Cancer Models Forum

Posted by Alicia, April 2019

4 factors hindering the development of new metastasis therapies in cancer

A staggering 90% of cancer patient deaths result from tumour metastasis. Yet astonishingly, there are very few cancer therapies available that target metastatic tumours. If we want to improve cancer survival rates, it’s vital that the translational oncology community works together to change this.

As part of Repositive’s commitment to enhancing preclinical cancer drug development, we hosted a roundtable discussion on the current challenges with modelling metastasis at AACR 2019. We were joined by specialist contract research organisations and model providers from around the world, including Hera Biolabs, EPO Berlin, Pharmatest and Woodland Biosciences, for a lively and insightful discussion.

In this blog post, we summarise the four key takeaways from the roundtable that highlight the current challenges with developing new therapies for treating tumour metastasis with precision.

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Industry is not prioritising preclinical testing for metastases

Pharma and biotech typically focus on developing therapies targeted to primary tumours rather than common secondary tumours, such as bone metastasis. However, developing treatments targeting bone metastasis comes with a high risk of failure during preclinical studies, due to the complex and poorly understood interactions between bone cells and the tumour microenvironment. But this shouldn’t deter pharma and biotech from developing therapies targeting metastases, since most initial indications for novel cancer therapies are now patient populations who have seen tumour progression following one or several standard-of-care treatments. Instead they should rise to the challenge and work closely with contract research organisations with expertise in preclinical models that can accurately predict patient response to promising metastasis drug candidates, minimising the risk of therapies failing during expensive human trials.

The traditional drug development process is outdated

With most therapies targeted to primary tumours, perhaps unsurprisingly, pharma and biotech do not routinely test new cancer therapies on metastasis models ahead of moving into clinical trials. However, to improve cancer survival rates and accelerate new personalised cancer treatments to the clinic, the traditional drug development process needs to change in a number of ways, which we explored with industry professionals in a recent webinar. One important change that should be incorporated into preclinical development is checking the efficacy of all promising cancer therapies at targeting tumours that have developed metastatic potential and at attacking the resulting metastases.

Species differences get in the way

Mice are usually the go-to species for assessing the safety and efficacy of cancer therapies in vivo during preclinical drug development. However, mice used as cancer models typically do not show spontaneous metastasis that we observe in cancer patients. While considerable advances have been made to model different stages of metastasis, most models developed to date can only recapitulate part of the metastasis process – typically either the homing of tumours cells in the circulation to secondary sites or the ability of tumour cells to develop metastases once placed directly into the bone or other orthotopic sites. Ultimately, researchers are aiming for an ideal scenario, where they are able to model the entire metastasis process in a preclinical model over a clinically relevant timeframe, but we’re not there yet.

The tumour microenvironment adds complexity to metastases models

It’s also essential to recapitulate the tumour microenvironment in preclinical metastasis models, particularly when looking at bone metastases as we know there is a highly complex interplay between the bone cells and surrounding tumour microenvironment. However, the challenge is how to accurately replicate such a complex microenvironment, including immune cells, peripheral blood cells, and stromal tissue, especially when mice used for creating patient xenograft models have to be immunocompromised. Luckily, there are a variety of models have recently been developed that are enabling pharma and biotech to better model the tumour microenvironment during metastasis. For example, one group used a novel scaffold to create mouse models with humanised bone and another team published a method of developing humanised mice with peripheral blood mononuclear cells.

Despite the considerable advances made to enhance metastasis modelling in preclinical drug development, there are still a number of key challenges to address. Pharma and biotech must firstly shift their focus to developing effective treatments for metastatic tumours. But to support this, contract research organisations need to broaden their efforts to create more physiologically representative models that can accurately model the entire metastasis process and capture the important influence of the tumour microenvironment. Through enhanced collaboration amongst the translational oncology community, better metastasis models can be developed and made more accessible to drug developers, helping to advance new therapies to the clinic which work to improve survival rates for the toughest tumour types.

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Our CEO, Fiona Nielsen, recently wrote an article for Technology Networks that discusses these key points in more detail. Read the full article here.

Image: Human metastatic breast cancer in the pleural fluid. Stained with H&E and magnified to 400x. Image credit - the National Cancer Institute.