The grant titled, ‘Developing a novel PROTAC-based NR4A1 degrader for breast-cancer therapy’ will focus on revolutionizing treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. This is a partnering PI option with Dr. Zheng, Guangrong; co-investigators: Dr. Zhou, Daohong, Dr. Bacher, Rhonda and was chosen for funding. It is a 3-year grant, with collective direct budget $750,000.
Benefit patient population: Breast cancer remains the most prevalent and second most lethal cancer types among woman worldwide. While most recent breakthroughs are related to cancer immunotherapy, the benefit of immunotherapies in breast cancer is very limited. The principle of immunotherapy is to activate patient immune system to fight and kill cancer. As we know cancer has a complex cellular composition including cancer cells, immune cells and other cells that are coordinated and evolved for cancer progression. Most if not all cancer drugs are purposely designed to target one cell type, either by directly killing cancer cells (including chemo or other targeted therapies) or activating immune systems (including current immunotherapies). Our goal is to step out the classic way of thinking and ask an important question: can we identify the optimal molecular target that can be inhibited to kill cancer cells and activate immune system simultaneously? Here we are able to present a molecule, namely NR4A1, as one of the optimal targets. Here are the evidence we believe NR4A1 is important molecular target in breast cancer:
1) NR4A1 plays a critical role in cancer cells, by maintaining cancer cell survival and promoting invasive process of cancer cells;
2) We also found that NR4A1 is critical to inactive immune system by various ways so that the patient immune system cannot kill cancer cells efficiently.
Based on these important functions, we want to develop a drug based on a state-of-the-art PROTAC technology that can inhibit and degrade NR4A1 to inhibit cancer cell function and active immune system. Based on our initial assessment, patients with triple negative breast cancer–the most aggressive breast cancer subtype–may benefit the most from this drug due to nature of this type of breast cancer with sensitivity to immunotherapy.
Clinical applications, benefits and risks: We chose NR4A1 as a target not only based on its potential efficacy but also its expected low toxicity. NR4A1 deletion in mouse has no obvious phenotype indicating it is dispensable for normal development and inhibiting NR4A1 is expected to have minimal toxicity to patient. The application will initially aim for breast cancer patients with advanced diseases who otherwise have no other better choices for therapy. If the efficacy is greater than other neoadjuvant therapeutics, we expect to expand the usage in cancer patients as frontline treatment that may benefit majority of breast cancer patients.
Projected Timelines: This level one award is expected to produce at least one lead compound to degrade NR4A1 efficiently. We already got a proof-of-principle compound that can specifically degrade NR4A1 and kill cancer cells. We will optimize, design, and validate new compounds to get the most efficacious one for further development. Mouse models are in place for preclinical testing. We aim to apply for higher level of breakthrough grant for further translation of this drug if proven feasible. We aim to have the first clinical testing within a 7-8 years, based on our experience on another similar drug development in the same team.
Impact: Our proposed studies use the emerging PROTAC technology to achieve the first proof-of-concept evidence for targeting NR4A1, a nuclear receptor, to proteasome-mediated degradation. We have tested a batch of NR4A1 PROTACs and found several with outstanding activity to degrade NR4A1 at an effective dose of sub-micromolar concentrations. The optimization will focus on varying linker length, composition, as well as using new NR4A1 ligands. Aim 2 will determine the efficacy, toxicity, as well as lineage specific functions of these novel PROTACs. This will contribute to our scientific understanding how NR4A1 contributes to breast cancer progression. Overall, this breakthrough level 1 project will lead to the production of at least a lead compound that fits our need, i.e. to be the one stone that kills three birds at the same time. The current effort is purposely aimed for next level of breakthrough grant applications for potential clinical translation of treating breast cancer patients, likely a better and safer option than current treatment regimens in late stage cancer patients.