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Commentary: Developing Humanized Cancer Models for
Cost-Effective and Productive Cancer Drug Discovery
06-03-2014
EDIT CONNECT
SHARING OPTIONS:
Developing Humanized Cancer Models for Cost-Effective and Productive Cancer Drug Discovery – Targeting the
Tumor Microenvironment
The drug discovery process is complex and protracted, and requires
drug development companies and contract research organizations (CROs) to overcome numerous obstacles in preclinical and clinical development before achieving
regulatory approval. As drug candidates progress, R&D costs increase sharply. In Oncology Drug Discovery, the attrition rate of candidates successfully
traversing clinical trials and reaching the market is very high at over 90 percent, and 50 percent of these failures are down to lack of
efficacy1.
Reducing these attrition rates underscores the need for improved clinical models, as well as
their translation to clinical trial design, analysis and prediction. A significant limitation in developing drug candidates for oncology is the challenge of
accessing relevant clinical models that truly mimic the diversity of a patient population and the stages of progression of a disease. As each tumor is unique
and cancer progression is non-uniform across all patients, treatments need to be tailored to subtypes of cancer, making discovery and development more
complex, time-consuming and costly.
A Personalized Approach to Drug Therapy
Over the past decade, treatment of cancer patients has changed considerably to incorporate a more personalized approach. Many
patients are now tested for key oncogenic mutations in their tumor DNA, and those who carry a specific mutation may be treated with a targeted therapy. In
order to study cancer progression and treatment response with clinically relevant samples, primary tumor cells can be taken directly from the patient and
kept in vitro or in vivo to undergo testing. These patient-derived xenograft (PDX) models are capable of providing cost-effective
and informative preclinical drug assessments, with large model populations screening drug candidates across a wide range of tumor subtypes, in order to
assess the efficacy of a drug candidate before advancing it into the clinic.
Traditionally, cell line-
derived xenograft models (CDX), which use cell lines maintained in plastic and therefore adapted to grow independently of the tumor microenvironment,
produced genetic and phenotypic characteristics distinct from those seen in the clinic2. This led to only 30-40 percent success rates in
predicting the clinical efficacy of anti-cancer modalities3. Many aspects of the tumor microenvironment need to be understood and considered, and
therefore it is unsurprising that anti-cancer agents developed using simplified models have not yielded the hoped for success in the clinic. In an attempt to
improve clinical predictivity and reduce drug attrition, PDX are being used to improve and refine preclinical xenograft modeling, by providing a more
relevant heterogeneous system in which human tumor and stromal cells are in close cooperation within a unique environment.
The Challenge to Develop Humanized Models of Cancer
Establishing models that fully
recapitulate the tumor microenvironment both in vitro and in vivo can be challenging. PDX models have been reported to sustain molecular,
genetic and histological heterogeneity of the original tumors, and as such, data generated from these models closely resembles clinical data, with over 90
percent prediction of tumor sensitivity and resistance4. However one challenge that needs to be overcome is that PDX lose human stroma.
Increasing evidence suggests that interactions between stromal and tumor tissues contribute significantly to cancer
development and growth, with cancer-associated fibroblasts (CAFs) reported to account for over 50 percent of the tumor mass in some tumors. Stromal reactions
to tumors have also been linked to drug resistance e.g. desmoplasia, where the buildup of fibrous tissue protects the tumor from the toxic effects of
chemotherapeutics. In order to retain the human stroma in both PDX and cell line models, human mesenchymal stem cells, or patient-derived CAFs, can be
supplemented with the tumor cells prior to implantation.
Moving Forward – Extending the
Diversity and Understanding of PDX models
Retaining primary cancer cells derived from PDX tumors in
passage ensures that the models retain more clinically relevant oncological materials than conventional cell lines passaged for decades. Such platforms
provide a shortcut to functional screening using the right PDX models with the right drugs, at the right doses, for in-vivo testing, which
intimately links together the robustness of the in-vivo analyses with the clinically relevant in-vivo models. In addition, the close
relationship to the original patient tumor supports the preservation of genetic features and biological heterogeneity for novel therapeutic target discovery
and functional validation.
Well-characterized PDX models are used to mimic human clinical trials in mice, known as
patient avatar trials or human surrogate trials, providing a clinically relevant diversity of patient population to help identify or confirm responders and
non-responders in a population. By identifying suitable biomarkers in response to treatment, Phase 2 clinical trials can be designed to improve the chances
of success of a drug candidate in the clinic, thereby reducing the overall cost of drug discovery.
A
Promising Future
The use of PDX models in Phase 2-type studies or human surrogate trials is significantly
accelerating the pace and reducing the costs of evaluating compounds prior to transitioning into the clinical setting. These models provide a significantly
higher level of confidence for decision-making in the drug discovery process and can provide deep biological insights into the pharmacological mechanisms of
a drug, helping to identify potential biomarkers important to clinical trial design.
The need to reduce drug
attrition is especially acute in the field of oncology, where drugs often fail not because of toxicity but rather lack of efficacy. By performing mouse
xenograft studies at significantly lower cost and in reduced time, it is possible for drug discovery and development companies to make better decisions
faster in their drug development programs before proceeding into the clinic. In addition, the identified biomarkers will help to improve the success rate in
development by providing more predictive screening platforms and selection tools to help identify patient populations that will benefit from specific
treatment regimens.
Preclinical models that more closely replicate the microenvironment and heterogeneity of the
human tumor are having a significant impact in guiding clinical strategies and patient selection in the quest to optimize novel cancer therapeutics. The
tumor microenvironment has a significant role in disease progression and drug resistance. Understanding the mechanisms of resistance in tumors from any given
patient is critical in identifying the most appropriate follow-on therapies as part of a personalized medicine strategy. These models not only provide a
greater understanding of the role of the tumor microenvironment and the impact on disease progression, but also offer the opportunity for new drug-target
identification and validation.
The future of cancer treatments lies in the development of tailored strategies for
subsets of cancer patients and by leveraging genomically characterized PDX assets to discover biomarkers and identify patient responder and non-responder
profiles. While there is no single treatment that is effective for all patients even within a single cancer type or subtype, by using more clinically
relevant models in conjunction with molecular profiling and large-scale data analysis, it is possible to optimize and accelerate drug discovery into the
clinic.
References
1
Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 2004 (3) p. 711-715
2
BC Giovanella, JS Stehlin, ME Wall, MC Wani, AW Nicholas, LF Liu, R Silber, M Potmesil. DNA topoisomerase I-targeted chemotherapy of human colon cancer
in xenografts. Science 1989, Vol. 246 no. 4933 pp. 1046-1048.
3 Fricker, J. Time for reform in the drug-development
process. The Lancet Oncology Volume 9, Issue 12, December 2008, Pages 1125–1126.
4 Feibig et al,
EJC 40;802, 2004
Dr. Jean-Pierre Wery is president of Crown BioScience, Inc., which is based in Santa Clara, Calif. CrownBio is a preclinical CRO that offers comprehensive drug discovery services,
with expertise in oncology and metabolic disease and broad offering of in-vitro and in-vivo models.
Code: E06021400 Back |
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