Targeted Therapy Flashcards
Therapeutic Index
The therapeutic index (TI) is a pharmacological concept that represents the ratio of the dose of a drug that causes a therapeutic effect to the dose that causes toxicity.
It is calculated by the ratio of the median toxic dose (TD50) to the median effective dose (ED50).
Therapeutic index (TI) = TD50/ED50
➢ A larger therapeutic index suggests a wider margin of safety, meaning that the drug is less likely to cause toxic effects at therapeutic doses.
➢ When the therapeutic index exceeds a certain value, such as 10, it is generally considered that the drug has a good safety profile.
Chemo vs Targeted Therapy
- Chemotherapeutic agents do not discriminate between normal cells and cancer cells = Narrow therapeutic index
- The majority of tumor cells have to be killed to achieve complete remission of the tumor, the application of high doses of chemotherapeutics is required at the expense of severe toxic side effects = Low selectivity
- Most chemotherapeutic agents do not preferentially accumulate at the tumor site = Poor drug distribution
1) Targeted cancer therapies are drugs that block the growth and spread of cancer cells by interfering with specific molecules “molecular targets”(detected by companion diagnostic kit*) that are involved in the growth, progression, and spread of cancer.
2) Targeted therapies differ from standard chemotherapy in the following
three aspects:
2.1)Targeted therapies act on specific molecular targets that are associated with cancer, whereas standard chemotherapies act on all rapidly dividing normal and cancerous cells. Higher selectivity
2.2)Targeted therapies are deliberately chosen or designed to interact with their targets, whereas standard chemotherapies were identified because they kill rapidly dividing cells. Better drug distribution
2.3)Targeted therapies are often cytostatic (that is, they block tumor cell proliferation), whereas standard chemotherapy agents are cytotoxic (that is, they kill tumor cells). Larger therapeutic index
What is a Biomarker?
The success of personalized medicine fundamentally depends on the development of biomarkers and companion diagnostics (CDx) that can be used to accurately identify the patient population suitable for the targeted therapies such as protein expression (HER2 overexpression-HercepTest for Trastuzumab/Herceptin), gene mutation (EGFR mutation-Therascreen PCR Kit for Gefitinib/Iressa), etc.
Characteristics of a good target.
Characteristics of a good target.
* Highly expressed in cancer cells
* Selectively expressed in cancer cells
* Contributes mechanistically to cancer pathology
* Expression correlates with cancer stage or clinical outcome.
Targeted Therapy Strategies
Small molecule drugs
* Advantage of low cost and high chemical stability (relative to biologic drugs)
* Drug discovery facilitated by high-throughput screening (HTS) techniques.
* Often cell permeable and can be used for intracellular targets.
Current Approaches: Therapeutic antibodies
* Advantage of high potential affinity/specificity
* High in vivo stability (very long half life)
* Amenable to engineering
Hormone Therapy
Hormone therapies slow or stop the growth of hormone-sensitive tumors, which require certain hormones to grow.* e.g., Tamoxifen targeting ER positive BC
Hormones contribute to the progression of several cancers, notably breast, ovarian, and prostate.
- Treatment of breast cancer with Tamoxifen was the first bona fide targeted cancer therapy (1977). : Estrogen receptor antagonist, Remains standard therapy for breast cancer
Androgen deprivation for prostate cancer
Neutralising Antibodies
- Ideal for cell surface receptors and
extracellular ligands. - Targets must be highly enriched in cancer cells, and mediate essential tumor-promoting pathways.
Effector-mediated Cytotoxicity
- Takes advantage of endogenous function of antibodies.
- Antibody-dependent cell-mediated cytotoxicity
(ADCC)
– Activation of Fc receptor on effector cells - Complement-dependent cytotoxicity (CDC)
– Activation of C1 complex on effector cells - Ideal for cancer. Less desirable for other indications.
- May be modulated by engineering or by post- translational modifications.
– IgG1 strongly activates ADCC, IgG4 weakly activates ADCC
Drug Conjugates
*Conferring specificity to cytotoxic drugs (i.e. higher tumor selectivity to drugs that are too toxic to be used on their own).
*Conferring cell killing power to monoclonal antibodies that are tumor-specific but not sufficiently cytotoxic.
*Ideally, a conjugate should be designed such that it remains non-toxic in circulation in vivo until it reaches its target
Brentuximab vedotin (Adcetris)
* Monomethyl auristatin E
o Highly toxic as free drug
Molecular Targeted Radiotherapy
- Similar to external beam therapy
– cancer cell destruction is achieved by means of radiation induced DNA
damage. - Similar to Chemotherapy
– it is a systemic treatment that uses a molecule, in this case bearing a
radiolabel, to deliver cytotoxic
substance to disease sites. - Has a “bystander” or crossfire effect
– potential destruction of adjacent cells.
– Very important since tumors are
heterogeneous tissues. - For primary and metastatic tumors
– including malignant cell populations
undetectable by diagnostic imaging.
CAR-T
- Adoptive Cell Transfer (ACT)
– Engineering patient’s own immune cells to target and kill cancer cells. - Chimeric Antigen Receptor (CAR) T-cells
– T cells are engineered to express CARs that can recognize tumor cells - Promising clinical trials, particularly in acute lymphoblastic leukemia (ALL) – CD19+ malignant B cells
- Extract T cells – collect T cells from patient
- Reprogramming T cells – viral vector inserts CAR gene into T cells.
- Manufacturing CAR T cells – CAR T cells are proliferated in vitro to a specific clinically relevant quantity and quality.
- Patient Pre-conditioning – Patients are treated with chemo to lower white blood cell count to more readily accept T cells.
- Treatment – Patient is given CAR T-cells.
Nanomedicine
*A wide range of nanomaterials with their own pros and cons
*Functionalize with a wide range of therapeutics and targeting mechanisms
*Capable of making multi-functional complexes (Swiss Army knives of cancer therapy
*Improve tumor-specific drug delivery and impair general systemic distribution
- Enhanced Permeation and Retention (EPR) effect –
- Interendothelial gap junctions are larger between tumor and blood vessels than normal tissue.
- Impaired lymphatic drainage prevent NP clearance from tumors.
- Targeting component– Not a homing missile. More like a lock and key enhancing binding affinity.
Other Kinases to target
Chronic myelogenous Leukaemia : bcr-abl2
t(9;22) 90-95% of cases
2bcr-abl fusion protein is produced, which results in a constitutively active abl kinase
Translocation results in “Philadelphia chromosome”
Results in fusion of BCR (multi-domain signaling protein) and Abl (non-receptor tyrosine kinase )
Imatinib (Gleevec, STI-571)
Indications: CML, gastrointestinal stromal tumors(GISTs)
Mechanism: competitive inhibitor of tyrosine kinases
Gene Expression Modulators
Gene expression modulators modify the function of proteins that play a role in controlling gene expression. e.g., panobinostat, a HDAC inhibitor targeting HDAC to suppress expression of some oncogenes
Apoptosis Inhibitors
Apoptosis inducers cause cancer cells to undergo a process of controlled cell death called apoptosis. e.g., Bcl-2 antisense (G3139) GENTA/Aventis in Phase II and III
