Application
A targeted polymeric nanoparticle drug that inhibits NADPH Oxidase (NOX1/4)-Reactive oxygen species (ROS) signal for the treatment of chemotherapy drug and radiotherapy resistant cancers.
Key Benefits
- Inhibits tumor growth.
- Dual chemo-and radiotherapy enhancer.
- Excellent biocompatibility and stability.
- CD44 targeted drug delivery and intratumoral cell drug release.
- High drug loading capability (18%).
- Capability of large-scale production.
Market Summary
Breast cancer is the most frequently diagnosed cancer in women and the leading cause of cancer death in women. Although surgery offers a curative treatment in cancer patient at the early stage, many patients are diagnosed with local or distant advanced cancer. Chemotherapy and/or radiotherapy are given to those patients before or after surgery. For the patients with advanced diseases that are surgically un-resectable, chemotherapy and/or radiotherapy are the most common therapy. Unfortunately, resistance to therapy is the major clinical challenge and cause of cancer death.
Technical Summary
Emory researchers have synthesized a biodegradable hyaluronic acid nanoparticle (HANP) encapsulating GKT831 for targeted cancer therapy and overcome therapy resistance. GKT831 is a putative NOX1 and NOX4 inhibitor, developed by Genkyotex (Switzerland) for the treatment of fibrosis by oral administration. GKT831 has beneficial effects on inhibition of fibroblasts without systemic toxicity. The anti-tumor effects of GKT831 have also been reported in prostate cancer. Hyaluronic acid has proven to be a natural selective CD44-targeting moiety. HANP/GKT831 nanoparticle/drug delivers into tumor cells by the binding to CD44 receptor that is highly expressed in many types of human cancers. Following systemic administration, HANP/GKT831 delivered into tumors by both the enhanced permeability retention (EPR) effect and inherent CD44 targetability. HANP/GKT831 then binds to CD44 highly expressed in tumor cells and is internalized into the endosomes/lysosomes for intratumor cell drug releases triggered by hyaluronidase 1 digestion of the HANP carrier. The developed nanoparticle/NOX inhibitor has demonstrated effects on tumor growth inhibition and enhancement of therapeutic response to chemotherapy drugs and radiation therapy to overcome therapy resistance in human cancers. Based on the design and mechanism of the action of the nanoparticle-drug, it has the potential for the development of new therapeutic approaches for many types of human cancers. Preclinical studies showed strong therapeutic effects after the combination therapy with chemotherapy and low-dose radiotherapy in breast and colon cancer models in mice, which are the common cancer types.
Developmental Stage
Preclinical efficacy studies have been conducted to evaluate therapeutic effect in two breast cancer patient derived xenograft (PDX) models, a human colon cancer (PDX) model and a mouse colon cancer model in immune competent mice. HANP/GKT831 treatment alone induced a modest inhibitory effect. The combination of HANP/GKT831 with chemotherapy drugs or radiotherapy significance inhibited tumor growth in all the above tumor models, and in some cases, led tumor regression. At present, the researchers are evaluating therapeutic responses in additional human PDX tumor models and mouse tumor models, such as lung cancer models, to determine therapeutic effect. Currently, NOX1/4 inhibitor, GKT831, is on clinical trials for the treatment of primary biliary cholangitis, idiopathic pulmonary fibrosis and kidney fibrosis by oral administration. Preliminary results indicate positive safety and tolerability profiles for GKT831 at 400mg OD and 400mg BID.