CANCER TYPES OVERVIEW

BREAST 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 benefited with 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 chance of successful treatment and survival. Patients whose cancer cells are positive for HER2 have a more aggressive disease and may be treated with the 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 be able to 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 in 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 coumpounds.

AIDS-associated Cancers

Three types of cancers are referred to as AIDS-related or AIDS-defining cancers, because if a person with HIV is diagnosed with them, it will signify the development of AIDS. These cancers are Kaposi’s sarcoma, invasive cervical cancer and non-Hodgkin lymphoma. The incidence of these cancers within the HIV population has been significantly reduced since the introduction of HAART, however they are still very common in people with HIV. 

Other non AIDS- defining types of Cancer are also more prevalent within the HIV population with respect to the non HIV infected population,  including cancers of the anus, liver, oral cavity/ pharynx, lung and Hodgkin lymphoma. 

The increased risk among the HIV population is due to several factors, including suppression of the immune system, inflammatory state, infection with cancer-related viruses and exposure to health-damaging substances such as tobacco and alcohol.

Today, people with HIV and cancer are usually treated similar to people without HIV infection, with the drawback that cancer therapy weakens the immune system and that the combination of some drugs can lead to increased toxicity.

Treatment with drugs active both against HIV and cancer, such as DDX3 RNA Helicase inibitors , not only can reduce the risk of developing cancer as HAART does, but can even specifically contrast virus associated cancers, tumor growth and proliferation while simultaneously reducing the medication maintenance in cases of low HIV load. As such DDX3 RNA Helicase inhibition represents a valuable approach to treat cancer in HIV-populations as a mono- or combinatorial therapy.

LUNG CANCER

Malignant lung cancers are among the most difficult to treat. Tobacco smoking related lung cancers are the most diffused and the cause of 80% of all primary lung cancers. Primary lung cancer frequently spreads and metastatizes to lymphnodes, brain, liver and bones. Similarly lung cancer can result from metastatization of other types of cancer, like bladder, breast, colon cancer and melanoma.

Non small cell lung carcinoma is most frequent within lung cancer populations (80% of all cases) and various driver mutations have been identified; the most frequent being mutations of KRAS and EGFR and HER2 overexpression (10-30 % of cases), followed by EML4ALK translocation, AKT1, PI3KCA, BRAF and others.  Although the development of targeted therapies has significantly improved the outcome of lung cancer diagnosis, the relapse and mortality rates are still far too high. Resistance to treatment frequently occurs, while not all mutations respond equally to treatment. At the same time there are subtypes for which a targeted treatment is not available or which have no (known) identifiable mutations. 

Data show that almost 50% of the lung cancer tissues from smokers or ex-smokers never infected with Human Papilloma Virus present higher DDX3 helicase levels with respect to surrounding tissues. This correlates with and affects therapy prognosis. In-vitro and in-vivo data have shown that DDX3 overexpression promotes lung tumor growth and metastatization, and its reduction contrasts tumor cell proliferation while at the same time synergizing with radiotherapy.

Prostate Cancer

Prostate cancer is one the most frequent cancers in male adults and survival correlates to the stage at diagnosis and the aggressivity of the tumor. Surgery, radiotherapy and androgen deprivation therapy are the main options in case of prostate cancer, with a high frequency of recurrence and a series of serious side effects and discomforts. Inherited mutations of DNA- repair genes such as ATM, CHEK2 and BRCA2 associate with an increase risk, while BRCA1 and HOXB1 account for some hereditary forms. Frequently the tumors are hormon- refractive due to mutation to the androgen receptor or other factors such as PTEN.

Upregulation of DDX3 helicases has been observed in 25% of prostate cancer cases in a study correlating overexpression with aggressivity. Similarly the pathways and mechanisms affected by DDX3 as Wnt/ beta-catenin signaling and senescence and cell migration seem to be involved.

Inhibition of the DDX3 Human RNA Helicase represents a powerful approach to contrast prostate cancer growth and spread in patients, as shown by the strong effect of our compounds in both in-vitro and in-vivo prostate cancer models.