Compounds and Their Uses for Targeted Cancer Therapy

PATENT STATUS

1. “Selective Anti-Cancer Compounds”: PCT application disclosing this invention was published in December 2016. International Publication No. WO 2016/200339 A1. 
   
   
2. “Anti-Cancer Compounds and uses thereof”: PCT application for this invention was published in June 2018. International Publication No. WO 2018/106192 A1. 

OVERVIEW OF TECHNOLOGY ON OFFER

Compounds and their use for specifically targeting cancer cells (or hyper-proliferating cells) while protecting normal cells from toxicity of chemotherapeutic agents.  

BRIEF DESCRIPTION

Targeting the proliferative ability and survival of cancer cells is one of the key therapeutic strategies in treating cancer. The Ras/Raf/MEK/ERK and PI3K/Akt/mTOR signalling pathways regulate cellular survival and proliferation. Mutations in these pathway proteins can perpetuate the proliferative ability of normal cells leading to development of cancers. Hence, these mutated proteins have been used as oncogenic targets, and selective inhibitors have been developed against them for cancer therapy. However, cross-talk between these signalling pathways impacts the normal downstream growth events. Further, it is known that single-agent therapies might cause activation of unintended signalling events leading to drug resistance. Therefore, it is necessary to tackle tumour growth and proliferation using a multi-pronged approach, i.e. by identifying and targeting candidates that mediate cross-talk between signalling mechanisms and mediate drug resistance.

Researchers at Duke-NUS Medical School have succeeded in identifying a candidate compound – a131 (abbreviation for anti-cancer compound 131) that selectively kills transformed BJ cells without affecting normal BJ cells. Cell cycle analysis revealed that a131 arrested only normal cells in the G1/S phase; which could be reversed once a131 was withdrawn. It simultaneously induced a mitotic catastrophe in transformed cells which escaped the G1/S phase arrest, thus showing a clear selectivity towards cancer cells. These effects were also observed in both mouse xenograft models wherein a131 treatment showed anti-tumour efficacies without any loss of body weight, and Ras-driven glioma initiating cells ex vivo model.

Based on a131 structure-and-activity relationship, the team further classified the properties of a131 compounds into four groups, Group 1: those that have the dual property of arresting normal BJ cells at G1/S phase and causing mitotic catastrophe of transformed BJ cells (a131, cancer selective). Group 2: those that only arrest normal BJ cells at G1/S phase (a166, chemoprotective). Group 3: those that only cause mitotic catastrophe in transformed BJ cells without arresting normal cells (a159, chemotherapeutic). Group 4: those that are inactive (a132).

In search for upstream mediators involved in the a131-mediated cancer selective lethality, the research team conducted a mass spectrometry analysis and found that members of the PI5P4Ks (phosphatidylinositol 5-phosphate 4-kinases) were among the most prominent hits. A131 treatment led to inhibition of PI5P4Kalpha kinase activity in vitro. It is well known that PI5P4K regulates the PI3K/Akt/mTOR pathway which is known to promote the G1/S phase transition. A131 treatment or siRNA-mediated knockdown of PI5P4K led to inhibition of the PI3K/Akt/mTOR pathway only in normal BJ cells, but not in transformed counterparts, indicating the mode of action of a131 in arresting normal cells in the G1/S phase. However, in normal BJ cells containing Ras activation, the a131-mediated PI3K/Akt/mTOR pathway inhibition was overridden by interaction with the Ras/Raf/MEK/ERK pathway, leading to G1/S transition in normal BJ cells despite a131 treatment.

Another upstream regulator of the PI3K/Akt/mTOR pathway is PIK3IP1, which negatively regulates this pathway thereby resulting in G1/S arrest. However due to Ras activation in cancer cells, the PIK3IP1-mediated negative regulation overrides a131 action causing cancer cells to transit the G1/S phase and undergo a131-mediated mitotic catastrophe. Taken together, these studies have led to identification of anti-cancer and chemoprotection compounds and their uses.

POTENTIAL APPLICATIONS

• Cancer therapy
• Treatment of other diseases that involve hyper-proliferation of cells.

KEY BENEFIT

Specific targeting of cancer cells (or hyper-proliferating cells) while protecting normal cells from toxicity of chemotherapeutic agents.

PUBLICATIONS

Kitagawa, M., Liao, P., Lee, K.H. et al. Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality. Nat Commun 8, 2200 (2017) doi:10.1038/s41467-017-02287-5
https://doi.org/10.1038/s41467-017-02287-5

CONTACT

Please email us for further enquiries: cted@duke-nus.edu.sg