NU 2016-100

Inventors

Ali Shilatifard*

Lu Wang

Short Description

Small molecule agonists for the treatment of immunotherapy-resistant triple negative breast cancer (TNBC).

Background

About 10-20% of all breast cancers are triple negative, that is test negative for estrogen and progesterone hormone receptors as well as the HER2 receptor. Without these receptors, triple neative breast cancer (TNBC) shows unlikely response to conventional hormonal therapies including tamoxifen and Herceptin. As a result, five-year survival rates for women with TNBC are lower than women with other types of breast cancer (77% versus 93%, respectively). Therefore, the need for novel therapeutic approaches that effectively target TNBC cells or, even better, protect against TNBC development are crucial for improving patient outcomes.

Abstract

Northwestern researchers have identified a series of orally active small molecule agonists that target the AdipoR1 / AMPK signaling pathway as a viable therapeutic treatment for triple negative breast cancer (TNBC). This pathway is notably inactivated in TNBC and is also implicated in obesity. In fact, obese women are at a greater risk of presenting with TNBC than non-obese women. In molecular studies, researchers found that AdipoRON, an AdipoR1 agonist that was originally developed for type II diabetes, was found to significantly inhibit colony formation in multiple TNBC lines. The researchers went on to validate the effectiveness of the AdipoRON treatment using in vivo mouse models of TNBC. Consistent with in vitro studies, oral treatment of mice with AdipoRON was found to significantly reduce tumor size by more than half and increase survival rates by up to 25% when compared to a control. These studies demonstrate the therapeutic potential of a host of small molecule agonists against AdipoR1 as inhibitors of TNBC cell growth in vitro and in vivo. Moreover, options for oral medication offer oncology patients a less invasive treatment and more convienient option reducing the need for specialists to administer the drugs.

Applications

• Therapeutic for triple negative breast cancer

Advantages

• An alternative or adjuvant treatment to chemotherapy
• Oral delivery
• Evidence of decreased inflammation and oxidative stress in vivo
• Potential preventative treatment to protect against the development of TNBC development

Publications

Wang L, Collings C, Zhao Z, Cozzolino K, Ma Q, Liang K, Marshall S, Sze C, Hashizume R, Savas J and Shilatifard A (2017) A cytoplasmic COMPASS is necessary for cell survival and triple-negative breast cancer pathogenesis by regulating metabolism. Genes & Development. 31; 2056-2066

IP Status

US patent application has been filed.