Example 4: Model approach for anti-tumor drugs

Problem: to identify potential biomarkers indicating high probability of hormonal resistance development in breast cancer cells.

Drugs assessed: tamoxifen, raloxifene, fulvestrant, etc.

Motivation:

  • The efficiency of endocrine therapy of estrogen receptor (ER)-positive breast cancer is limited by development of hormone-independent tumors which are resistant to antiestrogens initially or acquire resistance de novo during the therapy with antiestrogens (tamoxifen, raloxifene).
  • In most cases tumor cells do not lose ERs but capability for hormone-independent growth forms as a result of disorders or changes intracellular signal transduction pathways including growth factors receptors activation.

Approach:

  • to develop model of breast cancer development and progression,
  • verify it on the basis of available experimental facts and data,
  • apply the model to identify potential biomarkers indicating development of hormonal resistance.
ex4_breastcancer_1.jpg Result 1: Model of breast cancer development and progression has been developed and verified against data available in public sources.
ex4_breastcancer_2.jpg Result 2: Using the model we have identified potential biomarkers.

Conclusion:

NFkB-activity and expression levels of some NFkB-dependent genes (A20, COX2 and others) can be possible prognostic markers of endocrine therapy resistance development and probable targets for developing new strategies to prevent the emergence of acquired mechanisms of drug resistance in breast cancer.

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