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1587.Full-Text.Pdf Published OnlineFirst February 23, 2010; DOI: 10.1158/1078-0432.CCR-09-3108 Clinical Imaging, Diagnosis, Prognosis Cancer Research Development of Immunohistochemistry Assays to Assess GALNT14 and FUT3/6 in Clinical Trials of Dulanermin and Drozitumab Howard M. Stern1, Mary Padilla4, Klaus Wagner2,5, Lukas Amler2, and Avi Ashkenazi3 Abstract Purpose: In vitro sensitivity to the proapoptotic receptor agonists dulanermin (rhApo2L/TRAIL) and drozitumab (DR5-agonist antibody) is strongly predicted by the expression of the O-glycosylation en- zymes GALNT14 in non–small cell lung cancer (NSCLC) cell lines (among others) and of FUT3/6 in colorectal cancer (CRC) cell lines. We developed immunohistochemistry (IHC) assays that measure GALNT14 and FUT3/6 levels in archival formalin-fixed, paraffin-embedded human tumor tissue to de- termine marker prevalence in NSCLC and CRC tissue and to enable the future examination of these markers in clinical trials. Experimental Design: GALNT14 or FUT3/6 ELISA-positive hybridoma clones were screened through IHC on cell pellets with known mRNA levels. The specificity of staining was examined in cell lines, normal tissue, and tumor tissue. Results: GALNT14 and FUT3/6 IHC exhibited a golgi staining pattern and correlated with GALNT14 and FUT3/6 (but not GALNT2 and FUT4) mRNA expression levels in cell lines and normal tissues, suggesting specificity. GALNT14 and FUT3/6 H-scores were significantly higher in cell lines sensitive to dulanermin (P = 0.01 and P = 0.0004, respectively) and drozitumab (P = 0.03 and P < 0.0001, respec- tively) versus resistant cell lines. GALNT14 and FUT3/6 H-scores varied widely, with ∼45% of NSCLC samples exhibiting weak to moderate GALNT14 staining (H-score of at least 25) and 70% of CRC samples exhibiting moderate to strong FUT3/6 staining (H-score of at least 125). Conclusions: GALNT14 and FUT3/6 expression can be assessed in human tumors using sensitive and specific IHC assays. Both assays are being deployed in ongoing clinical trials of dulanermin and drozitumab to assess potential utility for patient selection. Clin Cancer Res; 16(5); 1587–96. ©2010 AACR. Developing oncology drugs that have significant effect drugs with patients who have a high probability of clinical for patients has proven to be challenging for many rea- benefit. Accomplishing this task during drug development sons. One contributing factor is the diversity, at the molec- involves early efforts to identify potential biomarkers in ular level, of tumors that are classified similarly on the preclinical models and the development of appropriately basis of histology. As a consequence, most oncology che- validated diagnostic assays that can test these biomarkers motherapeutics do not impart a clinically meaningful ben- in early-stage clinical trials. efit in all treated patients. One strategy for addressing this Agents that target apoptosis are currently the subject deficit is the identification of molecular correlates of re- of intense investigation and stand to benefit from the sponse (or resistance) to specific therapies to better match development of diagnostic biomarkers. Most cells with cancer-initiating potential are eliminated from the body Authors' Affiliations: Departments of 1Research Pathology, by apoptosis, but some cells harbor mutations that enable 2Development Oncology Diagnostics, and 3Molecular Oncology, them to escape apoptosis, resulting in cell survival and the Genentech, Inc., South San Francisco, California; 4Ventana Medical Systems, Inc., Tucson, Arizona; and 5M.D. Anderson Cancer Center, development of malignant tumors (2, 3). As our under- Houston, Texas standing of the molecular basis of apoptosis has increased, Note: Supplementary data for this article are available at Clinical Cancer so too has research in the development of proapoptotic Research Online (http://clincancerres.aacrjournals.org/). agents that tip the balance toward tumor cell death. The Corresponding Authors: Howard M. Stern, Department of Research Pa- complex signaling cascade that leads to apoptosis is initi- thology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080. ated either intracellularly through the intrinsic pathway or Phone: 650-467-8194; Fax: 650-225-8989; E-mail: [email protected] and Avi Ashkenazi, Department of Molecular Oncology, Genentech, as a result of extracellular signals that trigger the extrinsic Inc.,1DNAWay,SouthSanFrancisco,CA94080.Phone:650-225- pathway (2, 3). Manipulation of the extrinsic pathway has 1853; Fax: 650-467-8195; E-mail: [email protected]. been a major focus of drug discovery. Stimulation of this doi: 10.1158/1078-0432.CCR-09-3108 pathway begins with the binding of a proapoptotic ligand ©2010 American Association for Cancer Research. such as apoptosis ligand 2/tumor necrosis factor–related www.aacrjournals.org 1587 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst February 23, 2010; DOI: 10.1158/1078-0432.CCR-09-3108 Stern et al. cancer, non–small cell lung cancer (NSCLC), and melano- Translational Relevance ma cell lines, with up to 30% of tissue samples from a va- riety of human cancers having relative GALNT14 mRNA The use of predictive diagnostic biomarkers to expression at levels comparable with those seen in dula- identify patients who may best respond to a particular nermin-sensitive cell lines (1). In CRC cell lines, GALNT3 type of cancer treatment is emerging as a crucial para- rather than GALNT14 mRNA levels were correlated with digm in the development of novel cancer therapies. sensitivity (P = 0.026), as were levels of FUT3 and FUT6 Previous work (1) reported the identification of the mRNA. In fact, high FUT3 and FUT6 levels were better pre- O-glycosylation enzymes GALNT14 and FUT3/6 as po- dictors of sensitivity than was GALNT3 (P = 0.01 for FUT3 tential diagnostic biomarkers for predicting response and P =0.0013forFUT6).Notably,FUT3andFUT6 to proapoptotic death receptor agonists. We have de- mRNA expression levels were highly correlated with each veloped and validated immunohistochemistry assays other in these cell lines, suggesting that regulation of to detect GALNT14 and FUT3/6 in human tissue and expression of these genes is coordinated. Overall, the high – describe the prevelance of expression in non small cell expression of GALNT14, GALNT3, FUT3, and FUT6 could lung cancer and colorectal cancer. These assays will en- predict responsiveness to dulanermin in 61% of cell lines able the examination of GALNT14 and FUT3/6 in clin- (positive predictive value) and a lack of sensitivity in 88% ical trials of proapoptotic death receptor agonists. of cell lines (negative predictive value; ref. 1). Wagner et al. (1) also showed a functional link between death receptor O-glycosylation and apoptotic signaling. Both pharmacologic inhibition of glycosylation and apoptosis-inducing ligand to proapoptotic “death re- enzyme knockdown through small interfering RNAs ceptors” such as DR4 and DR5. Ligand-binding facilitates targeting GALNT14-, GALNT3-, and FUT6 reduced receptor clustering and the formation of a death-inducing dulanermin-induced apoptosis. Furthermore, GALNT14 signaling complex through the recruitment of the Fas- overexpression in pancreatic cancer cells substantially in- associated death domain adaptor protein. Fas-associated creased death-inducing signaling complex formation and death domain helps activate the downstream initiator caspase-8 and caspase-3 processing, whereas the prog- and effector caspases, which mediate apoptotic cell ressive mutation of DR5 at sites of O-glycosylation death (4–8). weakened apoptotic signaling. In addition, GALNT14 Several agents that trigger the extrinsic apoptosis knockdown in pancreatic cancer cells and FUT6 knock- pathway through the activation of the proapoptotic death down in colon cancer cells reduced caspase-8 processing, receptors are currently in development (2, 3). These “pro- but did not appreciably alter DR4 or DR5 levels (1), apoptotic receptor agonists” include the recombinant supporting the conclusion that the glycosylation status of human apoptosis ligand 2 tumor necrosis factor–related DR4/5 can affect apoptotic signaling independent apoptosis-inducing ligand (dulanermin), which targets from DR4/5 levels. Biochemical analysis further revealed both DR4 and DR5 (2, 3, 9–11), and monoclonal anti- that O-glycosylation facilitates ligand-induced clustering bodies that activate either DR4 (mapatumumab) or DR5 of DR4 and DR5, an event required for the efficient recruit- (drozitumab, lexatumumab, conatumumab, tigatuzumab, ment and activation of caspase-8 (1). and LBY-135; refs. 2, 3, 12–15). Preclinical studies using More recently, this body of work has been expanded certain cell lines and in vivo xenograft models have shown to the examination of sensitivity to the DR5-agonist anti- promising results with these agents in a wide range of body, drozitumab. As observed for dulanermin, drozitu- tumor types, both alone and in combination with tradi- mab sensitivity correlates with the expression of GALNT3, tional chemotherapies and molecularly targeted agents GALNT14, and FUT3/6 expression in several tumor cell (2, 16). However, in keeping with most oncology drugs, types (19). In pancreatic cancer and NSCLC cell lines, proapoptotic receptor agonists are not universally effective statistically significant correlations were observed between in all tumor cell lines, resulting in efforts to identify mo- GALNT14 levels and drozitumab
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