Accelerated discovery and development of novel therapeutic agents for the treatment of head and neck cancer patients

Head and neck cancer (HNC) is the sixth most common cancer worldwide (>500,000 cases/year) (1). Incidence of some types of HNC is rising rapidly: in the UK, oropharyngeal carcinoma incidence doubled between 1996 and 2006 and then doubled again between 2006 and 2010 (2).

The mainstay treatment is cytotoxic chemotherapy and radiotherapy, which result in considerable toxicity, and have high relapse rates (~50% within 2 years) (3). However, despite the significant unmet need, research into HNC is poorly funded – it is 15th by amount funded by CRUK, and has been a lower priority for pharmaceutical companies than the more common cancers (e.g. breast, colorectal). In Europe, HNC has been recently recognised as an orphan disease (EMA; orphanet.org).

There is an urgent need to rapidly develop more effective therapies with lower toxicity. Because of this, we have established the AcceleraTED drug repurposing platform in HNC

The platform consists of four stages:

Stage 1 – Screening and hit identification
Drugs are screened for phenotypic effect on a primary screen of cell viability and proliferation in several optimised HNC cell lines, using a high-throughput Alamar blue assay (Invitrogen).

Stage 2 – In Vitro Validation
Any hits are validated further, using several secondary in vitro screens including:
a. Full dose response curves of viability and proliferation using alamar Blue,
b. Clonogenic assays,
c. Annexin V (apoptosis)
Assays are undertaken with the drugs (a) alone, and (b) in combination with standard of care treatments: 1.cisplatin, 2. radiation and 3.cisplatin-radiation combination.
The assays above are initially conducted on:
Stage 2a: HNC cell lines, representing HPV+ and HPV- disease. If results are positive, the candidate progresses to:
Stage 2b: primary cell cultures from patients with primary and recurrent HNC.
Stage 2c: Following the completion of Stage 2a and Stage2b, the literature is reviewed to identify data on known or potential modes of action. Basic exploration of the known modes of action is then undertaken on HNC cell lines and primary cultures utilising appropriate molecular biology techniques.

Stage 3 – In Vivo Validation (Animal models)
Leads that are successful at all steps of stage 2 are then assessed for in-vivo toxicity and efficacy using xenograft animal models implanted with the same HNC cell lines used above. Using these models, we evaluate:
Stage 3a: in vivo safety, and
Stage 3b: tumour kill efficacy and pharmacokinetic (PK) profiles
PK profiles are determined in collaboration with XenoGesis Ltd.

Stage 4 – Clinical Trials
We have extensive experience in running clinical trials in HNC. We employ these skills to progress lead compounds into early phase clinical trials. Phase IB/IIA designs are used to test tolerability/safety of drugs alone and in combination with standard treatments, and window of opportunity designs are used to help elucidate modes and mechanisms of action.

The student would be involved in all aspects of stages 1-3, learning a variety of key experimental protocols. The student would be working as part of the group under the direction of the principal investigator. They will receive help, supervision and guidance from the translational team leader as well as a number of experienced research fellows and technicians to progress identified drug targets through the platform.