The Rho family GTPases Rho, Rac, and Cdc42 have emerged as key players in cancer metastasis, due to their essential roles in regulating cell division and actin cytoskeletal rearrangements; and thus, cell growth, migration/invasion, polarity, and adhesion. This review will focus on the close homologs Rac and Cdc42, which have been established as drivers of metastasis and therapy resistance in multiple cancer types. Rac and Cdc42 are often dysregulated in cancer due to hyperactivation by guanine nucleotide exchange factors (GEFs), belonging to both the diffuse B-cell lymphoma (Dbl) and dedicator of cytokinesis (DOCK) families. Rac/Cdc42 GEFs are activated by a myriad of oncogenic cell surface receptors, such as growth factor receptors, G-protein coupled receptors, cytokine receptors, and integrins; consequently, a number of Rac/Cdc42 GEFs have been implicated in metastatic cancer. Hence, inhibiting GEF-mediated Rac/Cdc42 activation represents a promising strategy for targeted metastatic cancer therapy. Herein, we focus on the role of oncogenic Rac/Cdc42 GEFs and discuss the recent advancements in the development of Rac and Cdc42 GEF-interacting inhibitors as targeted therapy for metastatic cancer, as well as their potential for overcoming cancer therapy resistance.

Background Even though targeted therapies are available for cancers expressing oncogenic epidermal growth receptor (EGFR) and (or) human EGFR2 (HER2), acquired or intrinsic resistance often confounds therapy success. Common mechanisms of therapy resistance involve activating receptor point mutations and (or) upregulation of signaling downstream of EGFR/HER2 to Akt and (or) mitogen activated protein kinase (MAPK) pathways. However, additional pathways of resistance may exist thus, confounding successful therapy. Methods To determine novel mechanisms of EGFR/HER2 therapy resistance in breast cancer, gefitinib or lapatinib resistant variants were created from SKBR3 breast cancer cells. Syngenic therapy sensitive and resistant SKBR3 variants were characterized for mechanisms of resistance by mammosphere assays, viability assays, and western blotting for total and phospho proteins. Results Gefitinib and lapatinib treatments reduced mammosphere formation in the sensitive cells, but not in the therapy resistant variants, indicating enhanced mesenchymal and cancer stem cell-like characteristics in therapy resistant cells. The therapy resistant variants did not show significant changes in known therapy resistant pathways of AKT and MAPK activities downstream of EGFR/HER2. However, these cells exhibited elevated expression and activation of the small GTPase Rac, which is a pivotal intermediate of GFR signaling in EMT and metastasis. Therefore, the potential of the Rac inhibitors EHop-016 and MBQ-167 to overcome therapy resistance was tested, and found to inhibit viability and induce apoptosis of therapy resistant cells. Conclusions Rac inhibition may represent a viable strategy for treatment of EGFR/HER2 targeted therapy resistant breast cancer.

Within the context of the UN Sustainable Development Goals for the Agenda 2030, this article aims to explain and understand the usefulness of energy audits and their potential to reveal energy efficiency opportunities in a small public building located in northwestern Mexico. The methodological structure was adopted from the Cleaner Production–Energy Efficiency Manual published by the United Nations Program for the Environment. A case study approach was employed to examine how energy audits might potentially increase energy efficiency opportunities in the participating building. Amongst the findings, the primary source of energy wastage was occupants’ behaviors. Furthermore, this study showed that energy audits could be useful to establish a baseline in situations where previous data were not available, to allow comparisons as well as to identify opportunities in old buildings for the purpose of increasing their energy efficiency performance. As a practical implication of this research, the Sonora government can be in a better position to assist the Mexico federal government in reaching some of the country’s General Law on Climate Change objectives, particularly the one related on cutting down greenhouse gas emissions by 30% by the year 2020, and 50% by the year 2050, compared to those registered in 2000.

The meat processing industry, due to its high energy consumption, needs to be assessed in an energy usage basis. This paper reports the results and implications of an energy audit in a meat processing industry. In addition, this work provides a comprehensive and practical approach to energy saving measures in the assessed company to recognize factors that can determine a possible transition to sustainable patterns of electricity consumption. The paper described the application to energy auditing, developed by AFNOR (2014) for efficient energy management along with ISO 50001 (energy management systems). For a more specific energy auditing the guide described by Dall "O" (2013) was used. In this case, a study of an integrative characterization of the company's energy consumption is made. The research has been divided in two main sections: the first includes an analysis about the characterization of the energy consumption within a meat processing company in the three sustainable approaches such as economical, societal and mainly environmental implications; second, a proposal for strategic energy management measures focusing on high consumer types of facilities. The results obtained allow the identification of main processes with significant correlations in terms of energy consumption within the company. This data has the potential for energy savings. The data acquisition process prompts the development of practical and accessible energy efficiency measures. In addition, a benchmarking analysis with several tools is performed. Altogether, this work gives guidance on the implementation of energy auditing in industries within its geographical and industrial sector limitations.

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Breast cancer is the second leading cause of mortality among women in the US. Among the various subtypes, human epidermal growth factor receptor 2 (HER2) positive breast cancer shows a very aggressive and invasive phenotype. This subtype is characterized by the overexpression of HER2 receptor on the cell surface that upon ligand binding and dimerization, leads to overactive cell signaling that promotes cell proliferation and metastasis. Even though therapies have been developed to treat this type of breast cancer by targeting HER2 and preventing dimerization (eg. Trastuzumab), patients can present with acquired or intrinsic therapy resistance. One of the mechanisms of resistance is the compensation of intracellular signaling from other receptors. This signaling converges on guanine nucleotide exchange factors (GEFs) that activate Rac and Cdc42 by exchanging GDP for GTP, thus activating downstream effectors that modulate the actin cytoskeleton to promote cell migration and invasion. Therefore, targeting Rac and Cdc42 activation selectively in HER2 positive breast cancer is a promising strategy for overcoming HER2-targeted therapy resistance. Previously, we characterized the dual Rac/Cdc42 inhibitor MBQ-167 that inhibits Rac and Cdc42 activity with IC50s of 103nM and 78nM, respectively. However, there is a need to develop selective delivery systems that transport MBQ-167 directly into HER2-positive breast cancer cells. Our objective is to deliver MBQ-167 selectively into HER2-positive cells using liposomes coated with Trastuzumab, a clinically used monoclonal antibody that targets HER2. We conjugated Trastuzumab to a lipid linker (DSPE-PEG-Maleimide) by reacting Trastuzumab with 2-iminothiolane (Traut’s reagent) under nitrogenated (low oxygen) conditions and then mixing with the lipid linker overnight. This reaction was characterized by measuring the thiol groups formed after the reaction with Traut’s reagent and after mixing with the lipid, followed by mixing the Trastuzumab-lipid conjugate with liposomes containing MBQ-167. To quantify the amount of MBQ-167 in the liposomes, we determined the excitation/emission parameters of the molecule and measured the concentration of MBQ-167 by fluorescence. We found an increase in thiol groups after the reaction with Traut’s reagent, which decreased after mixing with the lipids, suggesting the formation of the DSPE-PEG-Trastuzumab conjugate. Additionally, we determined the excitation/emission parameters (320nm/430nm), quantified a lower limit of detection (LLOD) at 0.1mM, and calculated an encapsulation efficiency of 97% (530μM). Future studies include testing our formulation in vitro and in vivo in HER2+ breast cancer models. Citation Format: Luis E. Velazquez, Suranganie Dharmawardhane. Characterization of immunoliposomes for HER2-targeted delivery of the dual Rac/Cdc42 inhibitor MBQ-167 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1998.

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