cancer biomarker strategy to develop companion diagnostics for predicting prescription drug induced...

7/30/2019 Cancer Biomarker Strategy to Develop Companion Diagnostics for Predicting Prescription Drug Induced Tumors - A

1/6

1 | P a g e Cancer Biomarker Strategy to Develop Companion Diagnostics for Predicting Prescription Drug Induced Tumors- Analysis using pioglitazone (Actos) and bladder cancer

h t t p : / / w w w . s c i c l i p s . c o m

Published online on November 20, 21012; Link to the original blog:http://www.sciclips.com/sciclips/blogArticle.do?id=1024&blog=Cancer%20Biomarker%20Strategy%20to%20Develop%20Companion%20Diagnostics%20for%20Predicting%20Prescription%20Drug%20Induced%20Tumors%20-%20Analysis%20using%20pioglitazon%20%28Actos%29%20and%20bladder%20cancer

Cancer Biomarker Strategy to Develop

Companion Diagnostics for Predicting

Prescription Drug Induced Tumors Analysis

using pioglitazone (Actos) and bladder cancer

Cancer biomarkers can be used for developing assays for clinical diagnosis, identifying patients

response to a particular drug, optimizing personalized drug treatment regimen (drug dose, drugtreatment schedule etc.), monitoring the efficacy of treatment (disease stage, tumor progression, tumor

recurrence etc.) and in cancer theranostics (1).With the growing trend towards the advancement ofpersonalized medicine concept, companion diagnostic tools may play a significant role in patient

stratification by identifying patients with positive clinical response to an existing or novel treatmentmethod. However, current limitations in identifying life-threatening side effects of therapeutic drugs

may have negative impact on developing efficient drug therapy strategies, often difficult to identify

short or long term side effects of drugs during clinical trials. Therefore, there is a need for developingpredictive methods and assays for identifying secondary disease causing side effects of drugs. Wepropose disease specific diagnostic biomarkers as an attractive tool for predicting the occurrence of

secondary diseases from a specific drug treatment method. In one of our earlier blogs, we haveproposed that drug-efficacy/drug response biomarkers might be possibly used for predicting disease

causing side effects of therapeutic drugs (2). In this blog, we tried to explore the potential of cancerdiagnostic biomarkers for predicting therapeutic drug (non anti-cancer drugs) induced cancer

occurrence in patients. We have adopted hypothesis driven intelligent data mining and contextualfunctional mapping of biomolecules associated with biomarkers and drug targets to identify possible

pathways and biomolecules that are associated with prescription drug induced tumor formation.Strategic identification of such biomolecules might lead to the development of companion diagnostic

tools that may help in identifying patients at risk of developing cancer following a therapeuticregimen. Moreover, success in this approach will also help in identifying alternative therapies, such as

combination therapy, and novel therapeutic drug targets. In order to test our hypothesis, we chose theanti-diabetic drug pioglitazone (Actos), which has been reported to form bladder cancer in patients

(3)(4)(5)(6)(7)(8)(9)(10) . For identifying biomolecules that might be potentially associated with

pioglitazone induced bladder cancer development in diabetic patients, hypothesis driven functional


2/6



Fig. 1: Potential pathways associated with pioglitazone (Actos) induced bladder cancer formationin patients with diabetes

integration and identification of biomolecules, incorporating traditional pathway analysis, linked to

bladder cancer specific diagnostic biomarkers and drug target (PPARgamma) were adopted (Fig. 1).Several diagnostic biomarkers have been reported for bladder cancer, among these biomarkers we

have randomly selected Cox-2(11), metalloproteinases (12)(13) and PGE2 (14) for this theoreticalexploratory analysis.

A. Potential companion diagnostic biomarkers for predicting tumor inducing properties of

therapeutic drugs (e.g. pioglitazone)

1. Prostaglandin2 (PGE2) and PGE2 induced bladder cancer stem cells

Pioglitazone (Actos) is a thiazolidinedione (TZD) anti-diabetic drug that selectively activates the

nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-gamma). Like other TZDs,pioglitazone induces insulin-sensitive genes (transcriptional regulation) associated with control of

glucose and lipid metabolism in muscle, adipose tissue, and the liver through the activation of PPARgamma (15). Studies have shown that expression of PPAR gamma represses activator protein-1 (AP-

1) and nuclear factor kappa B (NF-kappaB) transcriptional activity. Down-regulation of PPAR gammainduces the expression of COX-2 (16)(17), the PGE2-generating protein, which may induce

tumorigenesis by up-regulating VEGF ((19). Although pioglitazone was shown to inhibitcyclooxygenases-2 (COX- 2), several studies have reported that pioglitazone can also induce

increased expression and activity of COX-2 (20)(21)(22). In contrast, reduction in PGE2 levelsinduced by pioglitazone in lung cancer cells was shown to be through COX-2 independent pathway,

without affecting prostaglandin synthases (23). Whether pioglitazone induces reduction of PGE2

through COX-2 dependent or independent pathway, PGE2 can also be induced or produced by severalother signaling pathways that are not directly associated with pioglitazone. Increased expression andactivation of P2X7R in diabetic bladder urothelium was shown to induce the release of PGE2 and

ATP (24)(25) and VEGF signaling have also been shown to be associated with the production ofprostaglandins (26). Furthermore, increased production of COX-2-derived prostaglandin I2 (PGI2) has

been reported after pioglitazone treatment (27). PGI2 is a hypoxia induced metabolite, which isassociated with cancer and other diseases (28). Hypoxia may result in increased expression of COX-2(29)(30)(31)) and probably pioglitazone treatment induced hypoxia may result in the production of

COX-2 derived PGE2 production. Pioglitazone may increase the availability of arachidonic acid, theprecursor of production of prostaglandins, without affecting COX-1, COX-2, and cPLA2 expression

(32)(33). Increased COX-2 activity, without altering COX-2 expression, was reported in rat

myocardium after pioglitazone treatment (34)(35)(36)Thus, elevated levels of PGE2 can be induced by multiple mechanisms irrespective of COX-2inhibition by pioglitazone. Based on the above-mentioned observations, we believe deregulation of

PGE2 may play a critical role in the formation of bladder cancer from pioglitazone treatment.Therefore, PGE2 may be a potential companion diagnostic biomarker for predicting bladder cancer

formation in pioglitazone treated patients as well as a theranostics biomarker of bladder cancer. Thishypothesis can be further supported by following direct and indirect evidences:


3/6



Fig. 1: Potential pathways associated with pioglitazone (Actos) induced bladder cancer formation in

patients with diabetes

1) Increased production of PGE2 in glomeruli isolated from streptozotocin-induced diabeticrats (37) and in serum from children with diabetes (38) were reported. Elevated monocyteCOX-2 expression and circulating PGE2 levels were reported in diabetic patients (39) andincreased production of PGE2 was reported in all organs other than kidneys (40) in

diabetes. Up-regulation of PGE2 may be associated with pathogenesis of diabeticretinopathy (78). Moreover, PGE inhibitors have shown to improve insulin secretion in

type 2 diabetes (41).


4/6



2)

PGE2 may activate cancer formation though EP receptors, which can activate EGFRsignaling though the activation MMPs. PGE2 signaling stimulate cAMP productionthrough both EP2 and EP4 receptors and promote tumor growth by inhibiting apoptosis

(42). EP4 receptor as was reported to be a potential therapeutic target for pancreatic cancer(43)(44)(45). In human nonsmall-cell lung cancer (NSCLC), PGE2 can promote

malignant growth by stimulating angiogenesis, tumor invasiveness, apoptosis resistanceand inhibition of immune surveillance (46). PGE2 could be a candidate biomarker of

bladder transitional cell carcinoma (TCC) (47).3) Activation of EGFR signaling pathway was shown to be associated with induction of

urothelial proliferation over differentiation (48), where EGFR activation can be increasedby EGFR ligands such as HB-EGF produced by urothelial cells (49). EGFR signaling also

controls PGE2 catabolism through the downregulation of 15-hydroxyprostaglandindehydrogenase (15-PGDH), the enzyme that degrades PGE2, which was also shown to be

induced by pioglitazone (50). PGE2 can activate EGFR signaling through EP-receptor andthe release of AR from plasma membrane through activation of MMP activity (51).

Induction of MMP9 by EGF was reported in bladder cells and MMP9 may be a potentialbiomarker of bladder cancer (49)(52). PGE2 induces the expression of metalloproteinases

by a multistep process involving NF-kappaB (53).4) Increased expression of VEGF by PGE2 through EP2 and EP4 receptors have been

reported (54).5) Increased secretion of PGE2 was reported to be associated with inhibition of antigen-

presenting cell (APC) functions, secretion of Th2 cytokines, promotion ofimmunosuppressive microenvironment, malignant transformation and tumor progression

through local immune suppression (55)(56)(57)(58)(59)(60) . Secretion of significantamounts of PGE2 by bladder tumor cells have been reported (61).

6) The arachidonic acid (AA) PGE2 pathway is associated with aggressiveness of humantransitional carcinoma (TCC) (62). In prostate cancer cells, arachidonic acid (AA) was

shown to induce c-Fos mRNA expression in a PKA-dependent pathway via the EP4receptor (63). c-Fos was found to be associated with the development of human bladder

transitional epithelial cell carcinoma (BTCC) (64).7) Studies have shown that PGE2 can activate bladder cancer stem cells (65) and this was

further confirmed by the expression of stem cell markers Oct3/4 and CD44v6 in bladdercancer (66) (67)(68). CD44v6 was found to be a molecular marker of bladder cancer (69).

Therefore, bladder cancer stem cell markers could be used as potential biomarkers foridentifying pioglitazone induced bladder cancer formation.

8) Another important observation is the role of COX-2derived PGE2, as well as EGFRsignaling, in epithelial cell to a mesenchymal-like phenotype transition or transformation

(EMT), which was induced by reduced levels of E-cadherin. Over expression of COX-2can reduce the levels of E-cadherin through transcriptional repressors ZEB1and Snail (70).

Reduced expression of E-cadherin is associated with invasive bladder cancer (71).Moreover, Slug (Snail family of zinc finger transcription factor) plays a role in invasive or


5/6



metastatic bladder cancer and promotion of EMT through cadherin (72). Snail and Slugcan be used as biomarkers for predicting tumor recurrence in superficial bladder cancers((73). Slug may also be used as a potential marker or target for improving the diagnosis

and treatment of muscle-invasive bladder cancers (74). Studies have shown that the highmobility group A2 (HMGA2) gene, which was induced by the Smad pathway during EMT

(75), can be a potential prognostic marker for predicting tumor recurrence and progressionin bladder cancer (76).

9) COX-2/PGE2 signaling can lead to tumor initiation through aberrant activation of beta-catenin (80).

10)PGE2 activates phosophoinositide 3-kinase (PI3K) and protein kinase Akt through EP2receptor, and increased expression of the pro-survival protein Bcl-2, a suppressor of p53

induced apoptosis, via COX-2/PGE2 signaling (81). Activation of PI3K and decreasedexpression of p53 was shown to be associated with high susceptibility to bladder cancer in

type 2 diabetes mellitus model Zucker diabetic fatty (ZDF) rats (82).11)Wnt-PGE2 interaction regulates vertebrate development and organ regeneration (83) and

the deregulated wnt signaling palys a role in urothelial cell carcinoma (UCC) development(84).

It is also important to point out that, PGE2 derived from dietary fatty acids may also induce

increased PGE2 signaling that may contribute to the onset of cancer. Dietary fatty acids, consistedof essential polyunsaturated fatty acid, linoleic acid, have been shown to be associated with

prostate, colon and breast cancer (85). Arachidonic acid (AA) derived from linoleic acid is aprecursor of PGE2 and consumption of linoleic acid rich food may result in activating PGE2

signaling pathways. For example, corn consumption may result in increased levels of gastricPGE2 (86) and high linoleic acid diet may result in elevated urinary


6/6



3. Urinary citrate

Calcium-containing urinary solids, resulted from low citrate levels, induced by pioglitazone

treatment were found to be associated with increased urothelial cytotoxicity, necrosis, andregenerative proliferation (94). Although increased citrate synthase activity has been reported in

pioglitazone-treated patients, urinary citrate was decreased in these patients and induction ofmicrocrystalluria, which may be involved in the development of bladder cancer, have been

reported after pioglitazone treatment (95). High dose of pioglitazone (40 microM) was shown todecrease citrate synthase activity in NT2 cells(96). These studies indicate that urinary citrate

levels may be a potential biomarker for assessing the risk in developing bladder cancer followingpioglitazone treatment.

Although the results from our exploratory analysis are hypothetical and may not be conclusive, it

is evident from the strategy we have adopted for this analysis that cancer diagnostic biomarkersmay be potentially used for developing companion diagnostics tools that can be used for

predicting cancer forming side effects of non-anticancer therapeutic drugs. Comprehensive datamining and intelligent hypothesis driven data integration using different cancer specific diagnostic

biomarkers and therapeutic drug targets may help in identifying potential companion diagnosticbiomarkers, which may lead to the development of clinically viable diagnostic and theranostics

tools.

Note: This scientific blog is a contribution from Sciclips Consultancy team.

ReferencesReferences are hyperlinked to respective abstracts or full articles. Please click the referencenumbers to the citation details

Related blogs on biomarkers:

Strategies for Rational and Personalized Cancer Biomarker Discovery Cancer Theranostics Potential Applications of Cancer Biomarker Database How to Identify Clinically Successful Biomarkers? Potential Use of Drug Response-Efficacy Biomarkers for Predicting Life-Threatening Disease

Causing Side Effects of Therapeutic Drugs

Metabolon vs. Stemina Are Biomarkers Patents can be Considered as True Inventions?Related tools:

Comprehensive cancer biomarker database with companion diagnostics pathway Bioprotocols database

cancer biomarker strategy to develop companion diagnostics for predicting prescription drug induced...

Documents