Developing LG007 as a novel therapeutic agent to treat triple negative breast cancer

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PROJECT SUMMARY: For women in the United States, breast cancer is the most common malignancy and the second leading cause of death. In this application, we focus upon a specific subtype of breast cancer known as triple-negative breast cancer (TNBC). Compared to other breast cancer subtypes, TNBC is considered more aggressive and extremely difficult to treat with standard therapies. As a result, it has a high recurrence rate and a high overall mortality rate. TNBC accounts for up to 20% of all breast cancers, with a higher incidence in ethnic minority populations and young women (usually <40 years of age). Approximately 70% of patients with advanced TNBC die of disease recurrence and/or metastasis within 5 years of initial diagnosis. Therefore, there is an urgent need for the medical community to develop more effective therapeutic options for this deadly disease. In this project, we will investigate a novel experimental compound, named LG007, for its anti-cancer activity in TNBC. Of significance, we will utilize robust TNBC Patient-Derived Xenograft (PDX) mouse models to study the in vivo efficacy of LG007. Our preliminary results demonstrated that LG007 effectively inhibits TNBC tumor growth and metastasis. Notably, we found that LG007 treatment could robustly shrink large human-derived TNBC PDX tumors, with a near-complete response. These preliminary results strongly support the premise that LG007 is a novel and potent drug candidate capable of treating progressive TNBC and associated metastasis. Furthermore, we demonstrated that LG007 is able to target and regulate miR-10b, a well-known oncogenic miRNA that promotes tumor development and metastasis. Therefore, we hypothesize that miR-10b is a primary target of LG007 that is critically involved in the molecular mechanisms of action by which LG007 inhibits tumor growth and metastasis. Three specific aims are proposed in pursuit of the project’s objective to develop a new therapy for the treatment of TNBC. In Aim 1, we will determine the mechanistic roles of miR-10b and one of its targets, NR4A3, in the anti-TNBC activity of LG007. In Aim 2, we will investigate the in vivo efficacy of LG007 utilizing a variety of advanced mouse models that mimic the clinical setting of TNBC and its associated recurrence and metastasis. In Aim 3, we will characterize the pharmacological and toxicological properties of LG007 in preparation for future translation to clinical testing. We expect that the results obtained from this study will lead to the development of a novel, safe, and effective treatment for patients with advanced TNBC.