Generating evidence-backed hypotheses in silico for novel prostate cancer biomarkers, Part II

The story of how, within just a few weeks, a scientist can uncover plausible biomarkers for a complex disease using IPA® for in silico research. We invite you to register for a webinar to hear Dr. Billaud present this in silico study live on September 7 or 21 or to listen to a pre-recorded video recording of his presentation.

By Jean-Noel Billaud, Associate Staff Scientist, Ingenuity. September 6, 2011

Part II: Exploring molecular mechanisms of prostate cancer using canonical pathways and gene views

(View Part I: Introduction)

The outstanding number of “scientific findings,” now over four million, in the Ingenuity® Knowledge Base allowed me to scan the broad literature on prostate cancer and quickly understand the biology of this disease. The power of IPA to provide biological insight is directly linked to IPA’s ability to use updated and relevant scientific literature to shed light on different molecular networks and pathways involved in normal and abnormal biology.

Having limited knowledge in oncology and a fortiori in prostate carcinoma (PCa), I used IPA as a powerful exploratory tool. This exploration will be illustrated by displaying some of the features of IPA that I used to understand the mechanisms of PCa progression.

The molecular marker “prostate specific antigen,” or KLK3, is in use by clinicians and pathologist to diagnose PCa and to monitor cancer stages. Using Gene View in IPA for KLK3, I learned that KLK3 is an important enzyme, specifically a serine endopeptidase that participates in the liquefaction of the seminal coagulum. KLK3 belongs to the prostate cancer signaling pathway, and this canonical pathway (CP) represents the main molecular cascades involved in the early and late development of PCa.

Among these cascades, the androgen receptor signaling pathway (AR) is central for the tumorigenic process (see Figure 2). AR is a nuclear receptor complexed by Heat Shock Proteins (HSP) and resides in the cytoplasm when unbound. Androgens (testosterone or dihydrotestosterone: DHT) bind to the cytoplasmic AR, inducing this receptor to dissociate from the HSPs and to translocate into the nucleus. Once in the nucleus, AR will bind to its cognate response element (androgen response element or ARE), and with the recruitment of coregulators (coactivators or corepressors), it will promote the expression of target genes (KLK3 is one of them).

The first stages of PCa are dependent on the AR signaling to progress. The different therapeutic approaches are therefore aimed at inhibiting the activation of this AR signaling by either blocking androgens synthesis or by adding androgens antagonist. Androgen and estrogen metabolism pathways highlight how androgens are synthetized, and I was able to discover what steps are inhibited by the current drugs in PCa therapies, by overlaying drugs onto this pathway in IPA.

Next I wanted to explore potential biomarkers for this dreadful disease, by looking at the biomarker section in the gene view for KLK3 (see Figure 3). I learned that this enzyme has been used in various areas of biomarker development, from safety to efficacy and from diagnosis to disease progression applications, mainly for prostate carcinoma but also in other disease areas such as hypertension or COPD.

In summary, IPA effectively helped me to explore the biology of a very complex disease, using key features such as Canonical Pathways, Gene Views, and biomarker information.

Next week my investigation continues with the integration of an mRNA expression dataset to understand key molecular and cellular functions involved in tumorigenesis, and the integration of transcription factor analysis to validate these findings and develop new hypotheses.

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