Pharmacology Ch 8 - Molecular Targeted Therapy

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What are some Cancer targeted therapies?

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Drugs that block growth of cancer cells by:
interfering with specific targeted molecules needed for carcinogenesis (process by which normal cells become cancerous) and tumor growth

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Requirements for Cancer Targeted therapies?

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1. Requires a clear cut "molecular driver" of the cancer phenotype

2. The therapeutic index is high, and optimally effective treatment can be achieved at a dose below the maximal tolerated dose

3. therapy may be more effective than current treatments

4. may target specific characteristics of cancer cells, such as proteins, enzymes, or the formation of new blood vessels

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Names of "Molecular Targeted" Therapy include

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Targets sometimes called:
1. “molecular targets”, hence targeted therapies sometimes called
2. “molecular-targeted drugs,”
3. “molecularly targeted therapies”

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Immune targeted therapies are...

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antibodies that work like the antibodies made by the immune system

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Objective of Drug Discovery process is to...

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identify a molecule that is selectively active and potent against the cancer phenotype without exerting an undue toxicity to normal cells

And which produces clinical benefits with minimal toxicity in the patients

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The two main models of Drug Design/Development process are...

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Model One: Target-based Drug Discovery and Development process

Model Two: Reverse approach; drug-response (biology), then determine the target

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Model One: Target-Based Drug Discover steps

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1. begins with the identification and the validation of the target in in vitro and in vivo studies
2. Choice of the agents/compound libraries or approaches for obtaining agents to be screened
3. Development of assays based on the target
4. Evaluation of agents against target
5. Lead Discovery and optimization with medicinal chemistry
6. Evaluation of candidate drug against in vivo models of the cancer

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Target Identification:
Disease condition associated with...

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several molecular entities and biological events

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Target Identification:
To determine the altered molecular entities and biological events essential to the disease and...

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that make up underlying pathological mechanisms required for:
supporting & maintaining disease condition.
promoting disease progression.

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Drug Target represents...

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biological entity with molecular and biochemical functions that are critical to key biological processes underlying the existence of the disease.

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Altered biological entity (target) may be...

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1. genetic material
2. gene or gene product
3. molecular/biological mechanism present within the cancer

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Target Identification:
Other important considerations include...

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1. cellular location
2. expression profile of the target
3. molecular status in normal versus tumor cells
4. functional status in relation to the tumor phenotype
5. other physical/biochemical and biological properties

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In Drug Design, what is Target Validation?

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It establishes a causal role between a target and disease is the beginning of a potentially viable drug discovery process

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What are criteria for validating a target in Drug Design?

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To establish credibility of the hypothetical target as it relates to its activity in the context of the disease, and

its mechanism of action, and

to establish a cause and effect relationship between the disease and the candidate target

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What is the goal in validating a target in Drug Design?

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Goal is to present a clear definition of the position of the target in relation to the disease phenotype and the molecular and biological events leading the cancer

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3 Main criteria for Validating a Target in Drug Design:

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1. Evidence in cell-culture and whole animal models that changes in the function of the candidate target alone is sufficient to alter the relevant disease phenotype . Studies need to establish that the elevation of expression or function of putative target alone is sufficient to induce the cancer phenotype.

2. Definitive proof from studies in disease-relevant models of cell culture & animals, and clinical models that modulating molecular entity/target’s function alters disease. Appropriate disease models in vitro and in vivo need to be employed to investigate the underlying critical role of the potential targeti nthe incidence and progression of disease.

3. Clearly define molecular mechanism(s) of disease in accordance with the assertion that a potential biological entity as target has a critical role in the disease development. Verify that function of biological molecule is essential to the events that lead to disease to ensure targeting this entity modulates some critical underlying mechanism.