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Novel Prevention and Treatment
Approaches to Cancer
Cemile Kumas
Causes of cancer
Genetic changes
Smoking, diet, sunlight…
Treating cancer
Surgery
Chemotherapy
Radiation
Prevention of cancer
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/
Change in the US Death Rates by Cause,
1950 & 2003
Rate Per 100,000
600
586.8
1950
2003
500
400
300
231.6
200
193.9
180.7
100
53.3
190.1
48.1
21.9
0
Heart
Cerebrovascular
Diseases
Diseases
©2006, American Cancer Society, Inc.
Pneumonia/
Influenza
Cancer
General Treatment
• Surgery
• Radiation
• Chemotherapy
– Etoposide (epipodophyllotoxin, inhibits topoisomerase enzyme in DNA)
– Ifosfamide (alkylating agent, acts as a prodrug)
– Taxol (inhibit Tubulin protein depolymerization)
inability to cell division
– 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
http://www.mdanderson.org/
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
http://cancerhelp.co.uk/help/default.asp?page=129#inter
Immunotherapy
Novel targets for Cancer therapy
1.
2.
3.
Inhibitors of signal transduction pathways
Inducers of apoptosis and/or differentiation
Inhibition of survival pathways
 Like NF-KB
4.
Inhibitors of telomerase
5.
Agents acting on DNA directly and indirectly
6.
Inhibitors of angiogenesis
Inoue et al, 1996
Gerl et al,2005
The role of signal transduction in cancer
treatment and drug resistance
• RTK inhibitors
• G-protein inhibitors (Ras)
• Effector protein inhibitors
(tamoxifen)
• MAPK inhibitors
• Transcription factors and
CDKs (flavopiridol)
Liem et al, 2002
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).
Signal transduction
• Sunitinib (Sutent) is an orally-available small-molecule
multiple receptor tyrosine kinase inhibitor.
– Pfizer
Approved January 2006
Kidney Cancer/Gastrointestinal Stromal Tumors
• Sorafenib (Nexavar) is a multikinase inhibitor targeting a
number of serine/threonine and receptor tyrosine
kinases.
– Bayer/Onyx
Approved December 2005
Renal Cell Carcinoma
http://www.centerwatch.com/patient/drugs/dru867.html
Imatinib (Gleevec by Novartis)
Sunitinib (Sutent by Pfizer)
Sorafenib (Nexavar by Bayer)
Inducers of apoptosis and/or differentiation
Clinical therapeutics targeting caspases
Fischer et al, 2005
Inhibition of survival pathways
•
•
The susceptibility of cells to apoptosis appears to
be dependent on the balance between proapoptotic 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 2006
Jing Li
www.nature.com
Telomerase as a target for novel cancer
gene therapies
•
Telomerase directed gene therapy
– The telomerase gene promoters can be
used to target therapeutic genes to
cancer cells as a consequence of tumorspecific 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.
Keith et al., 2004
Targeting senescence pathways to reverse drug
resistance in cancer (by acting on DNA)
• 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.
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
Anti-Angiogenics
Bevacizumab (Avastin)
Nature Reviews Drug Discovery 4, 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
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
Causes of cancer
Genetic changes
Smoking, diet, sunlight…
Treating cancer
Surgery
Chemotherapy
Radiation
Prevention of cancer
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
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
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 Eschenbach
Director, National Cancer Institute