OUR RESEARCH

Cancer research has identified several oncogenes, but the biological meaning of their mutations or altered expression levels as well as the interactions between different oncogenes are usually not immediately clear and require extensive research.

Taking this into consideration our DDX3 Inhibitors were tested on metastatic breast cancer cell lines expressing DDX3, showing relevant activity for all compounds and very positive results in one specific compound. The possibilities for DDX3 based treatment in triple negative breast cancer is also under investigation.

Preliminary data in vivo showed no toxicity and a good tissues distribution. The development of our antitumor pipeline includes further improvement of the antitumor activity and the optimisation of the delivery and distribution in the body of the lead compounds.

Selective Inhibition

The DDX3 RNA helicase enzyme is highly multi-faceted in its activity and complex in its gene structure with ten highly conserved motives. It has ATP-ase dependent helicase activity as well as other functions and interactions independent from either ATP-ase or Helicase-activity. Down-regulation of DDX3 expression has been utilized to investigate the pathways and networks in which it is involved. Inhibition of a protein has however a totally different impact on the cellular pathways than genetic under-expression because its protein functions and interactions are typically only partially inhibited. For DDX3 compounds were designed either to inhibit or specifically not to inhibit the ATP related functions of the enzyme and it cannot as such be compared to the effects of mere genetic under-expression. Our group has disclosed pharmacophore models for unique pockets of the enzyme and consequently the DDX3 helicase inhibitors under development by our group are highly selective.

Targeted and Personalized Therapy

Our DDX3 inhibitors can be considered apoptosis-inducing targeted antitumor agents as, based on the current evidence, they specifically induce cell death in those cancer cells where increased levels of DDX3 modify the cell cycle and growth. In addition, the possibility to stratify patients in responders (high DDX3 levels) and non-responders (low DDX3 levels), offers the possibility to design a personalized optimal treatment regime for the patients.

Furthermore, both in lung cancer and in oral squamous cell carcinoma, differences in survival are related to DDX3 expression seem HPV / smoking dependent. Such knowledge also directly contributes to the possibility of selecting potentially responsive patients populations.

The role of DDX3 in cancer

DDX3 is overexpressed in various forms of cancer but its oncogenic role in breast cancer has been studied most extensively.

The treatment of breast cancer has dramatically improved by the introduction of estrogen and progesterone receptors as diagnostic and prognostic biomarkers, but for triple negative and aggressive breast cancers the survival expectancy is still poor.

Screening patients for the presence of estrogen and progesterone receptors, as well as the overexpression of the HER2 protein can direct the therapy and thus the chances of a successful treatment and survival. Patients, whose cancer cells are positive for HER2, have a more aggressive disease and may be treated with Herceptin, a monoclonal antibody that targets HER2 and improves the prognosis, whilst patients who do not test positive for estrogen (ER) and progesterone receptors (PR) will not respond to hormone therapy.

Treatment with our DDX3 inhibitors would follow a similar approach of pre screening the patient’s cancer cells for DDX3 overexpression, potentially offering an integration or alternative to available treatments.

Luckily mild to moderate forms of breast cancer respond well to available treatment options, but unfortunately metastatic breast cancers and triple negative types still have a very poor outcome. Even with optimal treatment the ten-year survival expectancy is no more than 10%. Triple negative breast cancer (ER, PR and HER2) is considered especially aggressive and difficult to treat. Also, the cancer is more likely to spread and recur.

Taking this into consideration our DDX3 Inhibitors were tested on metastatic breast cancer cell lines expressing DDX3, showing relevant activity for all compounds and very positive results in one specific compound. The possibilities for DDX3 based treatment in triple negative breast cancer is also under investigation.

Preliminary data in vivo showed no toxicity and a good tissues distribution. The development of our antitumor pipeline includes further improvement of the antitumor activity and the optimisation of the delivery and distribution in the body of the lead compounds.

Cancer stem cells

Substantial evidence supports the hypothesis of a presence of stem cells (or stem cell-like cells) amongst mature differentiated cancer cells. In particular, in Breast-, Skin- and Prostate Cancer as well as in Ewing Sarcoma, high components of stem cells have been observed and considered responsible for tumour relapses.

Cancer stem cells with high levels of DDX3 alone, or in an inhibitory complex with death receptors and sensitive to DDX3 modulation have been found in Ewing sarcoma and breast cancer.

As such our DDX3 inhibitors do not only act against differentiated cancer cells, but also against cancer stem cells, usually less or not responsive to the standard treatments, and will substantially increase the chance of a complete eradication of the tumour.