The pharmaceutical industry is faced with steadily declining R&D efficiency which results in fewer drugs reaching the market despite increased investment. A major cause for this low efficiency is the failure of drug candidates in late-stage development owing to safety issues or previously undiscovered side-effects. We analyzed to what extent gene expression data can help to de-risk drug development in early phases by detecting the biological effects of compounds across disease areas, targets and scaffolds. For eight drug discovery projects within a global pharmaceutical company, gene expression data were informative and able to support go/no-go decisions. Our studies show that gene expression profiling can detect adverse effects of compounds, and is a valuable tool in early-stage drug discovery decision making.

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Purpose Circulating tumor cells (CTCs) are prognostic in patients with breast cancer. Several technical platforms exist for their enumeration and characterization. Comparative studies between these platforms are scarce. The RareCyte CTC detection is theoretically more sensitive than the established CellSearch platform, which identifies only CTCs that express EpCAM and cytokeratin. This study prospectively compares CTC enumeration in patients with breast cancer in a paired analysis using these two platforms. It investigates survival outcomes in groups defined by a CTC count threshold. Design CTC enumeration was performed on 100 samples obtained from 86 patients with progressive metastatic breast cancer (MBC) in two independent laboratories each blinded to the clinical data and the results from the other platform. Results One hundred paired samples were collected and CTC counts were determined using the CellSearch and RareCyte CTC platforms. In total, 65% and 75% of samples had at least one detectable CTC in 7.5 mL blood with the CellSearch and the RareCyte systems, respectively. CTC counts with the CellSearch system ranged from 0 to 2289 with a median of 3 CTCs, the RareCyte CTC counts ranged from 0 to 1676 with a median of 3 CTCs. The number of samples with 5 or more CTCs in 7.5 mL of blood (the poor prognosis cut-off validated with the CellSearch system) blood was 45% with the CellSearch test and 48% with the RareCyte test. CTC counts quantified with the CellSearch and the RareCyte systems were strongly correlated (Spearman’s r = 0.8235 (0.7450–0.8795) p < 0.001). 86 patients were included for Kaplan–Meier survival analysis. An increased mortality risk in patients with CellSearch of 5 CTCs or more per 7.5 mL blood, with a log-rank hazard ratio of 5.164 (2.579–10.34) (p < 0.001) was confirmed. The survival analysis with RareCyte CTC counts with the identical cut-off showed a significantly impaired survival with a hazard ratio of 4.213 (2.153–8.244) (p < 0.001). Conclusion Our data demonstrate the analytical and prognostic equivalence of CellSearch and RareCyte CTC enumeration platforms in patients with MBC using the CellSearch cut-off. This is the first demonstration of prognostic significance using the RareCyte platform.

This study identifies and characterizes the antigen recognized by monoclonal antibody (mAb) 14C5. We compared the expression of antigen 14C5 with the expression of eight integrin subunits (A 1 , A 2 , A 3 , A v , B 1 , B 2 , B 3 , and B 4 ) and three integrin heterodimers (A v and lung (n = 16) cancer tissues. The colon carcinoma cells stained positive for 14C5 in 50% of tumors analyzed, whereas bronchoalveolar lung carcinoma and typical carcinoid were not positive for the antigen. More common types of non -small cell lung cancer, i.e., squamous (n = 5) and adenocarcinoma (n = 3), stained positive in 2 of 5 squamous carcinomas and in 1 of 3 investigated adenocarcinoma. Colon (95%) and lung (50%) carcinoma tissues showed extensive expression of antigen 14C5 in the stroma surrounding the tumor cells and on the membrane of the adjacent fibroblasts. We show for the first time that mAb 14C5 binds the vascular integrin A v B 5 , suggesting that mAb 14C5 can be used as a screening agent to select colon and lung cancer patients that are eligible for anti-A v B 5 -based therapies. [Mol Cancer Ther 2008;7(12):3771 -9]

The use of radiolabeled antibodies that are able to target primary tumors as well as metastatic tumor sites with minimal reactivity to normal tissues is a promising approach for treating pancreatic cancer. In this study, the integrin alpha(v)beta(5) is studied as a target for the diagnosis of and potential therapy for human pancreatic cancer by using the radiolabeled murine monoclonal antibody (mAb) 14C5. Biopsy specimens from human pancreatic tumors were examined for the expression of the integrin alpha(v)beta(5). The pancreatic tumor cell line Capan-1 was used to test the in vitro targeting potency of mAb 14C5 labeled with 125/131-iodine and 111-indium. Internalization, retention, and metabolism were investigated in cellular radioimmunoassays. Biodistribution and tumor-targeting characteristics were studied in Capan-1 xenografts. All tumor sections were positive for the integrin alpha(v)beta(5), with an extensive positive staining of the stroma. Saturation binding experiments showed high affinity with comparable K(d)s. In vitro internalization experiments showed a longer intracellular retention of (111)In-p-benzyl isothiocyanate-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bz-DOTA)-14C5 in comparison to (125)I-14C5 and (111)In-p-isothiocyanatobenzyl diethylenetriaminepentaacetic acid (p-SCN-Bz-DTPA)-14C5. In vivo radioisotope tumor uptake was maximum at 48-72 hours, with the uptake of (111)In-p-SCN-Bz-DOTA-14C5 (35.84 +/- 8.64 percentage of injected dose per g [%ID/g]) being 3.9- and 2.2-folds higher than (131)I-14C5 (12.16 +/- 1.03%ID/g) and (111)In-p-SCN-Bz-DTPA-14C5 (14.30 +/- 3.76%ID/g), respectively. Planar gamma imaging with mAb 14C5 indicated clear localization of the pancreatic tumors versus minimal normal tissue uptake. mAb 14C5 is a promising new antibody for targeting the integrin alpha(v)beta(5) for the diagnosis of and potential therapy for pancreatic cancer.