A cell-cell and cell-extracellular matrix (ECM) contacts

A growing bodyof evidence indicates that cell-cell and cell-extracellular matrix (ECM) contacts can modulatedrug resistance, and this phenomenon is called cell adhesion-mediated drugresistance (CAM?DR) 91, 92. Most mechanisms of CAM?DRare not fully understood, possibly due to multifactorial processes involving differentmolecular players, such as cell adhesion molecules and ECM components.The literature indicates that multidrug-resistant phenotypes ofcancer cells are associated with cell adhesion molecules that play a key rolein cell adhesion processes 92.An increasing number of studies demonstrate that different types of CAMs may beinvolved in the resistance to chemotherapy treatment 91, 93-98. This section discusses theliterature focusing on CAMs as attractive therapeutic targets to overcomechemoresistance in cancer therapy. The broadspectrum of CAMs are classified into different families, although most belongto four principal classes: Ig (immunoglobulin) superfamily (IgSF CAMs),integrins, cadherins and selectins. Some unclassified CAMs, including CD44 andEpCAM, are considered as separate to the above four classifications 99-101.

Over the past decade, anumber of studies have demonstrated that many CAMs are overexpressed inchemotherapy-resistant cancer cells, whereas some CAMs, such as integrin ?2?1,CD31 and E-cadherin, underexpressed in cancer cells 93, 102. The loss of E-cadherinexpression is related to chemoresistance  in response to Paclitaxel and DocetaxelTD1 , and epithelial-to-mesenchymaltransition 103, 104TD2 .Numerousstudies have demonstrated that cell-adhesion mediated drug resistance (CAM-DR) isbased on a number of mechanisms, such as decreasing of anticancer drug-inducedDNA damage and activation of DNA repair by the Fanconi anemiaTD3  (FA)/BRCA pathway 96, 105-109; increasing resistance todetachment-induced cell death (anoikisresistance), and inhibition of Fas-mediated apoptosis 110-113. Although CAM-DR is not main TD4 form of cancer drugresistance 114,recent studies have revealed a plethora of tumors that have altered expressionof CAMs associated with aggressive tumor growth, metastasis and resistance to chemotherapy.Therefore targeting CAMs introduces special interest TD5 for scientists andpharmacological companies as well as for the development of anti-CAM-DRstrategy to sensitize cancer cells 92, 115.Most research targetingCAM-DR TD6 has focused largelyon integrins 116-118 (see Table 2).

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Considerable efforts have been directed at examining the inhibitory action ofintegrin agonists, such as antibodies, peptides and small molecules 116, 119, 120. The syntheticArg-Gly-Asp-motif peptide integrin a5a3 inhibitor EMD-121974 (Cilengitide),was a very attractive drug for anti-CAM-DR strategyTD7 . Cilengitide was testedin several clinical trials for different types of tumors, including glioma,NSCLC and squamous cell carcinoma 121-125. Despite positive resultsfrom preclinical studies and second phase clinical trials, the addition ofcilengitide to temozolomide chemoradiotherapy did not improve patient’s overallsurvival with newly diagnosed glioblastoma in an EORTC phase III randomized,controlled, multicenter clinical trial 122. ExCentric, a multicentreopen-label phase II trial, showed that cilengitide combined with metronomictemozolomide and procarbazine in MGMT-promoter unmethylated glioblastoma didnot improve survival compared with historical data 125.Results of the randomized phase I/II ADVANTAGE trial (phase II part)demonstrated that cilengitide with cetuximab and platinum-based chemotherapy inrecurrent/metastatic squamous cell carcinoma of the head and neck did notresult in any positive outcome 124. Cilengitide combinedwith cetuximab and platinum-based chemotherapy was tested in an open-labelrandomized controlled phase II study (CERTO) as first-line treatment forpatients with advanced non-small-cell lung cancer (NSCLC) 123. The study showed thatpatients with advanced NSCLC had improved progression-free survival rate comparedwith control.

Different preclinicalin vitro and in vivo studies showed that targeting a4integrin by antibodies sensitizes multiple myeloma to chemotherapy using melphalanor bortezomib 126, 127 (Table 2), and a4 integrin small molecule inhibitorTBC3486 increases acute lymphoblastic leukemiasensitivity to vincristine treatment 128, 129.There is only one known phase I/II clinical trial (NCT00675428) in patientswith refractory multiple myeloma treated by Natalizumab, a recombinanthumanized IgG4 monoclonal antibody, which binds integrin-a4. However, this clinicaltrial was terminated due to low enrollment.

Itwas shown that the HMG-CoA reductase inhibitor simvastatin can selectivelyinhibit integrins and shows antimyeloma activity and up-regulates HMG-CoAreductase in chemotherapy-resistant cancer cells 130-132. Schmidmaier and co-authors showed that simvastatin at very lowconcentrations overcomes CAM-DR in multiple myeloma by geranylgeranylation ofRho proteins and activation of Rho kinase 133. Also,simvastatin reduces tumor cell adhesion to human peritoneal mesothelial cellsby decreased expression of VCAM-1 and ?1 integrin 134. Simvastatin as an inhibitor of CAM-DR in patients withrefractory multiple myeloma was tested in phase 2 clinical trials byLudwig-Maximilians – University of Munich. This clinical trial showed reductionof drug resistance by inhibition of HMG-CoA-reductase.Althoughmost studies in this area have focused on integrins, other CAMs have potentialfor anti-CAM-DR strategy. Thus, recent data showed that down-regulation ofendothelial adhesion receptor CD31/PECAM-1 was associated with resistanceagainst oxidative stress and DNA damage in angiosarcoma cells due to YAPsignaling, and inhibition of YAP by Pazopanib re-sensitized cancer cells to doxorubicin135. Pazopanibmay find use as a CAM-DR inhibitor as it inhibits VEGF-induced up-regulation ofadhesion molecules on tumor cells 136.

Pazopanibmaintenance therapy provided a statistically significant and clinicallymeaningful PFSTD8  benefit inpatients with advanced epithelial ovarian, fallopian tube, or primaryperitoneal cancers in phase III trials 137. E-cadherin TD9 is considered as a keyplayer in the process of acquiring chemoresistance 94, 103, 104, 138. Recently, Notchsignaling was identified to play a significant role in E-cadherin  associated cancer chemoresistance 103.The results of these preclinical studies suggest inhibitors of Notch signalingas potential anti CAM-DR drugs.

The ?-secretase inhibitorMK-0752 combined with docetaxel improved health of patients with advancedbreast cancer in Phase 2 clinical trial 139. Furthermore, thereis increasing evidence that selectins play an important role in the progressionof different types of cancer and CAM-DR 140-143. It was reported thatsmall molecule glycomimetic antagonist to selectins have the ability to inhibitselectins and to sensitize cancer cells. Recently, the addition of E-selectininhibitor GMI-1271 to standard agents based chemotherapy induction in untreatedelderly patients with acute myeloid leukemia demonstrated a high remission ratewith acceptable side effect profile and low induction mortality 144.CD44 atransmembrane receptor for hyaluronan is a functional component of celladhesion-mediated drug resistance 145, 146. Recently, Zheng  et all reported that small molecule aurora kinase inhibitorattenuates breast tumor-initiating cells and overcomes epirubicin  resistance by inhibition of CD44 147.

These data stronglysupport that translation of CAM-DR signaling pathway regulators to clinic incombination with standard therapy can be considered as a rational strategy toovercome resistance.Incomparison with the significant advances in other strategies for overcomingchemoresistance progress made with respect to anti CAM-DR has been relativelyslow. Main clinical trial failure became cilengitide in Newly DiagnosedGlioblastoma in phase III clinical trial. Despite the challenges in this areaand gaps in our knowledge our understanding is that a creation of effectivestrategies for overcoming chemoresistance will require a better understanding through cell adhesion drug resistance interactionwith other types of chemoresistance.

Table 2 summarizes CAM signalingpathways involved in chemoresistance.    TD1cancer types??prostatecancer  TD2what does this mean?   TD3this needs better explanation  TD4meaning?  TD5explain better TD6you need to double check these datawith the references and Table 2 as mistakes are being made.   TD7why??  TD8define abbrevs  TD9I stopped here as I am tired  Overto you to do a second dratft based upon my changes.


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