Dicerna Pharmaceuticals, Inc., a leader in the development of RNAi therapeutics, today announced the presentation of new preclinical data on its Dicer substrate short interfering RNA (DsiRNA) therapeutics targeting MYC and β-catenin (CTNNB1) oncogenes in models of hepatocellular carcinoma (HCC) and colorectal cancer (CRC).
The positive data, presented during a poster session on January 9 at MYC: From Biology to Therapy, a meeting of the American Association of Cancer Research (AACR) in La Jolla, Calif., provide additional insights into the parameters that impact the delivery and activity of DsiRNA therapeutics utilizing Dicerna’s proprietary EnCore™ lipid nanoparticle (LNP) technology in HCC and CRC tumor models.
“The preclinical findings provide new evidence of the ability of DsiRNA therapeutics to target MYC and β-catenin, two key driver oncogenes responsible for many types of cancers,” said Douglas M. Fambrough, Ph.D., chief executive officer of Dicerna. “These results further validate the therapeutic hypothesis behind our programs and will help guide Dicerna’s development efforts as we progress the DCR-MYC program in Phase 1 clinical trials in HCC and other tumor types.”
The poster (abstract #358), titled, EnCore-LNP mediated tumor delivery of MYC and CTNNB1 Dicer substrate RNAs (DsiRNAs), highlighted data from multiple preclinical models in HCC and CRC. These new data include a pharmacokinetic (PK) study, which demonstrated that the PK properties of EnCore can be optimized to increase the tumor bioavailability of DsiRNAs.
In addition, researchers confirmed a robust, quantitative way to measure target engagement and the mode of action of MYC DsiRNA in a mouse model of HCC. Using a quantitative RNAi target engagement assay and next-generation sequencing (NGS) technology, researchers showed that more than 90% of MYC messenger RNA (mRNA) fragments in the tumor match the predicted DsiRNA target site. Dicerna plans to apply this technology in the clinic, along with fluorodeoxyglucose positron emission tomography (FDG-PET) as a more conventional radiology marker to determine if silencing the MYC oncogene results in a favorable reduction of tumor metabolic activity.
Finally, in a subcutaneous xenograft model of CRC, researchers found that β-catenin DsiRNA robustly silenced the CTNNB1 gene, resulting in more than 75% tumor growth inhibition after a two-week dosing regimen that was well-tolerated. In addition, researchers demonstrated that optimizing the envelope cationic lipid, the key driver of DsiRNA delivery via EnCore LNPs, increases the potency of β-catenin silencing in CRC tumors and shows tissue selectivity.
Dicerna’s DCR-MYC oncology program is on track in human proof-of-concept clinical studies, with initial clinical data expected by the end of 2015.
About Hepatocellular Carcinoma (HCC)
Liver cancer is the second leading cause of cancer-related deaths worldwide, with 745,000 deaths per year.1 Hepatocellular carcinoma (HCC) is the most common form of liver cancer in adults. Most cases of HCC result from infection with the hepatitis B or C virus, which can lead to cirrhosis of the liver.2 However, non-alcoholic fatty liver disease, associated with obesity and diabetes, is also an important risk factor for HCC.3 Early-stage HCC is generally treated with surgery, which is potentially curative; however, given the nonspecific symptoms that are characteristic of HCC, the substantial majority of patients are diagnosed only after HCC is at an advanced stage. Patients with advanced HCC have limited treatment options, and the disease is associated with poor patient outcomes and high mortality.
DCR-MYC, Dicerna’s investigational Dicer substrate siRNA (DsiRNA) molecule, is a synthetic double-stranded RNA delivered via the company’s proprietary EnCore™ LNP delivery system. DCR-MYC is designed to serve as a potent and specific inhibitor of the MYC oncogene. MYC is a key target in oncology because it has been demonstrated to cause or promote cancer when abnormally expressed or activated. The MYC oncogene encodes for a small intracellular protein that lacks a good binding site, making it a challenging target for monoclonal antibodies or traditional small molecules. However, DsiRNA therapeutics may be able to overcome these challenges by “silencing” the MYC oncogene in cancer cells. In pre-clinical studies, Dicerna has shown that DCR-MYC inhibits gene transcript activity and reduces tumor volume in multiple mouse tumor models. Dicerna is investigating DCR-MYC in a variety of tumor types, including HCC, other solid tumors, multiple myeloma, and lymphoma.
RNA interference (RNAi) is a highly potent and specific mechanism for regulating the activity of a targeted gene. In this biological process, certain double-stranded RNA molecules known as short interfering RNAs (siRNAs) bind to complementary messenger RNAs (mRNAs) and recruit proteins that break the chemical bonds that hold mRNAs together, preventing the mRNAs from transmitting their protein-building instructions.
RNAi therapeutics have the potential to treat a number of human diseases by "silencing" disease-causing genes. The discoverers of RNAi, a gene silencing mechanism used by all cells, were awarded the 2006 Nobel Prize for Physiology or Medicine.
About Dicer Substrate Technology
Dicerna's proprietary RNAi molecules are known as Dicer substrates, or DsiRNAs, so called because they are processed by the Dicer enzyme, which is the initiation point for RNAi in the human cell cytoplasm. Dicerna's discovery approach is believed to maximize RNAi potency because the DsiRNAs are structured to be ideal for processing by Dicer. Dicer processing enables the preferential use of the correct RNA strand of the DsiRNA, which may increase the efficacy of the RNAi mechanism, as well as the potency of the DsiRNA molecules relative to other molecules used to induce RNAi.
Dicerna Pharmaceuticals, Inc., is a biopharmaceutical company focused on the discovery and development of innovative treatments for rare, inherited diseases involving the liver and for cancers that are genetically defined. The company is using its proprietary RNA interference technology platform to build a broad pipeline in these therapeutic areas. In both rare diseases and oncology, Dicerna is pursuing targets that have been difficult to address using conventional approaches, but where connections between targets and diseases are well understood and documented. The company intends to discover, develop and commercialize novel therapeutics either on its own or in collaboration with pharmaceutical partners.