The Evolution of Cancer Drug Discovery

The ultimate goal of any cancer drug discovery process is to discover and develop effective and non-toxic therapies. Over the years this goal has been pursued using approaches driven by the available understanding of the biology of cancer cells and technologies (Suggitt and Bibby 2005). Over time, a general transition has been observed from the empirical drug screening of cytotoxic agents against poorly characterized tumor models to the target-driven drug screening of inhibitors with a defined...

Insights Gained in the Role of EGFR in Cancer

In parallel to the clinical trials mentioned above and as the number of patients treated with these agents increased, a number of groups started to rationally seek factors that may be linked to the activity of the compounds. The first evidence came from clinical observations. It was known that female patients, patients of Asian origin, never -smokers and those with an adenocarcinoma type of NSCLC were the subgroups more likely to benefit from these agents. Subsequent molecular studies did not...

The Darwinian paradigm in oncology

In our opinion, oncology is going through a theoretical revolution that challenges the dominant paradigms. Oncology - as with other branches of biomedicine like, in the past, immunology, medical microbiology and some aspects of neurobiology - is acquiring a more coherent biological way of thinking about the causal dynamics of adaptive physiological and pathological phenomena. This change may still support new therapeutic strategies, but certainly allows better integrating of basic and applied...

Target Driven Drug Discovery 331 Target Identification and Validation

Cancer drug discovery is all about making the right decisions. The first crucial decision to be taken is about the target selection. A target should be validated at the start of the discovery process and resources should be focused on the most promising ones as early as possible. To this aim, a number of approaches are being used. It is important to underline that none of these approaches should be used in isolation to mark a decision, rather they must be used in combination to select the right...

Targeting Side Population Tumor Cells with Tumor Vaccines

One explanation for the failure of immunization to produce a clinical anti-B-CLL response, despite the presence of antitumor immunity, is that we have failed to eradicate a progenitor cell population. It is possible to define a subset of normal hematopoietic stem cells called Side Population (SP) cells, because of their appearance on FACS analysis with Hoechst dyes (Fig. 7-5a).21 These cells express a high Fig. 7-5 Normal and malignant Side Population (SP) Cells. a) Normal side population cells...

Advanced Small Molecule Aurora Kinase Inhibitors

As of today, it is estimated that more than 20 programs have been initiated for the development of small molecule Aurora inhibitors, and the majority of large pharmaceutical companies active in Oncology have or have had activities running in the field. As mentioned above, one of the major questions in developing small molecule inhibitors is whether specific or dual Aurora-A or -B inhibitors will be the best choice for having the best anticancer effect. But besides the kinase inhibition profile,...

CD40LIL2 BCLL Tumor Vaccines

We are treating patients with chronic B-lymphocytic leukemia using a vaccine in which human CD40 ligand and human IL2 are expressed transgenically.19 CD40 ligand has a number of immuno-stimulatory effects. It activates and matures dendritic cells, co-stimulates T cells, and it stimulates the B leukemia cells themselves through their CD40 receptor. B-CLL activation is, in turn, accompanied by up-regulation of MHC Class II molecules and of co-stimulator molecules CD80 and CD86 on the malignant...

From Speculations to Reality and Beyond Some Implications of a Darwinian View of Cancer Progression

The confirmation of Nowell's model came from the discovery that the acquisition of the resistance of cancer cells to chemotherapy was similar to other well-known evolutionary phenomena described in medical therapy. In 1978, Robert Schimke discovered a genetic mechanism that provides the condition for a selection of cancer cells resistant to methotrexate (MTX). He showed that resistance of mouse cells to MTXresults from a selection of cells of higher contents of a specific enzyme, due to an...

Hit Expansion and Hitto Lead

Routinely, a number of hits belonging to different chemical classes are identified by the above mentioned approaches. Hits are usually defined as chemical molecules with suboptimal potency and selectivity in biochemical assays against the intended molecular target. Since it is not uncommon that different chemical classes emerge from HTS, the key decision to be taken at this stage is the selection of a limited number of chemical classes (usually two to three) to be expanded by medicinal...

From Magic Bullets to Targeted Therapies Many Treatments but the Same Philosophy

The origins of modern cancer therapy can be seen as one of the main instantiations of the biomedical paradigm. In fact, Paul Ehrlich's view (1906-9) of specific chemotherapy as a therapia sterilisans magna and of drugs as artificially designed antibodies or magic bullets has inspired the search for effective anticancer drugs since the beginnings. Cancer chemotherapy started in 1946 when Goodmann and Gilman observed a dramatic reduction in tumor mass of a patient with non-Hodgkin lymphoma after...

TAMs Express Selected M2 Protumoral Functions

The cytokine network expressed at the tumor site plays a central role in the orientation and differentiation of recruited mononuclear phagocytes, thus contributing to direct the local immune system away from antitumor functions (Mantovani, et al. 2002). This idea is supported by both preclinical and clinical observations (Goerdt and Orfanos 1999 Bingle, et al. 2002) that clearly demonstrate an association between macrophage number density and prognosis in a variety of murine and human...