Please can you give a brief outline of the different types of anti-cancer treatments? Do they all suffer from the limitation of acquired resistance?
Cancer can be treated by a number of different ways depending on the location, grade and stage of tumour. A patient's age, medical history and lifestyle will also be taken into consideration and a combination of treatments will also be adopted to provide maximum effect.
Treatment can involve surgery, chemotherapy, radiotherapy, hormone therapy, immunotherapy or targeted therapy.
Unfortunately all cancer therapies, despite their success, are limited by the development of drug resistance.
The efforts of many scientific groups over the past few decades have resulted in the identification of genes and molecular signalling mechanisms that contribute to drug resistance which has helped us to understand the biology of cancer and how they adapt and change to survive and progress.
But despite this, the 5-year survival of most cancer patients remains poor therefore resistance to is a major problem in cancer treatment.
Why has the identification of the molecular mechanisms of resistance to chemotherapeutics been very challenging?
Resistance can occur for a variety of different reasons such as poor absorption of the cytotoxic drug, rapid metabolism or excretion of the drug, poor tolerance by the patient resulting in sub-optimal dosing, the tumour microenvironment which may affect the metabolism or delivery of drug and genetic and epigenetic factors which alter the cells sensitivity to apoptosis, DNA damage repair and cell cycle checkpoints.
There are still many other mechanisms that need to be unravelled. There are many different types of chemotherapeutic agents and combinations used to treat many different cancer types. The mechanism of action can be non-specific therefore understanding the mechanisms of resistance for chemotherapeutics is very challenging.
Nonetheless chemotherapy is still very effective as first line treatment – it is the resistant cancers that need to be targeted and patients identified as early as possible as to whether they will respond or relapse.
At PRECOS, and at our parent company Crown Biosciences, we have developed models of resistance using patient-derived tumour tissue implanted in mice. Some of these patient-derived xenograft (PDX) models show sensitivity to chemotherapeutic agents whereas as some don’t which gives us responder and non-responder profiles similar to what you would see in the clinic.
The sensitive models are then continually challenged with chemotherapeutic treatment until a resistance phenotype emerges i.e. does not respond to the chemotherapy which again reflects what would happen in the clinic.
In this way we have intrinsic resistant and acquired resistant models to chemotherapeutic treatment that would have been used in the clinic. These models therefore show relevant resistance phenotype can then be used to identify new or combination treatments that will specifically target the resistant cancer.
How has this affected the development of second-generation chemotherapeutics?
Although the combinations of multiple drugs with different mechanisms may improve overall effect the side effects would be a limiting factor. In addition, some of the mechanism of resistance may confer simultaneous resistance to many other drugs causing multi-drug resistance so second generation chemotherapeutics may not be effective.
By understanding what causes the resistance, targeting the resistant mechanism may prevent relapse or disease progression. For example the ABC transporters have a major role in drug resistance, causing decreased accumulation of drug within the cell. This family of proteins are therefore a major target for drug development.
Are the novel molecular targeted therapies, such as tyrosine kinase inhibitors (TKIs), more tractable in terms of understanding the mechanism acquired resistance?
The mechanism of action of targeted agents before they enter the clinic are well validated and understood which makes understanding mechanism of resistance easier.
Molecular characterisation of resistant patient samples have revealed both genetic and non-genetic mechanism. For example in non-small cell lung cancer (NSCLC) the role of epidermal growth factor receptor (EGFR) is well documented and targeted agents have been developed to block EGFR signalling.
EGFR inhibitor resistant mechanisms are also very well documented and include further mutations or amplifications – this knowledge provides unique opportunities to design strategies to overcome resistance and/or prevent it.
How important are the use of models in improving the understanding of acquired resistance?
Very Important - the 5-year survival of most cancer patients remains poor therefore resistance to treatment is a major problem and highlights the need for more treatment options to prevent resistance and/or effectively treat resistant cancer.
To effectively evaluate new treatments in the clinic we need the preclinical models that represent the disease at different stages such as relapsed cancer and metastasis. Such models would allow deeper molecular, genetic, SNP, epigenetic and proteomic knowledge relevant to the clinically-derived subsets of tumour models, in order to develop a greater understanding of the disease state.
These models can be used to discover and validate key biomarkers which may predict responder versus non-responder profiles, and translational research readouts which can be tested in the clinic
The pharmaceutical and biotechnology sectors are seeking more relevant and accurate preclinical models to underpin their drug discovery work. It is likely that a combination of therapies will be necessary to prevent and/or treat resistant tumours.
The number of therapeutic combinations is vast therefore preclinical models are needed to correctly identify the right combinations for the relevant resistance as well as define the patient populations in which they will be most efficacious. This will involve both in vitro and in vivo platforms, but both need to recapitulate the human resistant disease as closely as possible.
The tumour microenvironment is important in resistance and disease progression which is why this has been a focus for PRECOS.
What are the main limitations of standard cell-derived xenograft (CDX) models and how do patient-derived xenograft tumours (PDX) differ from CDX models?
Unfortunately the success rate in predicting clinical efficacy of anti-cancer modalities using standard cell-derived xenograft models has been reported to be only 30-40%.
Standard xenograft models use cell lines that are maintained in plastic, in monolayers and have adapted to grow independently of the tumour microenvironment resulting in models with genetic and phenotypic characteristics distinct from that seen in the clinic.
Clinically-derived models provide a more relevant heterogenous system with human tumour and stroma cells in close co-operation and the models never see plastic as the line is maintained in serial passage in mice.
Maintaining the human microenvironment is important in order to sustain molecular, genetic and histological heterogeneity of the tumours, which can be compromised in plastic.
Collectively PRECOS and CrownBio has the largest collection of fully profiled PDX models which can be used to mimic human clinical trials, but in mice – these are known as Avatar trials or as we refer to them as “HuTrials”.
These models provide clinically-relevant environment to interrogate new drugs as well as identify suitable biomarkers of response – this knowledge can be applied to the design of Phase 2 clinical trial to increase the success.
We are also using these models to develop resistant isolates to new targeted agents and analyse the mechanisms involved and rationally-designed combination studies to delay/overcome the resistance issues and generate evidence-based hypothesis testing suitable for clinical trials.
Can an improved understanding of the mechanism of acquired resistance lead to the development of follow-on drugs? Are there any examples of this?
Yes absolutely – a very good example of this is demonstrated in lung cancer where mutations in EGFR occurs in 10-15% of patients with non-small cell lung cancer (NSCLC), which results in an activation mutation. These types of mutated cancers respond very well to EGFR inhibitors such as Iressa and Tarceva.
However in the majority of cases resistance to these drugs develops within 9-11 months which, in many cases, is due to the cancer cells acquiring a second mutation in EGFR called T790M, also known as the “resistance mutation.” There are no approved therapies to treat lung cancer patients who develop the second mutation.
However a new investigational drug called AZD9291, which is a third-generation EGFR inhibitor, was reported last month to show promise in preclinical studies, targeting both the activating and resistant mutant forms of EGFR more potently than normal EGFR, which would benefit patients by reducing the side effects encountered with current available EGFR inhibitors. This new drug is undergoing clinical trials.
Another example is the development of Nilotinib which is approved in the US and Europe for drug-resistant chronic myelogenous leukemia (CML). Imatinib (Gleevec) which is a tyrosine kinase inhibitor (TKI) currently used as a first-line treatment for CML, was developed by rational drug design to target the hyperactive bcr-abl protein in cells harbouring the Philadelphia chromosome mutation.
Despite being called the “magic bullet”, resistance to treatment eventually emerges. A Phase I clinical trial found nilotinib to shows activity in cases of CML resistant to treatment with imatinib. Nilotinib is also a TKI possesses 30 times greater potency than imatinib in imatinib-resistant cells.
What are PRECOS’ plans for the future?
We will continue to focus on oncology, especially areas of unmet medical needs, and continue to develop patient-relevant models and technology that are better positioned in bringing new anti-cancer drugs to the patient successfully.
Drug resistance as well as resistance to radiotherapy are important areas for us to develop appropriate models. Patients often relapse after initial treatment and the cancer is more aggressive and spreads leading to poor survival.
In order to tackle this effectively the pre-clinical models need to reflect the patient, with relevant biology and tumour microenvironment, progression and resistance.
PRECOS will focus on building such models that allow us to understand resistance, recurrence and what combination of drugs or irradiation will work. These tools will be valuable for pharmaceutical and biotech and ultimately lead to patient benefit.
Where can readers find more information?
The whitepaper on PRECOS models of acquired resistance can be found on our website www.precos.co.uk as well as factsheets and information on other services and initiatives and also on our parent company, Crown BioSciences, webpage www.crownbio.com.
About Dr. Rajendra Kumari, Chief Scientific Officer & Founder, PRECOS
Rajendra received her Ph.D. in Molecular Pharmacology from the University of Leicester followed by postdoctoral fellowship in the Division of Pre-clinical Oncology, University of Nottingham (UoN).
Rajendra then took the role of Project & Business Manager of the PRECOS Business Unit where she built up and managed the portfolio of preclinical projects, team and clients, as well as marketing and developing the commercial processes of PRECOS.
Rajendra’s expertise in cancer cell biology & model development helped to build PRECOS scientific strengths as well as an academic career as a lecturer at UoN. She is also co-founder of the Ex Vivo Pharmacology Centre of Excellence (UoN), which recapitulates the tumour microenvironment through use of clinically-derived tissue.
Rajendra was pivotal in the growth of the business unit, commercialisation of research and the spinout of PRECOS in 2010 and took up the position of Chief Operations Officer and currently serves as Chief Scientific Officer leading scientific operations and R&D.
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