Cardiff University scientists have developed a novel anti-cancer stem cell agent capable of targeting aggressive tumour forming cells common to breast, pancreas, colon and prostate cancers.
The new OH14 compound has been licensed by Tiziana Life Sciences, a British-based pharmaceutical company. It will now undergo further development before proceeding to clinical trials. Pre-clinical studies have shown it to be effective in eliminating a number of different kinds of cancers cells, including cancer stem cells from human breast cancer patient biopsies.
The breakthrough comes almost exactly a year after the same research team announced that they had discovered a molecule capable of reversing the spread of malignant breast cancer. The multidisciplinary team is comprised of researchers based in Cardiff University's European Cancer Stem Cell Research Institute (ECSCRI) and the School of Pharmacy and Pharmaceutical Sciences.
Last January, state-of-the-art computer aided modeling enabled the researchers to identify an anti-cancer agent capable of deactivating a gene known to be essential for the metastatic spread of breast cancer. Using the same computer-based approach, the team has now been able to target the c-FLIP (cellular FLICE [FADD-like IL-1β-converting enzyme]-inhibitory) protein, known to play a key role in cancer stem cell maintenance and survival, described in previously published work by the Institute.
"Our computer aided drug screening process has now identified two new classes of anti-cancer agents, specifically targeting two distinct and novel mechanisms underpinning cancer," said Dr Andrea Brancale from Cardiff University's School of Pharmacy, who led on the compound's design.
According to the scientists' findings, targeting c-FLIP with the OH14 compound works on two fronts: first by helping to deactivate the tumour's self-defense mechanism against the immune system and second to prevent its regrowth. The main function of the c-FLIP protein is to prevent the TNF-related apoptosis-inducing ligand (TRAIL) from killing cells. TRAIL is a naturally occurring and crucial molecule that is used by the body's immune system to kill damaged or cancerous cells.
The researchers hope that ultimately human trials will prove the efficacy of the OH14 compound in sensitising tumour cells and cancer stem cells to existing drug-based therapies thus disabling tumours from seeding new growth after treatment.
The new compound is the first experimental anti-cancer stem cell agent to have emerged from the European Cancer Stem Cell Research Institute. Having acquired the licence for its commercialisation, Tiziana Life Sciences has committed funding for ongoing research that will focus on drug development.
Tiziana Life Sciences was founded in 2014 after licencing the BCL3 cancer agent that was developed by the same Cardiff University team.
Dr Richard Clarkson, lead researcher on the c-FLIP project and senior researcher at Cardiff University's ESCRI, said: "We are delighted to extend our relationship with Tiziana Life Sciences. OH14 is an example of a new generation of experimental agents designed to selectively target the pernicious stems cells within a tumour, thus improving the long-term prospects of cancer patients."
Gabriele Cerrone, Chairman of Tiziana Life Sciences, said: "We are very excited to help drive forward this project in the promising new field of cancer stem cell therapeutics, and delighted to have extended our relationship with Cardiff University. This agreement further strengthens our portfolio of exciting pre-clinical assets to complement our Phase II assets of milciclib and foralumab. We look forward to working with the University to identify further inhibitors of c-FLIP. We will then seek to develop the most promising of these into novel drugs for cancers, such as those of the breast, where up-regulation of this c-FLIP is believed to be important in cancer cell proliferation."
Dr Robert Clarke, from the University of Manchester's Institute of Cancer Sciences, said: "This is an exciting development from a Cardiff team that is expert in the mechanics of regulating cell death. The drug that they have developed appears to target cancer stem cell activity, which suggests it will prevent metastatic recurrence and be useful in combatting drug resistance."
Dr Lee Campbell, Research Projects and Science Communications Manager at Cancer Research Wales, who part-fund the study, commented: "This is an exciting breakthrough as cancer stem cells are thought to be responsible for the failure of many cancer treatments and the re-emergence of cancers, often many years after the initial disease.
"Therefore the ability to eliminate cancer stem cells from the body offers the opportunity to totally eradicate stubborn and residual disease once and for all. As a charity we are proud to be associated with such ground-breaking research here in Wales and look forward to seeing how these new compounds perform in patients."
For further information please contact:
Tomas Llewelyn Barrett
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Cardiff UniversityCardiff University is recognised in independent government assessments as one of Britain's leading teaching and research universities and is a member of the Russell Group of the UK's most research intensive universities. The 2014 Research Excellence Framework ranked the University 5th in the UK for research excellence. Among its academic staff are two Nobel Laureates, including the winner of the 2007 Nobel Prize for Medicine, University Chancellor Professor Sir Martin Evans. Founded by Royal Charter in 1883, today the University combines impressive modern facilities and a dynamic approach to teaching and research. The University's breadth of expertise encompasses: the College of Arts, Humanities and Social Sciences; the College of Biomedical and Life Sciences; and the College of Physical Sciences and Engineering, along with a longstanding commitment to lifelong learning. Cardiff's flagship Research Institutes are offering radical new approaches to pressing global problems. http://www.cardiff.ac.uk
Tiziana Life SciencesTiziana Life Sciences plc is a UK biotechnology company that focuses on the discovery and development of novel molecules that treat human disease in oncology and immunology.
In January 2015, the Company entered into an exclusive licence from Nerviano Medical Sciences relating to Milciclib, a molecule which blocks the action of specific enzymes called cyclin-dependent kinases (CDK) involved in cell division as well as a number of other protein kinases. Milciclib is currently in phase II clinical trials for thymic carcinoma in patients previously treated with chemotherapy.
The Company also in-licensed another clinical asset in December 2014 from Novimmune. Foralumab is the only fully human engineered anti-human CD3 antibody in clinical development. This phase II asset has potential application in a wide range of autoimmune and inflammatory diseases, such as multiple sclerosis, type-1 diabetes (T1D), inflammatory bowel disease (IBD), psoriasis and rheumatoid arthritis, where modulation of a T-cell response is desirable.
Tiziana Life Sciences' research team has discovered that Bcl-3 has a prominent role in the metastasis of mammary cancers, and has elucidated the mechanism of Bcl-3 action to be a regulator of cancer cell motility. Tiziana has also determined that Bcl-3 inhibition suppresses cell motility in triple-negative, HER-2-positive PR- and ER-positive breast cancer sub-types, suggesting that Bcl-3 may be a master regulator of this metastatic property not only in aggressive breast cancers, but across the clinical spectrum of breast disease.