Drug Repurposing

Case Study 01

The small molecule drugs Iressa (Gefitinib) and Tarceva (Erlotinib) have been approved for treatment of non-small cell lung cancer (NSCLC) and are effective in approximately 10% of patients carrying direct activating mutations in the EGFR gene (the target of these tyrosine kinase inhibitors).

In contrast, the monoclonal anti-EGFR antibodies Erbitux (Cetuximab) and Vectibix (Panitumumab) are thought to be ineffective on these same patients (Mukahora et al; Doody et al), even though they do provide benefit to colon cancer patients carrying non-mutated forms of EGFR [but are wild type for K-Ras (Benvenuti et al) or B-Raf (Di Nicolantonio et al)].

Here we present data using X-MAN™ 1 and 2 models that; (a) Recapitulate the K-Ras/B-Raf pathway resistance profile present in colon cancer patients, and; (b) Suggest that Erbitux can elicit potent effects on mutated EGFRs (del E746-A750) when studied in a definitive isogenic cell-based system.

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These data are now causing us to re-examine clinical data to understand whether there are subtleties in patient responses to EGFR-antibodies based on which type of EGFR mutation they posses and we are in the process of building additional X-MAN models to understand this further.

Excitingly, these validated models accurately predict patient drug-sensitivity and resistance profiles based on their tumours genetics, thus forming an ideal and definitive system to find synergistic drug combination that reverse their K-RAS/B-Raf mediated resistance to EGFR-targeted agents. Such combinatorial drug screens are now underway at Horizon’s research laboratories.

The availability of such data enables researchers to determine the full range of sensitive and resistant patient populations to the disease target in clinical trials. This will enable the design of smaller more efficient development phases that will read-out quicker, be more likely to succeed and reduce the high-rate of attrition currently observed at this critical phase of drug development.

Case Study 02

A recent paper from Prof. Ben Park at the Johns Hopkins University has also demonstrated the power of X-MAN isogenic cell-lines to reprofile a known drugs from non-cancer indications to new uses in specific types of cancer (Gustin et al PNAS 2009).

Prof. Park (a key advisor to Horizon Discovery) discovered a new use for the bi-polar disorder drug; Lithium Chloride, in cancer types carrying the mutant PI3K gene. This ‘re-profiled’ candidate cancer drug; which has already been proven to be safe in humans, is now directly entering new clinical trials for efficacy in breast cancers carrying mutant PI3K.