In vitro and in vivo Efficacy Studies

'Mechanistic' in vitro efficacy screens

CXR use a range of cell lines with defined mutational spectra to determine drug efficacy, identify responder cell types, and elucidate potential mechanism(s) of response or resistance.

• Identify responder tumour types to aid selection of clinical indication
• Determine cell-type specific mutations that confer sensitivity to cytotoxic agents

Current approaches to determine in vitro cytotoxicity of compounds do not take into consideration why some cells respond and others do not. This leads to variability in the clinical response and hence the failure of some promising drug candidates. Selection of compounds on the basis of mechanism-based efficacy studies enables patient selection based upon responder indicators and reduces the risk of clinical failure.

At CXR Biosciences we have a panel of >36 cell lines where the mutation spectra are known, which can be subdivided into altered biological pathways on this basis. These enable the identification of potential anti-cancer compounds that are selectively toxic to cells with phenotypic alterations resulting from the defined mutation. For example, mutations that confer a loss or alteration of function of p53 or activation of Ras, may impact on the response to cytotoxic agents. In this way the genotype of the responsive tumour/patient is identified, and the drug candidate’s mechanism of action defined. Information gained from such studies can also assist in the development of companion diagnostics to improve the targetting of the compound and the chances of clinical success.

Improved in vivo efficacy studies - the HRN™ nude 

The HRN™ nude lacks all hepatic P450 activity and hence can be used to increase circulating levels of compound to improve tumour exposure in human xenograft studies, thus maximising the chances of demonstrating in vivo efficacy.

 If the drug would normally undergo metabolism in the liver, the absence of hepatic cytochrome P450 activity leads to enhanced levels of circulating drug, and enables relatively small amounts of test compound to be evaluated in efficacy studies.  As the circulating levels of compound are elevated for longer, the frequency of repeat dosing can be reduced without affecting overall exposure.

Advantages of using HRN™ nude mouse

• Only relatively small amounts of test compound need be used
• Demonstration of the effects of drugs where there is a known lack of bioavailability to the tumour
• Reduce frequency of repeat dosing

For further information on the HRN™ mouse click here

Smart Xenografts

CXR Biosciences is developing Smart Xenograft in vivo models that will provide quantitative information on the number of viable implanted tumour cells, together with mechanistic information about the physiological response of tumour cells to anti-cancer agents, derived from simple measurements in urine or blood.

These models will enable the following:

• Quantitative determination of the effect of a particular treatment on tumour burden

• Results generated through detection of a proprietary reporter non-invasively in urine, or in blood

• Information obtained in real time – therefore effects can be followed over time and as each animal can act as its own control, the number of animals required to obtain valuable information is reduced.

CXR has proven the concept in vivo and is currently seeking collaborative partners to help validate and apply the Smart Xenograft system to cell lines of interest.