Historical Perspective: Targeted cancer therapies

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11 Apr 2012
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Cells in multicellular organisms continuously signal each other and the environment. This
leads to proliferation, differentiation, and apoptosis. In cancer, there is a loss of balance in
signaling.
Problem: Humans go through a large number of cell divisions in lifespan, each division
possible mutation.
Our bodies evolve defense against cancer formation.
One normal cell type multiply uncontrollably chaos (tumor)
Traditional Cancer Chemotherapy
Major medical advance of 20th century
In certain cancers, chemotherapy is curative
Adjuvant chemotherapy (chemotherapy along with removal of tumor) for breast,
colon, and lung cancer increases survival benefit.
Narrow Therapeutic Index
Side effects: Alopecia, GI symptoms, Myelosuppression (Decrease in immune
cells)
Responses are partial, unpredictable
More options are needed
Cancer mortality from 4 major killers has decrease in the past ¾ century
Male Stomach, Female Stomach, Colorectal, Uterine cancer has decreased
Reasons: Improvements in food storage practices, decreased H.Pylori infection
rates, improved screening (early detection)
Most cancers are resistant to traditional chemotherapy. Mortality has not significantly
changes. Lung cancer has increased.
Research findings are only starting to be exploited in clinic.
Therapy chosen based on diagnostic categories; Particular tumor type, Stage of
disease all receives same treatment.
Biological heterogeneity of tumors, significant with respect to drug responsiveness
just starting to be understood
Limited available drugs limited possibility to exploit differences for treatment
Conventional cytotoxic drugs interact with DNA, microtubules prevent cell
replication, but NOT specific to cancer cells.
Targeted therapies: Drug targets molecular pathway
Limited possibilities: only a subset of defective proteins in cancer cells are attractive
targets for drug development.
Drugs should be low molecular weight organic compounds that inhibit rather than
activate biochemical functions of proteins.
Tumor suppressors cancer development via their absence or mutation. Needs a
drug to reactivate them
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