Tiziana Life Sciences PLC   | AIM:TILS

Overview


Tiziana Life Sciences’ research team is attributed with the discovery that Bcl-3 has a prominent role in the metastasis of mammary cancers, and have elucidated the mechanism of Bcl-3 action to be the regulation of cancer cell motility. The research team has also determined that Bcl-3 inhibition suppresses cell motility in triple-negative, HER-2-positive and ER-positive breast cancer sub-types, suggesting that Bcl-3 may be a master regulator of this metastatic property not only in more aggressive breast cancers but across the whole clinical spectrum of breast disease (unpublished data, manuscript in preparation).

They have also determined that Bcl-3 inhibition suppresses cell motility in triple-negative, HER-2-positive and ER-positive breast cancer sub-types, suggesting that Bcl-3 may be a master regulator of this metastatic property not only in the more aggressive breast cancers but across the whole clinical spectrum of breast disease.


THERAPEUTIC APPROACH


BCL3i is a novel emerging therapeutic for metastatic disease, targeting a molecular mechanism that is common to the majority of cancer tissue types. This mechanism is distinct from the anti-proliferative effects of the taxanes and the anti-vascularising effects of the VEGF(R), targeting instead the ability of cells to migrate.



Using a computer-based mdel of the Bcl-3 protein complexed with its cognate protein partners within the cell and rational design of a molecule to inhibit the interaction of Bcl-3 with these proteins, the research team at Cardiff University has identified a small molecule (JS6) which is able to inhibit Bcl-3 at nanomolar  concentrations in in vitro  assays (Bcl-3/p50 protein binding assay; cell-based Bcl-3/NF-kB-dependent transcription reporter assay; human breast cancer cell motility assay) and shows no overt toxicity up to millimolar concentrations.

Furthermore, the lead compound shows significant anti-metastatic activity at 3.5mg/kg in preliminary in vivo assays (mouse) designed to demonstrate the inhibition of disease progression and further spread of metastatic lesions, and showed no toxicity in vivo  at the concentration used. This inhibitor class of the Bcl-3 protein is termed BCL3i, and the initial research programme is designed to discover further BCL3i molecules with improved or equivalent profiles compared to the JS6 initial lead.

Ongoing pre-clinical animal studies, which are scheduled for completion in 2015, are expected to determine if this leads to a significant improvement in survival when the agent is targeted to animal models with existing advanced metastatic disease. Furthermore, the efficacy of BCL3i in other cancer tissue types is expected to be determined, including colorectal, pancreatic, lung and prostate cancers -- combined, making up more than 50% of cancer incidences in the UK.


MECHANISM



Results indicate BCL-3 inhibition results in significant reduction in metastasis

Leads from in silico screening were synthesised and tested in in vitro assays; and in vivo in a mouse model with a human breast cancer cell line.

  1. P50 binding assays to assess ability to inhibit BCL-3 complex

  2. NF-kB activity as an indicator of BCL-3 bioactivity

  3. Cell migration assay as an indicator of metastatic potential

 

UNDERSTANDING THE UNMET NEED


  1. Data suggests that Bcl-3 may be a master regulator of this metastatic property not only in the more aggressive breast cancers but across the whole clinical spectrum of breast disease.

  2. In silico modelling of the BCL-3 complex & screening simulation has identified potential inhibitors

  3. Leads from in silico screening and their structural analogs were synthesised and found to be potently effective in in vitro assays; and in vivo in a mouse model with a human breast cancer cell line.

 

Breast Cancer BCL3

TRIPLE NEGATIVE BREAST CANCER

We have acquired a specific inhibitor of Bcl-3 function from Cardiff University capable of inhibiting triple-negative, HER-2-positive and ER-positive breast cancer metastases.

We anticipate filing an IND in 2016.