**1. Introduction**

More than 10 years after the first sequencing of the human genome and despite major advan‐ ces in scientific and technological expertise into drug research and development processes (R&D), the fact remains that we are facing a dearth of new drugs. Indeed, the number of drugs approved by the US Food and Drug Administration (FDA) has roughly fallen to 50% over the last ten years [1]. Unfortunately for pharmaceutical companies, at present this attrition in drug discovery combined with the expiration of major product patents logically lead to the devel‐ opment of generics. Facing both a major medical need and an obvious economical chal‐ lenge, there is an urgent need to make significant improvements in the research output.

Analyses of the clinical trials landscape reveal that a large number of promising drug leads fail in late stages, mainly in phase II, with an overall failure rate of 67% (Fig. 1a). All studies agree on the reasons by pinpointing either insufficient efficacy (~55%) or safety issues (~20%) as major causes of human trials failure [2, 3]. Remarkably, the therapeutic area show‐ ing the largest number of failures is oncology, with only 29% of success rate in Phase II and 34% in Phase III (Fig.1b). Within oncology indications, the status of colorectal cancer (CRC) is the most dramatic with an overall drug approval of only 3% (Fig.1c) over the last 10 years! More surprisingly, more than half of the drugs currently approved to treat CRC work through the general inhibition of DNA synthesis and cellular division, instead of targeting molecular processes specifically involved in CRC progression (Table 1). These observations highlight the necessity to both reduce failure rates in the clinic and shorten the time required for developing innovative therapies.

© 2013 Constant et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

From this perspective, one of the obvious strategies would be:


This strategy may save years of efforts and millions of dollars, giving that the average usual time for developing a new drug is ten years and with a total cost amount to billions of dollars.

But in contrast, because a new drug has to show a benefit compared to an already approved treatment, the number of patients involved in a pivotal trials is increasing more and more in order to reach significance, and a similar trend is noted for the duration of the trial, that is directly linked to safety. Therefore, regarding the constraints imposed by regulatory author‐ ities nowadays, it seems difficult to save on size and length of clinical trials.

In the mid-1990s, the pharmaceutical community has already attempted to increase R&D productivity by embarking in a technological shift. That was the time of the inevitable highthroughput screening, which combined with the "all-Omics" supposed to reduce costs and blew up success rates [4]. As we have seen, this approach, maybe too reductionist in the sense that it does not allow getting an idea of the full biological properties (ADME, toxici‐ ty,etc…) of a compound at an early stage, has favored the quantity instead of quality and has not kept its promises [1].

**Figure 1.** Success rate of drug development. Overall success rate of clinical trials for phases I-III from 2003 to 2010 corresponding to 4275 drugs and 7300 indications (a), success rate for phase II and III divided according to therapeu‐ tic areas (b) and overall success rate within specific oncologic areas (c). Source: Hay et al, 13th BIO CEO & Investor Con‐

Colon Cancer: Current Treatments and Preclinical Models for the Discovery and Development of New Therapies

http://dx.doi.org/10.5772/53391

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Colorectal cancer is one of the major health concerns in the Western world. CRC is the sec‐ ond most frequently diagnosed cancer in men and women, right after lung cancer. It repre‐ sents the second leading cause of cancer-related deaths, both in the United States and in Europe, with a significant rate of 9% and 13% of total cancer deaths, respectively (Fig.2). The vast majority (~75%) of colon cancers are sporadic adenocarcinomas, arising from mutations in the epithelial cells lining the wall of the intestine that is in continuous renewal. CRC often begins as an adenomatous polyp, a benign growth on the interior surface of the organ. Most of polyps remain benign, but over the years some of them become progressively more dys‐ plastic, accumulate mutations and progress to carcinoma and ultimately, to metastasis.

ference, 2011, New-York.

**2. Colorectal Cancer**

Today, efforts have to be made to clearly address the early clinical discovery steps, with the goal to better qualify "leads" to increase the signal-to-noise ratio of drugs entering into clini‐ cal trials. This point of view is supported by the important failure rate subsisting in Phases III (Fig1b), suggesting an overestimation of the efficacy of candidate molecules during pre‐ clinical tests. One of the important reasons may be the use of irrelevant models or models not predictive enough. Therefore, the development of relevant and predictive models is key to increase the quality of preclinical researches and to increase the success rate of new drugs.

Consequently, the foundations of the drug discovery process have to be reconsidered by giving definitively more emphasis to the quality of preclinical validations and by encourag‐ ing the design of new pertinent models, including human 3D (three dimensional) *in vitro* cell models and tissue explants.

This article is intended to give an overview of the current knowledge about CRC and the different models commonly used to study CRC, in order to identify the most suitable biosystems for optimal development of new CRC therapies. The first part will describe the pathology and its molecular basis, and the various drugs that are currently in clinical use or under development. Then, in the second part we will review and discuss the use of cancer cell line collections, genetically engineered mouse models (GEM), primary human tumors xenografts (PDX) and *ex vivo* organotypic cultures (EVOC) to identify and validate anticanc‐ er colon therapeutics.

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**Figure 1.** Success rate of drug development. Overall success rate of clinical trials for phases I-III from 2003 to 2010 corresponding to 4275 drugs and 7300 indications (a), success rate for phase II and III divided according to therapeu‐ tic areas (b) and overall success rate within specific oncologic areas (c). Source: Hay et al, 13th BIO CEO & Investor Con‐ ference, 2011, New-York.
