Tiziana Life Sciences PLC   | AIM:TILS

Overview


By 2020, almost 1 in 2 people in Western countries such as the U.K. will be diagnosed with cancer, presenting an enormous societal and clinical challenge (1). Breast cancer alone was estimated to account for around 522,000 deaths worldwide in 2012 (2). Cancer stem/progenitor cells are the focus of enormous interest within the cancer drug discovery field (3), based on the hypothesis that this sub-population of cells are primarily responsible for disease relapse and metastasis characteristic to cancer progression.

Despite significant advances in breast cancer therapy in recent years, around 40% of breast cancer patients will suffer disease relapse (3). Cancer stem (progenitor) cells are defined by their ability to re-initiate and re-populate tumour growth, and association with metastatic seeding and progression. The hypothesis that selective clearance of cancer stem cells will prevent disease relapse and lead to long-term clinical remissions, has been frequently postulated but never demonstrated clinically.


THERAPEUTIC APPROACH


Selective removal of stem-like cells from tumour populations is a highly attractive therapeutic approach, promising to eradicate those cells associated with the development of drug resistance and tumour relapse. Building on previous work within Cardiff University (4), we have used a computational drug design approach to identify an inhibitor of c-Flip, a protein implicated in resistance to apoptosis induction within cancer stem cells. This novel approach holds out the promise of a future “first-in-class” agent with broad potential as an adjunct to existing cancer treatment. Although current data focuses on breast cancer stem cells, if successful this approach could be applied across a range of cancers with unmet medical need.


MECHANISM


Tumour necrosis factor-related apoptosis inducing ligand (TRAIL) is a known anti-cancer agent that exhibits cancer cell specificity.  Its efficacy in breast and other cancers is limited, however, by the resistance demonstrated in a number of model systems.  Cellular FLICE-Like Inhibitory Protein (c-FLIP) has been demonstrated to play a key role in TRAIL resistance. c-FLIP promotes TRAIL resistance through competition with the apoptosis-inducing procaspase-8, for interaction with a protein known as FADD.

Work at Cardiff University’s European Cancer Stem Cell Research Institute has shown that removal of c-FLIP, using siRNA, is able to sensitize previously resistant breast cancer cells and cancer stem cells to TRAIL.  Inhibition of cFLIP appears therefore to have therapeutic potential. We have identified a hit compound (OH14) which is able to sensitize breast cancer cell lines and cancer stem cells to TRAIL, in a similar manner to c-FLIP siRNA.

The Figure shows the death domain complex induced by TRAIL on the cell surface, the role of intracellular c-FLIP in inhibiting apoptosis, and the potential of a c-FLIP inhibitor such as OH14 to induce cancer cell death.

   

REFERENCES


  1. 1.Maddams J, Utley M, Moller H. Projections of cancer prevalence in the United Kingdom, 2010-2040. Brit. J. Cancer. 2012;107(7):1195–1202.

  2. 2.Ferley J, Soerjomotaram I, Ervik M, et al. Cancer incidence and mortality worldwide: IARC CancerBase, available from http://globocan.iarc.fr

  3. 3.Smalley M, Piggott L, Clarkson R. Breast cancer stem cells: obstacles to therapy. Cancer Lett. 2013;338:57-62.

  4. 4.Piggott L, Omidvar N, Perez S, Eberl M, Clarkson R. Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL. Breast Cancer Res. 2011;13:R88.

 

UNDERSTANDING THE UNMET NEED


  1. Development of agents that selectively target cancer stem cells would present a new approach and could significantly impact on current cancer therapy.

  2. Applications would likely focus on diseases characterized by detailed understanding of underlying biology, with large patient populations, such as breast cancer.

  3. In principle, this approach could be directed towards many other poor prognosis tumour types, most likely as combination therapy alongside targeted agents (such as the apoptosis-inducing ligand TRAIL) or chemotherapy.

 

Breast Cancer cFLIP

TARGETING CANCER STEM-/PROGENITOR-LIKE CELLS AND SENSITISING TO TRAIL-INDUCED APOPTOSIS

Tiziana Life Sciences has recently acquired IP associated with a small molecule inhibitor of c-Flip (known as OH14). The company is funding early development studies to provide proof-of-principle for this new class of agent in targeting cancer stem cell sub-populations within pre-clinical model systems.