First-in-man study demonstrates the therapeutic effect of RNAi gene silencing in cancer treatment

(Press-News.org) The new study published in Cancer Discovery, the flagship journal of the American Association of Cancer Research (AACR), involving three Spanish and six American research centres, presents significant results in treating cancer patients with nanoparticles containing ribonucleic acid interference (RNAi) molecules. This marks the first time that the therapeutic effect of RNAi has been demonstrated in humans.

Barcelona, 11 February 2013. A study led by Dr Josep Tabernero, the Director of Clinical Research at the Vall d'Hebron Institute of Oncology (VHIO) and Head of the Medical Oncology Department at the Vall d'Hebron University Hospital, shows for the first time that ribonucleic acid interference (RNAi) is effective in the treatment of cancer patients. Harnessing these molecules to silence genes involved in the development and growth of cancer cells is an important step forward in developing a new and more targeted type of cancer therapy.

Dr Josep Tabernero, lead author of this study, said: "This is the first evidence to show that RNAi can be administered to cancer patients effectively, leading to significant tumour response."

RNAi is a gene-silencing mechanism that uses a subtype of RNA molecules to interfere with and silence genes. RNAi plays a vital role in normal cell development and differentiation, in cancer and viral defence, as it is powerful mechanism in the regulation of gene expression. Besides being a key natural cellular phenomenon, gene silencing shows great potential as a therapeutic device to shut down genes that have become hyperactive through cancer.

However, researchers have encountered difficulties in administering RNAi, as the molecules must penetrate cells in therapeutically effective concentrations, which in turn requires structural modifications. In the new study, led by the Vall d'Hebron Institute of Oncology (VHIO), along with several other cancer research centres and the U.S. biotech company Alnylam, scientists have developed a lipid nanoparticle approach that can deliver two of these molecules targeted against the genes encoding two key proteins involved in the development of cancer cells (VEGF and KSP). This system takes the form of a novel drug (ALN-VSP) made up of RNAi molecules and lipid nanoparticles (LNPs).

The new paper, published in the journal Cancer Discovery, presents the results of a Phase I clinical trial, involving 41 patients with advanced cancer that had metastasised to the liver. These patients were treated with the new drug twice a week with intravenous doses of between 0.01-1.5 mg/kg.

The trial found that not only was the drug safely administered, but also presented good evidence for clinical utility. In 11 of the 37 patients, the disease either did not progress or stabilized after six months of treatment. In some cases of patients with metastasis to the liver or abdominal lymph glands, there was a complete regression of metastasis. (It should be noted that the liver typically responds better to treatment due to its excellent capacity to absorb these molecules.)

The research team performed a pharmacodynamics analysis to determine the impact of the drug on the tumours by taking biopsy samples from the patients before and after the drug was administered. This revealed the presence of the RNAi constructs in the samples, thus showing that the structurally modified molecules reached the tumour and were effective.

Having previously tested the drug on animals, this first-in-man clinical test has demonstrated that an efficient formula has been developed to transport and deliver RNAi with clinically promising results. The results will have to be confirmed and extended in additional clinical studies.

The importance of clinical research

This study, which also involved other international research centres including the Dana-Farber Cancer Institute (Boston) and the Memorial Sloan-Kettering Cancer Center (New York), plus two other Spanish centres -- the Hospital Virgen del Rocío in Seville and the INCLIVA Health Research Institute in Valencia -- is potentially transformative for new drug discovery that will allow targeted, population-based studies.

Knowledge of the molecular biology of cancer has expanded greatly over the past decade, leading to the identification of potential therapeutic agents for developing tumour-selective drugs.

The Research Unit for Molecular Therapy of Cancer - "la Caixa", conducts Phase I clinical trials for new anticancer drugs. The choice of the most appropriate anticancer drug for each patient depends on a detailed analysis of the specific molecular changes in each tumour. This exciting approach entails a paradigm shift in the individualized treatment of patients.

Clinical trials play a vital role in developing new cancer treatments as they form the basis of scientifically recognised clinical research. Drugs must be proven to be both safe and efficacious in clinical trial volunteers before they can be formally approved by the appropriate government agency.

### For further information, please contact:

Amanda Wren
Communication Manager
Vall d'Hebron Institute of Oncology
+34 695 207 886
awren@vhio.net