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Proteins and Cancer

There are a large number of cancers in which the proteins on the cell surface are altered. This compositional alteration of the cell membrane or its proteins can alter the microenvironment of the cell and enhance tumour survivability, proliferation, and metastasis [1]. One common alteration of cell-surface protein occurs in malignant tumours expressing the trans-membrane proteins Carbonic Anhydrase (CA) IX/XII [1]. CA IX and XII are two of the fourteen isoforms of CA found in humans and rapidly convert water and CO 2 into carbonic acid or vice versa [1].

It has been hypothesized that the presence or overexpression of CA in malignant tumours aids in the maintenance of an acidic extracellular environment. This acidic extracellular environment property is essential for tumour proliferation [1 ]. Due to the specificity of the CA isoforms (over)expressed in various cancers and the fact that the structure and function of CA has been described in great detail, CA IX and XII may prove a convenient host molecule for targeted cancer therapies, as have various proliferative proteins such as HER2 in breast cancer. Through the application of anti-CA IX/XII monoclonal antibodies (mAbs) or transport molecules of similar specificity, the expression or function of CA IX/XII on the surface of tumour cells may be limited, a situation that would decrease overall survivability of the cells //in vivo// through the increase of extracellular pH. Many contemporary targeted cancer therapies use similar strategies to either recruit the immune system of the individual suffering from cancer or assist in targeting cytotoxic compounds to the tumour itself [2].

Such strategies are not, however, without their limitations. Two major sources of concern for such therapies are:

1) Cross-reactivity 2) Structural changes to the target molecule (mutations)

Antibodies are large molecules that interact with their targets via epitope-paratope interactions. Due to their size and the amount of variability found in their idiotypic region, there is the potential for a single antibody to interact with many different molecules throughout the body in a process known as cross-reactivity. Many immunogenic cancer therapies harness monoclonal antibodies (mAbs) derived from animal models, however, due to this inherent lack of specificity, the application of an immunogenic cancer therapy can often impact cells in the body that do not express the specific epitope targeted by the therapy - i.e. non-cancerous cells - an issue highlighted by the example of targeting carbonic anhydrase. Although over expressed in many cancers, CA is widely present throughout the body in various isoforms and it is unlikely that targeted therapies would be limited to cancerous cells.

In addition to cross-reactivity, mutations can also limit the therapeutic efficacy of immunogenic or targeted cancer therapies [2 ]. The targeted therapies are designed to achieve a relatively high level of specificity towards their target molecules, as a result, any mutation of the target molecule decreases the efficacy with which the therapy performs [2 ]. This mutation issue may be compounded by the fact that cross-reactivity may //not// be lessened concurrently and, as such, the patient receives the negative side-effects of the treatment but may see fewer positive outcomes.

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