There is an increasing demand for the development of intermediate biomarkers to assess colon cancer risk. We previously determined that a live cell bioassay, which assesses apoptosis resistance in the nonneoplastic colonic mucosa, detects f50% of patients with colon cancer. A hypothesis-driven biomarker that reflects apoptosis resistance in routine formalin-fixed, paraffin-embedded tissue would be easier to use. Cytochrome c oxidase is a critical enzyme that controls mitochondrial respiration and is central to apoptosis. We did an immunohistochemical study of cytochrome c oxidase subunit I expression in 46 colonic mucosal samples from 16 patients who had undergone a colonic resection. These included five patients without evidence of colonic neoplasia (three normal and two diverticulitis), three patients with tubulovillous adenomas, and eight patients with colonic adenocarcinomas. Analysis of aberrancies in expression of cytochrome c oxidase subunit I showed that, compared with nonneoplasia, the patients with neoplasia had a higher mean incidence of crypts having decreased expression (1.7 versus 22.8, P = 0.03) and a higher mean incidence having crypt-restricted loss (0.6 versus 3.2, P = 0.06). The percentage with segmented loss was low and was similar in the two groups. Combining these results, the mean % normal (i.e., with none of the three types of abnormality) was 96.7 in nonneoplasia versus only 73.2 in patients with neoplasia (P = 0.02).

General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms 1 Mammary analogue secretory carcinoma of the salivary glands: a diagnostic dilemma AbstractMammary analogue secretory carcinoma (MASC) is a recently identified salivary gland neoplasm that can mimic other salivary gland tumours such as acinic cell carcinoma and cystadenocarcinoma. It is distinguished from these by differences in immunohistochemical profile and the identification of an ETV6-NTRK3 translocation (12;15)(p13;q25), which is also found in secretory carcinomas of the breast. Previous publications have suggested that MASC tumours have similar biological behaviour to acinic cell carcinoma. We report two cases of MASC that affected the upper lip, and showed an infiltrative and locally aggressive growth pattern that required several operations to ensure clearance of microscopic tumour cells. We report two cases of MASC of the upper lip, which showed locally aggressive biological behaviour and required a more aggressive treatment than that adopted for histological mimics such as acinic cell carcinoma. Keywords Case 1An otherwise healthy 27-year-old woman presented with a one-year history of a slowgrowing 1.5 cm lump, on her right upper lip. Cytological analysis of ultrasound-guided fine needle aspirate suggested a salivary gland neoplasm that raised the possibility of acinic cell carcinoma. The lesion was excised and histopathological analysis confirmed the diagnosis of MASC after immunohistochemical studies had stained for S100 and mammaglobin. It did not stain for DOG1. Fluorescent in situ hybridisation confirmed rearrangement of the ETV6 gene.Staging scans showed no evidence of metastases. The margins of the specimen were invaded on histopathological analysis despite the impression of macroscopic clearance at operation.She subsequently had a wedge excision of the scar with a 1cm margin but then required a repeat resection after microscopic identification of residual dispersed islands of tumour that had reached the margins. The patient had no signs of local or regional recurrence nine months after her operation (Figs. 1-3). Case 2A 51-year-old man who used to smoke and had no other relevant medical history presented with a three-year history of an asymptomatic, firm, mobile lump in his upper right labial mucosa. Histopathological examination of an excisional biopsy specimen together with immunohistochemical profile and fluorescent in situ hybridisation again suggested a diagnosis of MASC. Staging scans showed no abnormality. 3The patient had a further excision of the scar with a 1cm margin under general anaesthetic.Final histopathological analysis again showed residual tumour with a close margin at the deeper aspect of the specimen. The patient declined any further intervention so a policy of close follow-up was adopted. There were no signs of local or regional recurrence at hi...

Pms2 protein is a component of the DNA mismatch repair complex responsible both for post-replication correction of DNA nucleotide mispairs and for early steps in apoptosis. Germline mutations in DNA mismatch repair genes give rise to hereditary non-polyposis colon cancer, which accounts for about 4% of colon cancers. However, little is known about the expression of mismatch repair proteins in relation to sporadic colon cancer, which accounts for the great majority of colon cancers. Multiple samples were taken from the non-neoplastic flat mucosa of colon resections from patients with no colonic neoplasia, a tubulovillous adenoma, or an adenocarcinoma. Expression of Pms2 was assessed using semiquantitative immunohistochemistry. Apoptosis was assessed in polychrome-stained epoxy sections using morphologic criteria. Samples from patients without colonic neoplasia had moderate to strong staining for Pms2 in cell nuclei at the base of crypts, while samples from 2 of the 3 colons with a tubulovillous adenoma, and from 6 of the 10 colons with adenocarcinomas, showed reduced Pms2 expression. Samples from patients with an adenocarcinoma that had reduced Pms2 expression also exhibited reduced apoptosis capability in nearby tissue samples, evidenced when this paired tissue was stressed ex vivo with bile acid. Reduced Pms2 expression in the colonic mucosa may be an early step in progression to colon cancer. This reduction may cause decreased mismatch repair, increased genetic instability, and/or reduced apoptotic capability. Immunohistochemical determination of reduced Pms2 expression, upon further testing, may prove to be a promising early biomarker of risk of progression to malignancy.

Focal Adhesion Kinase (FAK) is a cytoplasmic non-receptor tyrosine kinase important in mediating signal transduction in cell migration, survival and proliferation. Up-regulation of FAK in the tumor cells has been shown to enhance tumor malignancy and correlate with poor prognosis. FAK signaling has also been implicated in impacting tumor microenvironment, including endothelial cells and fibroblasts. However, much less is known about how FAK in the tumor stroma affects tumor progression, or how stromal FAK cross-talks with cancer cells. Here we use an inducible Col1α2-creERT, FAK f/f genetic engineered mouse model (GEMM) to specifically delete FAK in the fibroblasts. Using the GEMM, we found that FAK in stromal fibroblasts facilitates breast tumor growth and metastasis in vivo. We further showed that conditioned media (CM) from human breast cancer cells induced FAK Y397 autophoslphorylation and expression of smooth muscle actin (SMA, a marker for cancer-associated-fibroblasts [CAFs]) of normal human lung fibroblasts. Interestingly, only the breast cancer CM educated fibroblasts, but not the naive un-treated fibroblasts, were able to promote breast cancer cell migration and invasion. Lastly, knockdown of FAK in these “educated” fibroblasts abolished their ability to promote breast cancer cell migration and invasion. Taken together, these data suggest a potential role of stromal FAK in creating a pro-tumorigenic microenvironment for breast cancer development and progression, and provide further rationale in therapeutic benefits of FAK inhibition against various solid tumors.    Citation Format: Hsin-Jung Wu, Syn Kok Yeo, Megan Wilson. The role of FAK in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5887. doi:10.1158/1538-7445.AM2017-5887

e13509 Background: Glioblastoma (GB) is characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone containing lipid nanodispersion effectuates a switch in cancer energy sourcing from glycolysis towards mitochondrial OXPHOS, i.e. reverses Warburg effect, providing rationale for its potential utility in treatment of GB. The current study investigated utility of BPM31510 alone and in combination with temozolomide. Methods: In vitro (U251-MG human GB cell line) and in vivo (C6 glioma rat model) preclinical models of GB were used to assess the anti-cancer activity of BPM 31510 alone (100 mg/kg/d) and combination with TMZ/bevacizumab (BEV). In addition, an in vitro model of acquired TMZ chemo-resistance was established by progressive adaptation of parental U251-MG cells to increasing doses of TMZ. Parental and resistant subclones (TMZ-R) were used to define activity of BPM31510 in the TMZ-refractory setting. Results: In vitro results demonstrated that BPM 31510 has anti-cancer activity in both parental and TMZ-R U251-MG cells with EC50 values of ~400 µM and 800 µM, respectively. Importantly, BPM 31510 treatment also resensitized TMZ-R cell lines to TMZ. In vivo, BPM 31510 treatment was associated with increasing duration of survival; one fifth of the rats treated achieved survival greater than 15 days post implantation, a response not observed in the control or irradiation arms of the study. Assessment of the combination of BPM 31510 with TMZ or BEV in the in vivoC6 glioma rat model is ongoing. A phase I open-label, non-randomized clinical trial to evaluate the safety and tolerability of BPM31510 in patients with recurrent BEV-refractory GB, as well as the changes in GB metabolism by SUV-PET imaging in response to treatment is under investigation. Conclusions: Preclinical data demonstrate that BPM 31510 has potential anti-cancer activity alone and in combination with standard therapy regimens and alleviates TMZ chemo-resistance in preclinical models of GB. These results provide support of a Phase 1 clinical study of BPM31510 in GB; this study is actively enrolling.