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
Terry W. Moody, Ph.D.
Bldg. 31, Rm. 4A48
Sept. 12Introduction, Lung CancerMoody, Giaccone
Sept. 19Metastasis, AngiogenesisHunter, Zudaire
Sept. 26Topoisomerases, Lymphoma
Oct. 3HIV, EpigeneticsMaldarelli, Verma
Oct. 12Breast Cancer, Health Disparities
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
Nov. 21Colon cancer, ImagingYoung, Choyke
Nov. 28Inflammation, Case Report Harris, Olaku
Dec. 5Nanotechnology, TBA Hall, TBA
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/)
Registrants can attend tumorboards, grand rounds, visit technology and/or core facilities. Please contact Dr. Moody, if interested to make appropriate reservations.
Registrants can obtain a course certificate upon passing a computer graded final examination.
Jemal, Ward and Thun, “Cancer: Principles & Practice of Oncology.” Edited by DeVita, Hellman and Rosenberg. (2006), pp. 226-241
BaPP450sBap-7,8-oxideEpoxide hydrolaseBaP-7,8-diolP450sBPDEDNABPDE-N2-dGAcid hydrolysisBP-tetraolBoysen and Hecht, Mutation Res. 543:17(2003).
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
interstrand DNA crosslinks are removed by nucleotide excision repair.
●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.
●DNAdamage increases p21 and p53.
●P53 drives programmed cell death or apoptosis after DNA damage
●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.
Migration, Invasion and Metastasis.
c-myc, cyclin D1, EGF receptor, erbB-2
SCLC (small cell lung cancer)
SCLC patient survival.TreatmentSurvivalNone< 3 monthsSurgery6.5 monthsRadiotherapy10 monthsMurren et al., Cancer: Principles and Practice of Oncology (2001) pp 983-1018
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).
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.
SCLC cell linesSCLC 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).
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).
Gene locusTumor suppressor gene
Paez et al., Science 304:1497 (2004)
patients and delays disease progression.
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.
Translocation of Bcr-Abl Genes●Translocated chromosome 9 appears larger and translocated chromosome 22 appears smaller: Freebies for Teachers”; D. Kerrigan.
Fusion protein with tyrosine kinase activity
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).
●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
●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.
PRACTICAL STEPS TO PREVENT CANCER (continued)
●Eat fruits and vegetables.
●Reduce red-meat consumption.
●Minimize fried foods.
●Drink alcohol in moderation.
●Avoid unnecessary x-rays.
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.