Natsar Pharmaceuticals is an applied research and drug development company focused on the development of novel treatments for cancer and other diseases. In our quest to characterize cellular pathways that are essential for the oncogenic state, we have focused on helicases which are dysregulated in many cancer types.
One such helicase is DDX3, which is overexpressed in many cancer types and has been associated with lower survival in lung cancer patients. We have synthesized a DDX3 inhibitor, RK‐33, which can potentially be used in cancer treatment. Binding of RK‐33 to DDX3 impedes the function of DDX3, resulting in activation of cell death pathways, inhibition of the Wnt‐signaling pathway, and abrogation of non‐homologous end‐joining (NHEJ) activity. In combination with radiation, synergistic cell death effects have been observed both in vitro and in multiple preclinical cancer models. We are currently moving this synthesized compound into clinical trials.
Based on our identification of an RNA helicase, DDX3, which is overexpressed in many cancer types and has been associated with lower survival in lung cancer patients, we have designed a first‐in‐class small molecule inhibitor, RK‐33, which binds to DDX3 and abrogates its activity. Inhibition of DDX3 by RK‐33 causes G1 cell cycle arrest, induces apoptosis, and promotes radiation sensitization in DDX3‐overexpressing cells. Overall, inhibition of DDX3 by RK‐33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for cancer therapy.
The target. DDX3 is a member of the DEAD‐box family which is involved in a number of cellular processes such as transcription, RNA splicing, mRNA export, and translation initiation (Lorsch, 2002; Rocak & Linder, 2004). DDX3 has also been associated with cancer biogenesis (Hu et al, 2004). We identified DDX3 in a microarray screen of breast cancer cells exposed to cigarette smoke and demonstrated its role in cancer progression (Botlagunta et al, 2008).
DDX3 promotes proliferation and cellular transformation (Hu et al, 2004; Shih et al, 2007; Lee et al, 2008), has anti‐apoptotic properties (Li et al, 2006; Sun et al, 2008, 2011), modulates cell adhesion and motility (Chen et al, 2014), and responds to hypoxia via HIF‐1α (Botlagunta et al, 2011; Bol et al, 2013). Besides the oncogenic role of DDX3 in cancer biogenesis, there is a report that indicates loss of DDX3 via p53 inactivation can promote tumor malignancy in non‐small cell lung cancer (Wu et al, 2014).
Also, recent evidence has identified that DDX3 acts as an allosteric activator of casein kinase 1 in the Wnt/β‐catenin pathway (Cruciat et al, 2013). Initially, the Wnt/β‐catenin pathway was described in colon cancer. Activating mutations of DDX3 were also shown to be involved in pathogenic Wnt pathway activation in medulloblastoma (Jones et al, 2012; Pugh et al, 2012; Robinson et al, 2012) and chronic lymphatic leukemia (CLL) (Wang et al, 2011). Recently, it has been shown that activated Wnt signaling predicts decreased survival in lung cancer patients (Xu et al, 2011; Shapiro et al, 2013) and decreases sensitivity to radiation therapy (Woodward et al, 2007; Zhang et al, 2010).
The solution. RK‐33 binds to DDX3 and abrogates its activity, causing G1 cell cycle arrest, inducing apoptosis, and promoting radiation sensitization in DDX3‐overexpressing cells. Mechanistically, loss of DDX3 function either by shRNA or by RK‐33 impaired Wnt signaling through disruption of the DDX3–β‐catenin axis and inhibited non‐homologous end joining—the major DNA repair pathway in mammalian somatic cells. Inhibition of DDX3 by RK‐33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for cancer therapy. RK‐33 combined with radiation therapy has been shown to induce tumor regression in lung cancer models, with no toxicity at the therapeutic dose.
Our clinical development plan will begin with a focus on sarcomas. Sarcomas are cancers of the musculoskeletal system for which there are very limited treatment options and very few FDA-approved drugs. Although these are rare tumors in adults (comprising only 1% of all adult cancer), they are more common in children, accounting for over 20% of childhood cancer. Because they are rare, sarcomas tend to draw less attention in developing specific therapies, and as a result, there are few sarcoma-directed drugs in the pipeline. We will use a novel, biomarker-driven Phase I trial design. Enrollment will be limited to patients with DDX3 expression demonstrated on a pre-treatment tumor biopsy. Dose finding will be based on a Continual Reassessment Model, and there will be a sarcoma-only expansion cohort at the recommended Phase II dose to obtain preliminary evidence of efficacy, increased data on toxicity, and to allow pharmacodynamic and pharmacokinetic studies.
Read more about Natsar below.
Dr. Venu Raman, PhD, of Natsar Pharmaceuticals Inc., an applied research and drug development company focused on the development of novel treatments for cancer, will present at the BIO Investor Forum in San Francisco, California. The Natsar team also will participate in one-on-one meetings with industry stakeholders during the conference.
Preclinical tests show novel molecule called RK-33 stops cell proliferation and makes cells more sensitive to radiation
A multidisciplinary team led by Johns Hopkins researcher Venu Raman, Ph.D.
Researchers at Johns Hopkins believe down the road, the drug could be extremely effective in the fight against certain cancers.
On Dec. 15, 2015, an FDA-approved contract research organization started preparations for a Phase I trial, with completion estimated during November 2016.
Targeting DDX3 with a small molecule inhibitor for lung cancer therapy. View these RK-33 manuscripts for additional reference: