CANCER TYPES OVERVIEW
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.
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.
Prostate Cancer
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.
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.
The DDX3 RNA helicase enzyme is highly multi-faceted in its activity and complex in its gene structure with ten highly conserved motives.
Our DDX3 inhibitors can be considered apoptosis-inducing targeted antitumor agents as they specifically induce cell death in those cancer cells.
The role of DDX3 in cancer is a subject of continues investigation by many research groups world wide.
First Health Pharmaceuticals’ cancer research concerns different types of cancer like breast-, lung-, prostate- and AIDS-associated cancers.
Substantial evidence supports the hypothesis of a presence of stem cells (or stem cell-like cells) amongst mature differentiated cancer cells.
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.
