L15 March 8 Biomarkers Flashcards
What are the 3 main classes of diagnosed tumors?
- Indolent tumors that have low invasive and metastatic potential and will remain in such a state during the lifetime of the patient.
- Highly aggressive tumors with a propensity to metastasize that have, with high probability, disseminated by the time that the primary tumor has been diagnosed.
- Tumors of intermediate grade that have the potential to disseminate but can be excised or treated with cytotoxic therapies before dissemination occurs and life-threatening metastases are formed.
What are the 3 traditional cancer therapies?
- Surgery
- Radiotherapy
- Chemotherapy
What is adjuvant vs. neoadjuvant thearpies?
adjuvant: a treatment that is given in concert with or following another treatment. (from the Latin adjuvare which means “to help” or “to assist”
neoadjuvant: a treatment that is undertaken before the main therapy is applied e.g. neoadjuvant radiotherapy to reduce tumor size before surgery
What are the 2 forms of resistance acquired by tumors?
Intrinsic resistance = Pre-existing
Acquired resistance = Induced by drugs (or other treatments)
How to get over resistance acquired by tumor cells? Problem?
Approach: Treat tumors with multiple anti-cancer agents “Combination Therapy”
Problem: often constrained by concerns of toxicity
What is a Biomarker?
- A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention
- a biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease” such as cancer
Examples of Biomarkers
- Can include proteins, nucleic acids, antibodies, peptides
- Can be a collection of alterations, eg. gene expression or proteomic signature
- A cancer biomarker is present in tumor tissue or serum; “tumor biomarkers” are measured in tumor tissue (e.g. IHC) and “tumor DNA biomarkers” are measured from tumor tissue
Potential applications of biomarkers
- risk assessment
- screening (discriminates btwn healthy individuals and those in the early stage of disease; ideally while subjects are asymptomatic
- differential diagnosis
- determination of prognosis (likely course of disease)
- prediction of response to treatment (used to stratify patients)
- monitoring of disease progression
- Safety (indicates an adverse response to treatment)
What are the 2 Main Types of Biomarkers in Cancer
A prognostic biomarker is a clinical or biologic characteristic that is objectively measurable and that provides information on the likely outcome of the cancer disease in an untreated individual. Prognostic markers are helpful for identifying patients with cancer who are at high risk of metastatic relapse and therefore potential candidates for adjuvant systemic treatments.
A predictive biomarker is a clinical or biologic characteristic that provides information on the likely benefit from treatment (either in terms of tumor shrinkage or survival). Predictive factors can be used to identify subpopulations of patients who are most likely to benefit from a given therapy.
What are the steps in Development of a gene expression biomarker
- Take tumor samples of known clinical outcome
- whole genome analysis
- generate signature of genes that correlate w/clinical parameter
- apply to independent validation cohorts
- evaluate clinical performance
- regulatory approval
- clinical implementation
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How to stratify patients using gene expression signatures?
- good signature (40% of patients)
- 4% die of BC
- 96% survive BC - poor signature (60% of patients)
- 50% die of BC
- 50% survive BC
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How can cfDNA/cfNA be used as a “liquid biopsy”
- Tumor related cfDNA, which circulates in the blood of cancer patients, is released by tumor cells in diff forms and at diff lvls. DNA can be shed as both dsDNA or ssDNA. Release of DNA from tumor cells can be thru apoptosis, necrosis, secretion etc.
- Can be used to detect both genetic and epigenetic alterations - Problem: But levels of cfNA may also reflect processes that are not tumor-specific (e.g. inflammatory disease, tissue trauma)
Circulating tumor DNA (ctDNA)
Q: Which mutations to look for?
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Circulating tumor DNA (ctDNA)
Q: Q: “If ctDNA hints at the presence of an undetected cancer, what then?”
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What is the main limitation of drug design?
most drugs inhibit biochemical functions rather than enhance biochemical functions (ie. very difficult to restore a function)
Which type of molecule is the most attractive target for drug development?
oncoproteins are the most attractive targets for drug development (and signal-transducing proteins immediately downstream of oncoproteins)
What are the 3 characteristics of a “druggable” target protein?
- Functional considerations (e.g. oncoprotein)
- Therapeutic index (measurement of the extent to which a treatment affects a tumor compared to its effects on normal tissues; the ratio of these two effects.)
- Biochemical properties (e.g. well defined catalytic cleft and measurable enzymatic function)
Describe the function of mechanism of the drug Gleevac
Drug (Gleevec) binds to the catalytic cleft of the Abl tyrosine kinase domain; inhibits tyrosine kinase activity of the Bcr-Abl fusion protein in CML
What are the characteristics of a “drug-like compound”?
Lipinski’s Rule of Five (RO5) (reduce attrition)
- MW 500 daltons
- ClogP 5 (octanol-water partition coefficient log P; hydrophobicity)
- H-bond donors 5
- H bond acceptors (sum of N and O atoms) 10
Remarks: no more than 1 violation; not applicable for substrates or transporters and antural products
You now have a good drug-like compound; what next?
Pre-clinical testing
what is Pre-clinical testing
refers to all of steps in research and development of an agent or therapeutic protocol leading up to but NOT including initiation of clinical testing
