Novel inhibition of central carbon metabolism pathways by Rac and Cdc42 inhibitor MBQ-167 and paclitaxel.

Triple negative breast cancer (TNBC) represents a therapeutic challenge where standard chemotherapy is limited to paclitaxel. MBQ-167, a clinical stage small molecule inhibitor that targets Rac and Cdc42, inhibits tumor growth and metastasis in mouse models of TNBC. Herein, we investigated the efficacy of MBQ-167 in combination with paclitaxel in TNBC pre-clinical models, as a prelude to safety trials of this combination in advanced breast cancer patients. Individual MBQ-167 or combination therapy with paclitaxel was more effective at reducing TNBC cell viability and increasing apoptosis compared to paclitaxel alone. In orthotopic mouse models of human TNBC (MDA-MB-231 and MDA-MB-468), individual MBQ-167, paclitaxel, or the combination reduced mammary tumor growth with similar efficacy, with no apparent liver toxicity. However, paclitaxel single agent treatment significantly increased lung metastasis, while MBQ-167, single or combined, reduced lung metastasis. In the syngeneic 4T1/BALB/c model, combined MBQ-167 and paclitaxel decreased established lung metastases by ~80%. To determine the molecular basis for the improved efficacy of the combined treatment on metastasis, 4T1 tumor extracts from BALB/c mice treated with MBQ-167, paclitaxel, or the combination were subjected to transcriptomic analysis. Gene set enrichment identified specific downregulation of central carbon metabolic pathways by the combination of MBQ-167 and Paclitaxel but not individual compounds. Biochemical validation, by immunoblotting and metabolic Seahorse analysis, shows that combined MBQ-167 and paclitaxel reduces glycolysis. This study provides a strong rationale for the clinical testing of MBQ-167 in combination with paclitaxel as a potential therapeutic for TNBC and identifies a unique mechanism of action.

Incidental finding of a gastric schwannoma: a case report.

Gastric schwannomas are rare peripheral nerve sheath tumors which are usually found incidentally while undergoing workup for other conditions. Despite their benign nature, they require surgical resection with negative margins. It is important to differentiate gastric schwannomas from gastrointestinal stromal tumors prior to surgical excision, as this can alter the recommended surgical plan. This can be achieved with endoscopic ultrasound and fine needle aspiration with analysis of the sampled tissue using immunohistochemical stains. We present the case of a 68-year-old female patient with an incidental finding of a gastric fundus schwannoma. Laparoscopic gastric wedge resection was performed with complete excision of the tumor and negative margins. Pathology was confirmed with immunohistochemical stains positive for S-100 and negative for CD117 and DOG1. Post-operative recovery was uneventful without tumor recurrence.

Intracystic papillary carcinomas of the breast: a reevaluation using a panel of myoepithelial cell markers.

Intracystic papillary carcinomas (IPC) of the breast have traditionally been considered to be variants of ductal carcinoma in situ (DCIS). However, it is not clear if all lesions categorized histologically as IPC are truly in situ carcinomas, or if some such lesions might represent circumscribed or encapsulated nodules of invasive papillary carcinoma. Given that the demonstration of a myoepithelial cell (MEC) layer around nests of carcinoma cells is a useful means to distinguish in situ from invasive carcinomas of the breast in problematic cases, assessment of the presence or absence of a MEC layer at the periphery of the nodules that comprise these lesions could help resolve this issue. We studied the presence and distribution of MEC at the periphery of the nodules of 22 IPC and, for comparison, 15 benign intraductal papillomas using immunostaining for 5 highly sensitive markers that recognize various MEC components: smooth muscle myosin heavy chain, calponin, p63, CD10, and cytokeratin 5/6. All 22 lesions categorized as IPC showed complete absence of MEC at the periphery of the nodules with all 5 markers. In contrast, a MEC layer was detected around foci of conventional DCIS present adjacent to the nodules of IPC. Furthermore, all benign intraductal papillomas, including those of sizes comparable to those of IPC, showed a MEC layer around virtually the entire periphery of the lesion with all 5 MEC markers. In conclusion we could not detect a MEC layer at the periphery of the nodules of any of 22 lesions categorized histologically as IPC. One possible explanation for this observation is that these are in situ lesions in which the delimiting MEC layer has become markedly attenuated or altered with regard to expression of these antigens, perhaps due to their compression by the expansile growth of these lesions within a cystically dilated duct. Alternatively, it may be that at least some lesions that have been categorized as IPC using conventional histologic criteria actually represent circumscribed, encapsulated nodules of invasive papillary carcinoma. Regardless of whether these lesions are in situ or invasive carcinomas, available outcome data indicate that they seem to have an excellent prognosis with adequate local therapy alone. Therefore, we believe it is most prudent to continue to manage patients with these lesions as they are currently managed (ie, similar to patients with DCIS) and to avoid categorization of such lesions as frankly invasive papillary carcinomas. Given our observations, we favor the term "encapsulated papillary carcinoma" over "intracystic papillary carcinoma" for circumscribed nodules of papillary carcinoma surrounded by a fibrous capsule in which a peripheral layer of MEC is not identifiable.