Novel Prevention and Treatment Approaches to Cancer

1. Novel Prevention and Treatment Approaches to Cancer Cemile Kumas

2. Causes of cancer Genetic changes Smoking, diet, sunlight… Prevention of cancer Cancer • Treating cancer • Surgery • Chemotherapy • Radiation

3. What causes cancer? From earliest times till 19th century • Humoral Theory • Lymph Theory • Blastema Theory • Rudolf Virchow, the founder of cellular pathology • the modern pathologic study of cancer. “All cells, including cancer cells, are derived from other cells.” • Chronic Irritation • Trauma • Parasite Theory • A Nobel Prize was wrongly awarded to Johannes Fibiger in 1926 for scientific research documenting stomach cancer being caused by a certain worm. http://www.cancer.org/

4. Change in the US Death Rates by Cause, 1950 & 2003 Rate Per 100,000 1950 2003 HeartDiseases CerebrovascularDiseases Pneumonia/Influenza Cancer ©2006, American Cancer Society, Inc.

5. General Treatment • Surgery • Radiation • Chemotherapy • Etoposide (epipodophyllotoxin, inhibits topoisomerase enzyme in DNA) • Ifosfamide (alkylating agent, acts as a prodrug) • Taxol (inhibit Tubulin protein depolymerization) • Vincristine (inhibit polymerization of microtubules) • Hormonal Therapy • Biological Therapy • Interferon alpha was one of the first immunotherapies used to treat cancer.  • Stem cell & bone marrow transplants inability to cell division http://www.mdanderson.org/

6. Current~Novel Treatments • Photodynamic therapy (PDT) • a novel cancer treatment which works by exposing a photosensitizing drug to specific wavelengths of light to kill cancer cells. • Biological Therapy • Monoclonal antibodies • Cancer vaccines • Cancer growth blockers • Anti angiogenics • Gene therapy drugs • Complementary therapy Immunotherapy http://cancerhelp.co.uk/help/default.asp?page=129#inter

7. Novel targets for Cancer therapy • Inhibitors of signal transduction pathways • Inducers of apoptosis and/or differentiation • Inhibition of survival pathways • Like NF-KB • Inhibitors of telomerase • Agents acting on DNA directly and indirectly • Inhibitors of angiogenesis Inoue et al, 1996 Gerl et al,2005

8. The role of signal transduction in cancertreatment and drug resistance • RTK inhibitors • G-protein inhibitors (Ras) • Effector protein inhibitors (tamoxifen) • MAPK inhibitors • Transcription factors and CDKs (flavopiridol) Liem et al, 2002

9. Signal transduction • Tyrosine Kinase Inhibitors • Imatinib (Gleevec) is the first market drug that introduced for Chronic Myeloid Leukaemia (CML) bcr-abl kinase, which causes CML, inhibited by imatinib (small molecule).

10. Signal transduction • Sunitinib (Sutent) is an orally-available small-molecule multiple receptor tyrosine kinase inhibitor. • PfizerApproved January 2006Kidney Cancer/Gastrointestinal Stromal Tumors • Sorafenib (Nexavar) is a multikinase inhibitor targeting a number of serine/threonine and receptor tyrosine kinases. • Bayer/Onyx Approved December 2005Renal Cell Carcinoma http://www.centerwatch.com/patient/drugs/dru867.html

11. Imatinib (Gleevec by Novartis) Sunitinib (Sutent by Pfizer) Sorafenib (Nexavar by Bayer)

12. Inducers of apoptosis and/or differentiation Clinical therapeutics targeting caspases Fischer et al, 2005

13. Inhibition of survival pathways • The susceptibility of cells to apoptosis appears to be dependent on the balance between pro-apoptotic and survival (antiapoptotic) signals. • Akt pathway, NF-kB pathway Tsuruo et al,2003 Enhanced Sensitivity to Chemotherapy in Esophageal Cancer through Inhibition of NF-κB  Journal of Surgical Research, May 2006Jing Li www.nature.com

14. Telomerase directed gene therapy The telomerase gene promoters can be used to target therapeutic genes to cancer cells as a consequence of tumor-specific gene expression of telomerase. Suicide gene therapy transfer of a therapeutic gene encoding a prodrug-activating enzyme into tumor cells followed by treatment with the prodrug. inactive non-toxic prodrug active cytotoxic drug. Oncolytic virus therapy generate conditionally replicative adenovirus (CRAd) vectors for cancer therapy, tumor-specific promoters can be used to drive adenoviral genes essential for replication. Telomerase as a target for novel cancer gene therapies Keith et al., 2004

15. Infinite life spans inactivation of the tumor suppressor p53 and to constitutive activation of telomerase. Targeting DNA damage and cell cycle molecules to force cancer cells into senescence and reversal of drug resistance Alterations of senescence pathways without disruption of apoptosis may be sufficient to accomplish these goals and enhance chemotherapy efficacy. Targeting senescence pathways to reverse drug resistance in cancer (by acting on DNA) Rebbaa et al, 2004 Four papers in Nature show that, as previously suggested by in vitro studies, oncogene-induced cellular senescence represents a safety mechanism to suppress tumor progression in vivo. Collado M. et al. Braig M. et al. Michaloglou C. et al. Chen Z. et al., 2005

16. Anti-Angiogenics Bevacizumab (Avastin) Nature Reviews Drug Discovery4, 448-449 (2005) Endostatin; a natural antiangiogenic protein that inhibit the growth of blood vessels Vaccines targeting tumor angiogenesis—a novel strategy for cancer immunotherapy Y. Okaji et al, 2006

17. Gene therapy: Cancer-specific killing delivering a therapeutic gene Gene therapy vector design strategies for the treatment of cancer. Dong JY, Future Oncol. 2005 Or combined with other therapies… Chemogene therapy: osteocalcin promoter-based suicide gene therapy in combination with Methotrexate in a murine osteosarcoma model.Cheon J, Cancer Gene Ther. 1997 Non-viral cancer gene therapy: Beyond delivery S Akhtar et al,2005

18. Causes of cancer Genetic changes Smoking, diet, sunlight… Prevention of cancer Cancer • Treating cancer • Surgery • Chemotherapy • Radiation

19. How to prevent cancer so far? • Nutrition • Physical Activity • Occupancy • Quiting Tobacco and Alcohol lung cancer, oral cancers • limiting sun exposure, UV radiation • Prostate cancer early detection • Testicular cancer early detection • Breast cancer  early detection • Cervical cancer  early detection • colon cancer by following screening guidelines, increasing activity levels, and eating a low-fat, healthy diet. • Colon is the third most common cancer in both men and women

20. Future • Molecular Epidemiology Understanding the Causes of Cancer • Promoting relationships between basic, clinical, and population sciences • Strategies and technologies that promote a multi-disciplinary approach; • to identifying risk factors • underlying mechanisms • studying the interaction of genetic and environmental determinants of cancer risk • shaping the design of preventive interventions • Integrative Cancer Biology • Early Detection, Prevention, Prediction • More integrated Clinical trials • Bioinformatics

21. By 2015… • “I am confident that we can transform cancer into a disease that can be both prevented and managed like other chronic illnesses.” Dr. Andrew C. von EschenbachDirector, National Cancer Institute