Research Project
10138223
PROJECT SUMMARY An estimated 1 million cases of breast cancer (BC) are diagnosed annually worldwide. Of these, approximately 170,000 are triple-negative (ER-/PR-/HER2-) breast cancer (TNBC). TNBCs have an aggressive clinical course, worse prognosis, shorter disease-free interval, and worse overall survival compared to receptor positive breast cancers. Owing to the lack of target receptors, chemotherapy remains the only systemic therapeutic option in the adjuvant and metastatic setting of this disease. Even with combined surgery, cisplatin, and radiotherapy, response rates remain low at 50-60%. Thus, novel therapeutics are greatly needed. Obesity increases the risk of BC in postmenopausal women by 30-50% and decreases the efficacy of BC therapies in all patients. Many studies have shown the critical role of leptin, and leptin receptor (ObR/LEPR) in TNBC recurrence and metastasis. To counteract the oncogenic activity of leptin in TNBC, several groups have designed ObR antagonists and have shown success in TNBC studies. However, previous ObR antagonists had intrinsic limitations in their potency, solubility, and limited activity in obese mice. To overcome this, we are proposing to advance a novel second-generation ObR antagonist called Allo-aca, that binds ObR with a Kd of 2 pM and inhibits leptin-induced mitogenic activity at picomolar and low nanomolar concentrations. Studies have shown Allo-aca enhanced survival by 51% compared to treatment with cisplatin (28.1 vs 18.6 days respectively) in a MDA-MB-231 TNBC mouse model and also inhibits VEGF activity. Furthermore Allo-aca: 1) is the most potent ObR antagonist in vitro and in vivo; 2) has a wide therapeutic index of ~ 50:1 in mice; 3) is highly soluble in aqueous solution and crosses the blood-brain barrier; 4) inhibits proinflammatory transcription factor NF?B and reduces inflammatory disease; 5) and has shown efficacy in numerous disease models with obese mice. These studies suggest that Allo-aca has the potential to overcome the limitations of previous ObR antagonists. In this Phase I proposal, we propose to assess whether Allo-aca exerts any off-target effects in a standard screen against key channels and receptors in Aim 1. In parallel in Aim 2, we will assess the in vitro effects of Allo-aca on cell proliferation and its impact on molecular markers such as epithelial-mesenchymal transition and ObR signaling. We will follow-up with mouse studies in Aim 3 to identify the most optimal dose of Allo-aca (Aim 3A) that results in the greatest enhancement in survival against the well-defined 4T1 xenograft model and assess inhibition of tumorigenesis and metastasis against two additional PDX models (Aim 3B). These studies will be conducted in mice fed a high fat diet to induce weight gain. Altogether, this proposal will allow us to directly test our hypothesis that Allo-aca can increase survival and is an effective suppressor of tumorigenesis and metastasis through inhibition of the LEP-ObR axis and translate these results in PDX strains isolated from TNBC patients. If successful, these results will remove the current roadblocks on ObR antagonist development and serve as a critical step in translating decades of leptin BC research into a tangible clinical therapeutic.
