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Purpose Rectal cancer is often clinically resistant to radiotherapy (RT) and identifying molecular markers to define the biologic basis for this phenomenon would be valuable. The nuclear factor κ-light chain-enhancer of activated B cells (NF-κB) is a potential anti-apoptotic transcription factor that has been associated with resistance to RT in model systems. The present study was designed to evaluate NF-κB activation in patients with rectal cancer undergoing chemoradiotherapy to determine whether NF-κB activity correlates with the outcome in rectal cancer patients. Methods and Materials A total of 22 patients underwent biopsy at multiple points in a prospective study and the data from another 50 were analyzed retrospectively. The pretreatment tumor tissue was analyzed for multiple NF-κB subunits by immunohistochemistry. Serial tumor biopsy cores were analyzed for NF-κB–regulated gene expression using reverse transcriptase polymerase chain reaction and for NF-κB subunit nuclear localization using immunohistochemistry. Results Several NF-κB target genes (Bcl-2, cellular inhibitor of apoptosis protein [cIAP]2, interleukin-8, and tumor necrosis factor receptor-associated-1) were significantly upregulated by a single fraction of RT at 24 h, demonstrating for the first time that NF-κB is activated by RT in human rectal tumors. The baseline NF-κB p50 nuclear expression did not correlate with the pathologic response to RT. However, an increasing baseline p50 level was prognostic for overall survival (hazard ratio, 2.15; p = .040). Conclusion NF-κB nuclear expression at baseline in rectal cancer was prognostic for overall survival but not predictive of the response to RT. Larger patient numbers are needed to assess the effect of NF-κB target gene upregulation on the response to RT. Our results suggest that NF-κB might play an important role in tumor metastasis but not to the resistance to chemoradiotherapy.

Standard therapy for stage II/III rectal cancer consists of a fluoropyrimidine and radiation therapy followed by surgery. Preclinical data demonstrated that bortezomib functions as a radiosensitizer in colorectal cancer models. The purpose of this study was to determine the maximum tolerated dose (MTD) of bortezomib in combination with chemotherapy and radiation.Patients with locally advanced rectal adenocarcinomas, as staged by endoscopic ultrasound, were eligible. Bortezomib was administered on days 1, 4, 8, and 11 every 21 days for 2 cycles with 5-fluorouracil at 225 mg/m2/day continuously and 50.4 Gy of radiation. Dose escalation of bortezomib was conducted via a standard 3 + 3 dose escalation design. A subset of patients underwent serial tumor biopsies for correlative studies.Nine patients in 2 dose cohorts were enrolled. Diarrhea was the principal dose-limiting toxicity and occurred at the 1.0-mg/m2 dose level. There was no clear evidence of suppression of nuclear factor-kappaB target gene expression in biopsy samples.The MTD of bortezomib in combination with chemotherapy and radiation may be below a clinically relevant dose, limiting the clinical applicability of this combination. Performing biopsies before and during irradiation for determining gene expression in response to radiation therapy is feasible.

Yearly, 50,000 Americans die of colorectal cancer metastases to liver and lung. EGFR-targeted agents improve survival in a subset of metastatic colorectal cancer (mCRC) cases, and overexpression of the HER-family ligands amphiregulin (AREG) and epiregulin (EREG) correlates with EGFR-targeted agent susceptibility. Here we present evidence of association between EREG overexpression and disease aggression by showing that knockdown of EREG or HER3 impede anchorage independent growth in the HCT 116 CRC cell line. We also find that a HER3-EREG axis gene signature groups mCRC tumors into prognostically distinct groups. Snap-frozen CRC hepatic metastases (65) with patient matched normal liver, as well as 71 primary CRC tumors with patient matched normal colonic mucosa were analyzed via qRT-PCR for receptors (HER1-4) and ligands (AREG, and EREG). Among the mCRC cases HER2, HER3, AREG, and EREG were expressed at higher levels than unmatched normal mucosa (p50 um diameter) of 170 for HER3, and 285 for EREG as compared to 530 for the empty vector (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4527. doi:1538-7445.AM2012-4527