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Supplementary Data from Radiosensitization of Epidermal Growth Factor Receptor/HER2–Positive Pancreatic Cancer Is Mediated by Inhibition of Akt Independent of Ras Mutational Status

Purpose: Epidermal growth factor receptor (EGFR) family members (e.g., EGFR, HER2, HER3, and HER4) are commonly overexpressed in pancreatic cancer. We investigated the effects of inhibition of EGFR/HER2 signaling on pancreatic cancer to elucidate the role(s) of EGFR/HER2 in radiosensitization and to provide evidence in support of further clinical investigations.Experimental Design: Expression of EGFR family members in pancreatic cancer lines was assessed by quantitative reverse transcription-PCR. Cell growth inhibition was determined by MTS assay. The effects of inhibition of EGFR family receptors and downstream signaling pathways on in vitro radiosensitivity were evaluated using clonogenic assays. Growth delay was used to evaluate the effects of nelfinavir on in vivo tumor radiosensitivity.Results: Lapatinib inhibited cell growth in four pancreatic cancer cell lines, but radiosensitized only wild-type K-ras–expressing T3M4 cells. Akt activation was blocked in a wild-type K-ras cell line, whereas constitutive phosphorylation of Akt and extracellular signal-regulated kinase (ERK) was seen in lines expressing mutant K-ras. Overexpression of constitutively active K-ras (G12V) abrogated lapatinib-mediated inhibition of both Akt phosphorylation and radiosensitization. Inhibition of MAP/ERK kinase/ERK signaling with U0126 had no effect on radiosensitization, whereas inhibition of activated Akt with LY294002 (enhancement ratio, 1.2-1.8) or nelfinavir (enhancement ratio, 1.2-1.4) radiosensitized cells regardless of K-ras mutation status. Oral nelfinavir administration to mice bearing mutant K-ras–containing Capan-2 xenografts resulted in a greater than additive increase in radiation-mediated tumor growth delay (synergy assessment ratio of 1.5).Conclusions: Inhibition of EGFR/HER2 enhances radiosensitivity in wild-type K-ras pancreatic cancer. Nelfinavir, and other phosphoinositide 3-kinase/Akt inhibitors, are effective pancreatic radiosensitizers regardless of K-ras mutation status. Clin Cancer Res; 16(3); 912–23

61 Background: Despite recent advances, pancreatic cancer remains an exceedingly morbid disease. This is often attributed to the lack of effective screening tools and the consequent late presentation of patients. The best prognosis is reserved for patients with resectable tumors thus highlighting the importance of swift evaluation and the initiation of treatment following a diagnosis. Multidisciplinary clinics allow for the expedient evaluation of patients by different subspecialties in the same day. Methods: A newly designed, multidisciplinary workflow (MDC-multidisciplinary care clinic) for patients recently diagnosed with pancreatic adenocarcinoma was established at a single, tertiary-care comprehensive cancer center in September of 2021. Patients presenting to MDC undergo same day consultation by surgical oncology, medical oncology, receive genetics counseling and testing, nutrition counseling, and additional support services as indicated. Patients from a prospectively maintained database were compared from before (n = 14) and after (n = 30) implementation of the new workflow. Average time to provider consultation, port placement, and initiation of neoadjuvant chemotherapy were compared using student’s t-test. Results: After a biopsy diagnosis of pancreatic adenocarcinoma, the time interval from initial surgical consultation to initial medical oncology consultation improved from 7d to 1d ( p=.003) with the implementation of MDC. Over 90% of patients were seen on the same day after the MDC was established, compared to just 7% before. There was no difference in the time from initial biopsy diagnosis to initial surgical consultation, biopsy to initial medical oncology consultation, biopsy to port placement, or biopsy to chemotherapy initiation. Conclusions: In this early experience with a new pancreatic cancer multidisciplinary clinic, patients experienced improvements in time to subspecialty evaluation by nearly 7 days. Additionally, prospective data on oncologic outcomes and patient quality-of-care metrics are ongoing; however, this quality improvement effort has already reduced patient burdens in accessing timely care. Our continued efforts focus on further improving care coordination along the entire patient cancer care trajectory.

Background: Neoadjuvant chemoradiation is a standard therapy for stage II-III rectal adenocarcinoma, and the degree of pathologic response observed upon resection informs prognosis. However, there is a need to identify novel biomarkers of response to chemoradiation and survival after chemoradiation, particularly using modern next-generation sequencing methods. Methods: We prospectively collected pretreatment endoscopic tumor biopsies from 43 patients with stage II-IV rectal adenocarcinoma prior to neoadjuvant chemoradiation with concurrent fluoropyrimidine. Tumor samples were fresh frozen, and subsequently RNA was extracted, paired end libraries for mRNA sequencing (RNASeq) were prepared using TruSeq RNA Access library prep kits (Illumina), and samples were sequenced on Illumina HiSeq. Differentially expressed genes were determined using DESeq2 and Ingenuity pathway analysis (Qiagen) was performed. Additionally, the association between “claudin-low”-like gene sets established in breast and bladder cancers and clinical outcomes was determined. Results: Among the 36 patients with adequate RNA quality, 7 had a pathologic complete response (pCR) and 29 did not, with 22 differentially expressed genes with false discovery rate (FDR) Conclusions: There are multiple differentially expressed genes associated with response to neoadjuvant chemoradiation in rectal adenocarcinoma. EME2, which forms an endonuclease that cleaves stalled replication forks, was one of the most differentially expressed genes overexpressed in patients with pathologic complete response and thus is a rational target for further investigation. Extension of “claudin-low” gene expression signatures to rectal cancers may serve as a new prognostic biomarker. Further investigation into the association of gene expression subtypes and responses to neoadjuvant chemoradiation is warranted. Citation Format: Michael S. Lee, Cheryl Carlson, Benjamin F. Calvo, Bert H. O'Neil, Dante S. Bortone, Benjamin G. Vincent. Differential gene expression is associated with response to chemoradiation and relapse-free and overall survival in rectal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3609.

12112Background: Alterations in gut microbial composition are associated with development and progression of colorectal cancer (CRC), and may contribute to interpatient biologic and clinical hetero...

656 Background: Alterations in gut microbial composition are associated with development and progression of colorectal cancer (CRC), and may contribute to interpatient biologic and clinical heterogeneity. While recent studies have emphasized primary CRC tumor site as explaining much of these differences, there is still marked heterogeneity in clinical outcomes among the more homogeneous subgroup of rectal cancers. As such, we hypothesized that differential mucosal microbial populations are associated with distinct clinicopathologic characteristics among patients with locally advanced rectal cancer. Methods: Patients with T3-4 or N+ rectal adenocarcinoma were prospectively identified and underwent endoscopic tumor biopsy before starting neoadjuvant chemoradiation. Tumor samples were fresh frozen, bacterial DNA was extracted, and the V1-V2 region of the 16S bacterial ribosomal RNA was sequenced (IonTorrent). Sequences were processed through QIIME and an average of 16,189 reads per sample was obtained after quality filtering. Multivariate analyses were conducted using PRIMER VII and SPSS v24 software. P-values were determined using Mann-Whitney tests, and Benjamini-Hochberg procedure for false discovery rate was used and only results with false discovery rate < 0.25 are presented. Results: Among the 37 patients, mean age at diagnosis was 54 (range 30-77) and pre-treatment clinical stage was II (30%) vs. III-IV (70%). Younger patients (age < 50) had samples underrepresented for Streptococcus (0.9% vs 7.1%, p = 0.016, FDR 0.224) genus. Higher clinical stage was associated with enrichment of Fusobacterium (16.2% vs 5.6%, p = 0.019) and Parvimonas (4.6% vs 1.4%, p = 0.033) genera. Conclusions: Differential composition of tumor mucosal microbiota is associated with key clinical features among rectal adenocarcinomas, including age of diagnosis and tumor stage. Further investigation to determine associations between gut dysbiosis and transcriptomic subtypes may shed light on etiology of interpatient heterogeneity of rectal cancers.

Although nephrectomy for renal cell carcinoma with inferior vena cava invasion is a common procedure, it is rare to have level IV invasion necessitating cardiopulmonary bypass (CPB). Furthermore, it is exceptionally rare to perform cardiac surgery concomitantly with this resection. We report a case in which an aortic valve replacement was done in the same surgical setting as a level IV thrombectomy. We have demonstrated that although it can be difficult to manage the coagulopathy post-CPB, this can be successfully accomplished with adequate prior preparation and a coordinated team effort.

Question: A 53-year-old man was referred for evaluation of a large cyst found during evaluation for abdominal fullness, early satiety and weight loss, and an abdominal mass on physical examination. Two endoscopic ultrasound (EUS) examinations with cyst fluid aspiration were performed before referral to our center revealing negative cytology with low levels of carcinoembryonic antigen (CEA), and absent levels of amylase and lipase. There was no history of alcohol use, pancreatic disease, family history of pancreatic disease, or personal history of malignancy. An abdominal MRI was performed before referral (Figure A). At our institution EUS was repeated. What is the diagnosis? Look on page 1229 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

Background: There has been great interest in developing novel agents and strategies to improve chemoradiotherapy (CRT) for locally advanced rectal cancer. Irinotecan, a campothecin (CPT) analogue, held high potential, but the combination was clinically infeasible due to severe gastrointestinal toxicities. CRLX101, is an investigational nanoparticle drug conjugate (NDC). Preclinical experiments showed that CRLX101 differentially delivers CPT into cancer cells and appears to durably suppress HIF-1α as well as topoisomerase 1, but with less gastrointestinal toxicities than irinotecan. We therefore hypothesized that the addition of CRLX101 to rectal CRT (5-FU + XRT) may further improve the therapeutic index in this setting. Methods: Synergy with CRLX101 in combination with either XRT or CRT was studied in vitro (SW480 and HT29 colorectal cancer cell lines) and in vivo (murine flank xenograft models). Skin toxicity and hematologic toxicity were also characterized. In order to test the synergy hypothesis in the clinic, a Phase Ib/II clinical trial (LCCC1315) evaluating the addition of CRLX101 to CRT in the neo-adjuvant treatment of rectal cancer is currently underway. A standard 3 + 3 design is being employed for the phase Ib with a CRLX101 starting dose of 12 mg/m2 in the first cohort escalating to the CRLX101 monotherapy MTD of 15 mg/m2 in the second. The primary phase 2 end-point is the pathological complete response (pCR) rate from treatment. Results: CRLX101 was found to be as potent as camptothecin in vitro. We have demonstrated that CRLX101 functions by inhibition of both DNA repair and HIF-1α signaling. The addition of CRLX101 to radiotherapy increased and prolonged the number of γH2AX foci, even at 24 hours post radiotherapy. We also confirmed that CRLX101 decreased HIF-1α and its downstream targets VEGF and carbonic anhydrase IX in mice bearing HT29 xenografts. Our findings were further validated in vivo: we demonstrated that both CRLX101+5FU+XRT and CRLX101+XRT delayed tumor growth more than other regimens (p-values < 0.05). More importantly, we found CRT with CRLX101+5FU is significantly more effective than CRT with oxaliplatin+5FU (25 days to double tumor volume vs. 11 days), a regimen that has been extensively studied clinically. Preclinical toxicity studies demonstrated that the addition of CRLX101 did not increase hematologic or skin toxicities. In the ongoing clinical trial, none of the first 6 patients enrolled have experienced dose-limiting toxicities, and 1 out of 3 patients who underwent surgery had a pCR. The other 2 patients had extensive treatment response with minimal residual tumor. Conclusions: Preclinical data suggests that CRLX101 improves the therapeutic index of CRT for rectal cancer. Preliminary clinical data is encouraging, and supports further clinical assessment of CRLX101+5FU+XRT in patients with locally advanced rectal cancer. Citation Format: XI TIAN, Minh Nguyen, Henry Foote, Kyle T. Wagner, Hanna K. Sanoff, Autumn J. McRee, Bert H. O'Neil, Benjamin F. Calvo, William A. Blackstock, Joel E. Tepper, Edward Garmey, Scott Eliasof, Andrew Z. Wang. Neoadjuvant chemoradiotherapy for rectal cancer with CRLX101, an investigational nanoparticle-drug conjugate with a camptothecin payload. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5515. doi:10.1158/1538-7445.AM2015-5515