Novel Prevention and Treatment Approaches to Cancer

Cemile Kumas

Treating cancerTreating cancerSurgery

Chemotherapy Radiation

CancerCancer

Prevention of cancerPrevention of cancerCauses of cancerCauses of cancer

Genetic changesGenetic changes Smoking, diet, sunlight… Smoking, diet, sunlight…

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/

21.9

180.7

48.1

586.8

193.9

53.3

190.1

231.6

0

100

200

300

400

500

600

Rate Per 100,000

1950

2003

Change in the US Death Rates by Cause, 1950 & 2003

HeartDiseases

CerebrovascularDiseases

Pneumonia/Influenza

Cancer

©2006, American Cancer Society, Inc.

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 http://www.mdanderson.org/

inability to cell division

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

Novel targets for Cancer therapy

1. Inhibitors of signal transduction pathways

2. Inducers of apoptosis and/or differentiation

3. 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 cancertreatment and drug resistance

Liem et al, 2002

• RTK inhibitors• G-protein inhibitors (Ras)• Effector protein inhibitors

(tamoxifen)• MAPK inhibitors• Transcription factors and

CDKs (flavopiridol)

bcr-abl kinase, which causes CML, inhibited by imatinib (small molecule).

•Tyrosine Kinase Inhibitors

Imatinib (Gleevec) is the first market drug that introduced for Chronic Myeloid Leukaemia (CML)

Signal transduction

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

Sunitinib (Sutent by Pfizer)

Sorafenib (Nexavar by Bayer)

Imatinib (Gleevec by Novartis)

Inducers of apoptosis and/or differentiation

Fischer et al, 2005

Clinical therapeutics targeting caspases

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 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 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.

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

Braig M. et al. Michaloglou C. et al. Chen Z. et al., 2005 Collado M. et al.

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.

Bevacizumab (Avastin)Bevacizumab (Avastin)

Anti-Angiogenics

Nature Reviews Drug Discovery 4, 448-449 (2005)

Vaccines targeting tumor angiogenesis—a novel strategy for cancer immunotherapy Y. Okaji et al, 2006

Endostatin; a natural antiangiogenic protein that inhibit the growth of blood vessels

Gene therapy: Cancer-specific killing delivering a therapeutic gene

Gene therapy vector design strategies for the treatment of cancer.

Dong JY, Future Oncol. 2005

Chemogene therapy: osteocalcin promoter-based suicide gene therapy in combination with

Methotrexate in a murine osteosarcoma model.Cheon J, Cancer Gene Ther. 1997

Or combined with other therapies…

Non-viral cancer gene therapy: Beyond deliveryS Akhtar et al,2005

Treating cancerTreating cancerSurgery

Chemotherapy Radiation

CancerCancer

Prevention of cancerPrevention of cancerCauses of cancerCauses of cancer

Genetic changesGenetic changes Smoking, diet, sunlight… Smoking, diet, sunlight…

• 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

How to prevent cancer so far?

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 EschenbachDirector, National Cancer Institute