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Breast cancer is a leading cause of cancer mortality in women due to the high frequency of metastatic disease, which, despite advances in therapeutic options, is still essentially incurable. The role of Myc in promoting tumorigenesis is beyond doubt, but there are contradictory reports in the literature on its role in the metastatic process. Using a Myc dominant negative termed Omomyc, we have demonstrated in various mouse models that Myc inhibition is a safe and effective therapeutic approach against several types of cancer, regardless of the tissue of origin or the driver oncogenic lesion. So far, Omomyc has only been tested in primary tumors. However, since many steps of the metastatic cascade have been reported to depend on Myc, we hypothesized that Omomyc could be extremely effective in both the prevention and treatment of metastasis too. Here we show that Omomyc expression has a dramatic effect on colony formation capacity in human breast cancer cell lines representative of all the molecular subtypes of the disease. In MDA-MB-231 cells, not only did it impair their proliferation but also migration, invasion and their capacity to induce angiogenesis, key aspects of the metastatic process. We demonstrate that, in vivo, Omomyc reduces the growth of orthotopically-implanted human breast cancer cells in immunocompromised mice, induces regression of established metastases after primary tumor resection and impairs the development of lung metastases after tail vein injection. In the immunocompetent MMTV-PyMT transgenic model, Omomyc expression dramatically delays the formation and growth of mammary fat pad tumors, thereby preventing the appearance of lung metastases. When the purified Omomyc mini-protein is administered exogenously, we observe remarkable growth inhibition in vitro that recapitulates transgenic expression of Omomyc. Intravenous administration of the mini-protein reduces lung colonization and tumor growth in vivo. We have demonstrated for the first time the applicability of Omomyc against metastasis, challenging the pre-established notion that Myc inhibition could potentiate, rather than inhibit, invasion. Finally, we have validated the use of the purified Omomyc mini-protein as the first directly-deliverable Omomyc-based drug for the treatment of metastatic breast cancer, providing a new therapeutic opportunity for patients suffering from this dreadful and incurable disease. Citation Format: Daniel Massó-Vallés, Marie-Eve Beaulieu, Toni Jauset, Erika Serrano, Sandra Martínez-Martín, Laia Foradada, Virginia Castillo, Francisco Castillo, Génesis Martín, Sílvia Casacuberta-Serra, Mariano F. Zacarias-Fluck, Antonio Luque-García, Marta Escorihuela, Jonathan R. Whitfield, Joaquín Arribas, Laura Soucek. Translating Myc inhibition to the clinic in metastatic breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1823.

Introduction: The gastrointestinal tract (GI) is the second most affected organ system in systemic sclerosis or systemic/localized scleroderma (SSc) and is an important topic for research. Approximately 90% of patients with scleroderma exhibit pathology of the GI tract. The systemic scleroderma has the potential to impact any part of the gastrointestinal tract, between the oral cavity and anorectum. The pathological complications of scleroderma adversely impact the health-related quality of life of the affected patients and increase the treatment burden of patients and medical professionals. Study Aim: We summarized the epidemiology, commonly reported clinical manifestations, complications, and available therapies for treating the GI pathology in systemic scleroderma patients. Methodology: We performed a literature review using the keywords "systemic sclerosis," "scleroderma," "GI manifestations in scleroderma," and "GI complications of scleroderma" across databases, including Google Scholar, Medline, Embase, and PubMed. We also analyzed a range of case reports concerning scleroderma manifestations and treatment modalities. Results: Our research revealed the annual incidence of SSc attributing to19.3 cases per million adults in the United States. We found the highest incidence of systemic scleroderma in patients within the age range of 44-55 years. Our results affirmed 5:1 incidence of systemic scleroderma that confirmed the higher impact of this disease condition in females than male populations. We found that the gastrointestinal manifestations of systemic scleroderma predominantly elevate the morbidity and mortality incidence among the affected patients. Esophageal and intestinal manifestations impact 90% and 40-70% of patients with systemic scleroderma. The small bowel hypomotility and small intestinal bacterial overgrowth (SIBO) in systemic scleroderma cases trigger the episodes of malabsorption and malnutrition that eventually add to 50% of the mortality rate. Systemic sclerosis is associated with the high incidence of fecal incontinence that triggers depression and its deleterious mental health manifestations in many clinical scenarios. Conclusion: The gastrointestinal complications in systemic sclerosis potentially deteriorate the daily living activities of the affected patients. The systematic management of the gastrointestinal complications of systemic scleroderma warrants multidisciplinary approaches. Prospective studies should focus on developing targeted therapies for improving the recovery patterns and prognostic outcomes in systemic scleroderma cases.

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