U.S. annually.

  • Is a neuroendocrine tumor.

  • Is responsive to chemo- and radiation therapy, but relapse frequently occurs. The median survival time is less than one year.


Sclc biopsy specimen

SCLC Biopsy Specimen


Translational research in clinical oncology traco

Neural enzymes, peptides and transmitters may be stored in the dense core neurosecretory granules associated with SCLC.


Lung cancer symptoms cough chest pain shortness of breath pneumonia or bronchitis bloody sputum

Lung cancer symptoms●Cough●Chest pain●Shortness of breath●Pneumonia or bronchitis●Bloody sputum


Lung cancer chest x ray

Lung cancer: chest X-ray


Lung cancer chest ct scan

Lung cancer: chest CT-scan


Lung cancer bronchoscopy

Lung cancer: bronchoscopy


Staging of sclc

Staging of SCLC

  • Physical examination

  • Serum chemistries and whole blood cell counts

  • CT scan of chest and upper abdomen

  • FDG PET scan

  • CT or MRI of the brain

  • Bone marrow biopsy (optional)


Translational research in clinical oncology traco

SCLC patient survival.TreatmentSurvivalNone< 3 monthsSurgery6.5 monthsRadiotherapy10 monthsMurren et al., Cancer: Principles and Practice of Oncology (2001) pp 983-1018


Translational research in clinical oncology traco

Combination Chemotherapy Active combinations include:cyclophosphamide, doxorubicin, VP-16(CDE), C, doxorubicin, vincristine (CAV),E, cisplatin (EP),VP-16, ifosfamide, P (VIP), andI, carboplatin, VP-16 (ICE).


Translational research in clinical oncology traco

SCLC relapse●Initially, SCLC often responds to chemotherapyAfter relapse, chemotherapy is often ineffective.Field effect


Sclc metastasis liver 27 bone 41 adrenals 31 brain 14 lymph nodes mediastinal 80

SCLC metastasis Liver (27%)●Bone (41%)●Adrenals (31%)●Brain (14%)●Lymph nodes, mediastinal (80%)


Translational research in clinical oncology traco

SCLC carcinogenesis Is SCLC derived from neuroendocrine Kulchitsky cells or stem cells?●Initiated by tobacco smoke carcinogens.


Translational research in clinical oncology traco

SCLC cell lines.Bone marrow aspirates were obtained from patients and mononuclear cells collected.Lymph node aspirates and other solid tumors were mechanically dissociated and cell suspensions obtained by mincing and passing through 60 gauge steel mesh.The cells were cultured in a serum free medium containing selenium, IGF-I and transferrin. SCLC cells grew as suspension cultures.


Numerous cell lines were isolated from sclc biopsy specimens

Numerous cell lines were isolated from SCLC biopsy specimens


Translational research in clinical oncology traco

SCLC cell linesSCLC make their own autocrine growth factors.From 1982-4, NCI established 31 SCLC cell lines. Subcutaneous injection of each of the cell lines into nude mice resulted in tumor formation.The classic SCLC cell lines had high levels of Dopa decarboxylase (DDC:2-657 unit/mg), Bombesin (BB:0.2-22 pmol/mg) and neuron Specific enolase (NSE:1200-18000 ng/mg).Carney et al., Cancer Res. 45:2913 (1985).


Translational research in clinical oncology traco

SCLC cell lines.•Over a 20 year period, NCI established 113 SCLCand 110 NSCLC continuous human cell lines. A subset of SCLC is variant SCLC, which has low levels of DDC, BB and NSE.Phelps et al., J. Cell Bioc. Supp. 24:32(1996).


Loss of heterozygosity in lung cancer occurs on several genes

Loss of heterozygosity in lung cancer occurs on several genes.

Gene locusTumor suppressor gene

  • 3p12FHIT

  • 11q12p15, p16

  • 13q14Rb

  • 17q13p53


Translational research in clinical oncology traco

p53.

  • Mediates the G1 to S-phase checkpoint of the cell cycle.

  • Drives programmed cell death or apoptosis after DNA damage.


Translational research in clinical oncology traco

Rb mutations (truncations, deletions, nonsense mutations and splicing abnormalities) occur in many lung cancer patients.

  • Usually the wild type allele is lost especially in SCLC. The Rb protein is absent or abnormal in 90% of the SCLC patients.


Bcl2 is overexpressed in approximately 85 of the sclc tumors

BCL2 is overexpressed in approximately 85% of the SCLC tumors.

  • BCL2 suppresses apoptosis and inhibits responses to chemotherapy and radiotherapy.

  • Antisense-BCL2 therapeutic trials are being conducted (Genasense is an 18-mer phosphothioate oligonucleotide).


Patients which have egfr mutations are responsive to small molecules such as gefitinib or erlotinib

Patients which have EGFR mutations are responsive to small molecules such as Gefitinib or Erlotinib.

  • EGFR mutations occur in the activation loop, especially L858R and G719S.

    Paez et al., Science 304:1497 (2004)


Cml patients are sensitive to the small molecule gleevec

CML patients are sensitive to the small molecule Gleevec.

  • This restores blood counts in

    patients and delays disease progression.


Translational research in clinical oncology traco

CML patients have a genetic abnormality on chromosome 22 (Philadelphia chromosome).●Segments of chromosome 9 and 22 are fused resulting in the bcr-abl gene. ●The resulting tyrosine kinase is constituitively active. ●Bcr-abl tyrosine kinase actvity is inhibited by Gleevec.


Translational research in clinical oncology traco

Translocation of Bcr/Abl.●Chromosome 22 translocates with chromosome 9. Molecular Biology of the Cell; Alberts et al., 2001.


Translational research in clinical oncology traco

Translocation of Bcr-Abl Genes●Translocated chromosome 9 appears larger and translocated chromosome 22 appears smaller: Freebies for Teachers”; D. Kerrigan.

9

9

(q+)

Ph

22

(22q–)

bcr

bcr-abl

abl

Fusion protein with tyrosine kinase activity


In a phase i clinical trial gleevec tm was effective orally at a daily dose of 300 mg or greater

In a Phase I Clinical Trial,GleevecTM was effective orally at a daily dose of 300 mg or greater.

  • Dose limiting toxicities included nausea, vomiting, edema and rash. (Sawyers and Druker. Cancer J. Sci. Am. 1999;5:63).


Translational research in clinical oncology traco

In a Phase II Clinical Trial,GleevecTM restored normal blood counts in 53 out of 54 chemotherapy-resistant CMLpatients.

  • After a year on Gleevec, 51 of

    these patients were still doing well. (Druker et al. N. Engl. J. Med. 2001; 344: 1038.).

    .Over a 5 year period, 89% of the patients treated with Gleevec had progression-free survival (O’Hare et al., Clin. Cancer Res. 2011; 17: 212).


Translational research in clinical oncology traco

Gleevec mechanism of action●Gleevec blocks the ATP binding site. Molecularbiology of the cell; Alberts et al., 2001.


Gleevec resistance

GLEEVEC RESISTANCE

●Over a 5 year period, 17% of the patients initially sensitive to Gleevec became resistant.

●BCR-ABL point mutations occurred such as T315I near the ATP binding site impairing Gleevec interactions

●New drugs such as ponatinib or DCC-2036 are being developed which bind with high affinity to mutated BCR-ABL


Practical steps to prevent cancer

PRACTICAL STEPS TO PREVENT CANCER

●Check your house for radon.

●Check your house for asbestos.

●Take precautions at your workplace.

●Check your community water system.

●Avoid breathing polluted air.

●Protect your skin.

●Don’t breathe smoke.

●Exercise daily.


Practical steps to prevent cancer continued

PRACTICAL STEPS TO PREVENT CANCER (continued)

●Avoid pesticides.

●Eat fruits and vegetables.

●Reduce red-meat consumption.

●Eat fish.

●Minimize fried foods.

●Drink alcohol in moderation.

●Avoid unnecessary x-rays.

●Reduce infections.


Translational research in clinical oncology traco

REFERENCES●Hanahan, D. and Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011; 144(5): 646-74.●O’Hare, T., Deininger, M.W.N., Elde, C.A., Clackson, T., and Druker, B.J. Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia. Clin. Cancer Res. 2011; 17(2):212-21.


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