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DCC and Targeted Cancer Therapies

Drug discovery has historically been a slow and expensive process. Sufferers of various pathologies, including cancer, are often limited in therapeutic modalities to treatments that can be years or even decades old. Though many of these treatments may still be effective, very few, if any, therapies are without limitations or side effects, and designing and testing new compounds for use in the human model is the bottleneck through which all new drugs must pass.

When designing a drug for use as a cancer therapy, there are numerous possible ways to limit the survivability of the tumour. The cellular pathways that can be targeted include, but are not limited to, those involved in apoptosis, cell migration, angiogenesis, and signal transduction pathways [1]. These pathways are associated with tumour survival and proliferation and are targeted through a variety of mechanisms including Antibody Dependent Cell-mediated Cytotoxicity (ADCC), improved radiation therapies, and targeted chemotherapies [1].

Figure 1 : An immunofluorescent stain of mitochondria in the human colon. This assay is using anti-TFAM (__T__ranscription __F__actor __A__, __M__itochondrial) protein antibodies with the fluorescent assay attached. The same principles are used in targeted cancer therapy. Although the field of oncology has seen and continues to see improvements in available treatment modalities, one of the most persistent challenges faced by clinicians and patients is tumour resistance to treatment [1]. This resistance can happen for a variety of reasons, and is quite prevalent in the field of targeted cancer therapies. In targeted cancer therapies, methods through which tumour resistance can be acquired include target mutation, cross-talk (activation of alternate cellular pathways and downstreams), and activation of drug-resistant genes such as those expressing drug-efflux pumps [1]. Currently, some of the more effective anti-cancer therapies use monoclonal or polyclonal antibodies to induce ADCC or complement dependent cytotoxicity. Several challenges with using these approaches have been outlined previously, but include cross-reactivity, limited therapeutic window due to mutation, and limited target-binding due to mass-dependent diffusion kinetics in the tumour [1].

Dynamic Combinatorial Chemistry may be able to provide researchers with a method by which the discovery stage of drug design can be expedited, cross reactivity can be limited, and tumour resistance can be minimized. It has already been shown that DCC can be used to identify effective inhibitors to cellular proteins, through processes such as receptor assisted casting [3]. Further, it has been shown that DCC can accurately identify structural and chemical characteristics of protein structure through the use of substrate assisted molding [1].

In addition to the techniques described above, a novel approach known as "tethering" that is related to DCC, has recently been described for biomolecule recognition [2]. T ethering takes advantage of naturally occurring, or mutation induced cysteine residues on the surface of a protein in a process known as site-directed ligand discovery. Through the use of a disulfide exchange-based DCL, the most effective binding constituents can be assessed for the protein structure surrounding specific residues ( the site), including low-affinity binders that may not generally bind to the protein surface. The specificity of such an interrogative technique enables researchers to more efficiently determine the characteristics of the surrounding protein surface. This, in turn, can help to quickly determine the most appropriate design of a lead drug that is intended to capitalize on interactions with a specific segment of the protein [4]. Figure 2 : The basics involved in tethering process. The details of the steps are described above. The rapid and effective identification of such structural and functional characteristics of tumour-related or tumour-dependent proteins can be used to provide a template, on which classical immunogenic therapies, small molecule kinase inhibitors, or cell protein ligands or inhibitors can be based [1] [3] ; for example, standard or single-chain antibodies can be screened against protein-surface templates for the most efficient binder and these efficient binders can be trialed for clinical use. In addition to standard immunogenic therapies, it has been shown that small molecules and different antibodies can be used to deliver radiotherapies or chemotherapies to target cells, thus increasing the efficacy of the immunogenic treatment, while minimizing the negative effects that the radio or chemotherapy might have systemically. Return to Cancer and Proteins Page

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Go to Future Application of DCC in Cancer Therapies Drug development in cancer medicine: challenges for targeted approaches. From: Current Clinical Oncology: Targeted Cancer Therapy 1]