**2. Colorectal Cancer**

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

**2.** to streamline the critical Phase II and Phase III to obtain faster and more reliable re‐

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‐

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

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

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‐

ities nowadays, it seems difficult to save on size and length of clinical trials.

**1.** to directly target the key regulators of CRC cancers

sponses regarding the drug's efficacy.

434 Drug Discovery

has not kept its promises [1].

models and tissue explants.

er colon therapeutics.

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.

**Figure 2.** Cancer deaths anticipated in 2011. Estimated leading cancer sites mortality in US and in European Union (EU-27) for the year 2011 expressed as percent of total cancer deaths. Column diagrams highlight the mortality rate within the population specifically affected by colon cancer. Rates are standardized to the World Standard Population. Source: American Cancer Society and Malvezzi et al, Annals of oncology, 2011, 22(4):947-56.

**Figure 3.** Shematic representation of the WNT signaling pathway. WNT proteins bind to receptors of the Frizzled and LRP families on the cell surface. Through several cytoplasmic components, the signal is transduced to β-CATENIN, which enters the nucleus and forms a complex with LEF and TCF4 to activate transcription of WNT target genes. Muta‐ tions in APC, Axin and β-CATENIN genes lead to constitutive activation of WNT signaling and ultimately to cancer de‐

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

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

437

It is commonly accepted that CRC results from complex interactions between inherited and environmental factors, with a large contribution of dietary and life style factors as suggest‐ ed by wide geographical risk variations. However, the primary risk factor of CRC is age, as 90% of the cases are diagnosed over the age of 50 years [9]. Surgical removal remains the most efficient treatment for early stage colorectal cancer, and may be curative for can‐ cers that have not spread. Patients whose cancer is detected at an early, localized stage present a 5-year survival around 90% [9]. For these reasons, US and European Union have implemented preventive screening programs that have contributed to slightly reduce mor‐

Unfortunately, as in many other forms of cancer, colon cancer does not display too many symptoms, develops slowly over a period of several years, and only manifests itself when the disease begins to extend. Adjuvant chemotherapy in combination with surgery or radia‐ tion is then the usual treatment. However, 5 of the 9 anti-CRC drugs approved by the FDA today are basic cytotoxic chemotherapeutics that attack cancer cells at a very fundamental level (i.e. the cell division machinery) without specific targets, resulting in poor effectiveness

velopment.

**2.2. Clinical management**

bidity and mortality [10].

and strong side-effects (e.g., oxaliplatin; Table 1).

#### **2.1. Molecular mechanisms**

Loss of APC function is the initial molecular event that leads to adenoma formation. Indeed, germline mutations in the gene APC have been identified as the cause of familial adenoma‐ tous polyposis (FAP), an inheritable intestinal cancer syndrome [5], and APC is mutated in more than 80% of all sporadic cancers [6]. APC belongs to the WNT signaling pathway (Fig‐ ure 3) where it interacts with other proteins like AXINS and GSK3β to make a complex that down-regulates the cellular levels of β-CATENIN (see [7] for review). Activating mutations in β-CATENIN gene have also been observed in more than 10% of CRC [8]. When activated, β-CATENIN interacts in the nucleus with the transcriptional complex LEF/TCF to induce the expression of growth promoting genes, like MYC and CYCLIN D1. Additional waves of genetic and epigenetic alterations (KRAS, P53, etc…) will follow this early set of molecular changes to sustain the progression of the transformation process until carcinoma and meta‐ stasis stages.

**Figure 3.** Shematic representation of the WNT signaling pathway. WNT proteins bind to receptors of the Frizzled and LRP families on the cell surface. Through several cytoplasmic components, the signal is transduced to β-CATENIN, which enters the nucleus and forms a complex with LEF and TCF4 to activate transcription of WNT target genes. Muta‐ tions in APC, Axin and β-CATENIN genes lead to constitutive activation of WNT signaling and ultimately to cancer de‐ velopment.
