Research and Development that creates hope. Natsar is developing innovative therapies that could deliver profound impact in fighting lung, brain & breast cancer, sarcoma, and many other diseases.

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Who is Natsar?

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.

Photo of Venu Raman Ph.D

Venu Raman Ph.D

Professor, John's Hopkins University, Founder & Director, NATSAR

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Photo of David Loeb M.D.,Ph.D

David Loeb M.D.,Ph.D

ACTING CHIEF CLINICAL OFFICER

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Photo of Phuoc Tran M.D.,Ph.D

Phuoc Tran M.D.,Ph.D

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Photo of Paul van Diest M.D., Ph.D

Paul van Diest M.D.,Ph.D

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Photo of Vered Stearns M.D.

Vered Stearns M.D.

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photo of Yoon-Jae Cho M.D.

Yoon-Jae Cho M.D.

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The Technology

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).

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.

Results Include:

  • Knockdown of DDX3 in highly aggressive lung cancer cell lines (H1299 and A549) curbed their colony‐forming abilities.
  • A small molecule inhibitor of DDX3, RK‐33, designed to bind to the nucleotide‐binding site within the DDX3 protein was synthesized.
  • RK‐33 was able to induce cell cycle arrest causing apoptosis in aggressive lung cancer, but not in normal cells, and promoted sensitization to radiation in DDX3‐overexpressing cells. Mechanistically, RK‐33 inhibited non‐homologous end joining and impaired Wnt signaling by disrupting the DDX3–β‐catenin axis.
  • RK-33 displays strong efficacy in multiple solid tumor models including: sarcoma, breast, prostate, colorectal, lung, and medulloblastoma.
  • RK‐33 in combination with radiation, induced tumor regression in multiple mouse models of lung cancer, while showing no toxicity at the therapeutic dose.
  • No observable toxicity in rat blood/liver profiles in both immune competent & immune suppressed mice.
  • Demonstrated RK-33’s effect to preferentially kill cancer cells while sparing normal cells.
  • Generated an antibody that can detect DDX3 in biopsy samples and therefore identify appropriate patients.

Clinical Development

Our clinical development plan will include sarcoma and breast cancer. 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. Subsequent clinical development is planned in multiple solid tumors including prostate, and medulloblastoma, and in combination with radiation.

News & Press Releases

Read more about Natsar below.

New Review Article: Targeting Host DEAD-box RNA Helicase DDX3X for Treating Viral InfectionsNew Review Article: Targeting Host DEAD-box RNA Helicase DDX3X for Treating Viral Infections
January 1, 2021

January 2021 – A new review article “Targeting host DEAD-box RNA helicase DDX3X for treating viral infections” is published in Antiviral Research by Natsar's founder and Professor of Radiology and Oncology at Johns Hopkins School of Medicine, Dr. Venu Raman.  Natsar’s small molecule, RK-33 has been demonstrated to effectively abrogate virion production in both + ssRNA (DENV, WNV, and ZIKA) and -ssRNA (RSV and hPIV-3) infections.

RNA Polymerase II-Associated Factor 1 Regulates Stem Cell Features of Pancreatic Cancer Cells, Independently of the PAF1 Complex, via Interactions with PHF5A and DDX3RNA Polymerase II-Associated Factor 1 Regulates Stem Cell Features of Pancreatic Cancer Cells, Independently of the PAF1 Complex, via Interactions with PHF5A and DDX3
November 1, 2020

In pancreatic CSCs, PAF1 forms a sub-complex that regulates expression of genes that control stem cell features. Knockout of PAF1 reduced the ability of pancreatic tumors to develop and progress in mice and numbers of CSCs.

Target Update: "RNA-binding protein DDX3 mediates posttranscriptional regulation of androgen receptor: A mechanism of castration resistance"Target Update: "RNA-binding protein DDX3 mediates posttranscriptional regulation of androgen receptor: A mechanism of castration resistance"
October 26, 2020

In this paper by Vellky et al. the authors have demonstrated that high DDX3 expression downregulates androgen receptor (AR) expression, leading to the generation of castration-resistant prostate cancer phenotypes. Interestingly, the authors showed that treatment with RK-33, both in vitro and in vivo, deregulates DDX3 expression, thus sensitizing the castration-resistant prostate cancer cells to AR-signaling inhibitors. Significance of this finding is that use of RK-33, in a clinical setting, for castration-resistant prostate cancer treatment is a strategy that can be exploited both to decrease the generation of castration-resistant prostate cancers as well as potentially prevent the recurrence of castration-resistant prostate cancer.

Natsar releases new podcast, “Cancer Matters with Dr. Bill Nelson – Developing a Cancer Drug”.Natsar releases new podcast, “Cancer Matters with Dr. Bill Nelson – Developing a Cancer Drug”.
February 3, 2020

In this week's Cancer Matters podcast, Dr. Bill Nelson speaks with Dr. Venu Raman about his work to develop a cancer drug targeting a gene that stabilizes tumors.