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Cancer Care Using an Array of Radiolabelled Small Molecules

The inherent ‘intelligence’ of cancer cells to survive under adverse conditions makes cancer a difficult disease to cure. In this issue of BioEssays, Kolodny et al. hypothesize the use of an array of radiolabeled small molecules (RSMs) to target unique proteins present in cancer cells of the patient. This is in contrast to the use of a single peptide to target a single type of receptor protein on cancer cells. RSMs unleash a multipronged attack on several cellular targets, and hence could offer better therapeutic efficacy. Being small molecules (SMs), in vivo distribution to target cells, and elimination from normal cells, will be quicker, thus producing diagnostic images with excellent target/non-target ratio, and therapy with lower radiation toxicity to off-target organs. Use of DNA-encoded SM libraries (DELs) for drug discovery is not novel. However, applying this approach for the selection of target specific SMs with pendant side arms suitable for appending radioisotope tags for radiation therapy application is innovative. The hypothesis proposes interrogation of DEL members with proteins, both intracellular and membranebound, extracted from the surgically removed primary cancer cell samples of the patient. The DNA encoded SMs (DESMs) bound to the cancer cell proteins in the primary selection process undergo a counter selection process with proteins extracted from the normal tissue of the same patient. The result by subtraction is a set of DESMs specific to cancer cell proteins only. The authors propose further refinement of this ensemble to reduce non-specific binding and to improve specificity to cancer cell proteins by further selection and counter selection cycles. At any stage, the DNA-codes of the selected SMs are useful for amplifying the mixture to compensate for the losses and enable several such selection cycles. The customized DELs proposed in this work incorporate a photo-cleavable linkage to detach theDNA-tag prior to application. The authors envisage incorporating an alkynyl arm at one end of the SMs to append a flurophore or a radioisotope for imaging or therapy. The preference for employing radiation therapy over the conventional drug therapy is justified for several reasons. While conventional drug therapy depends on the drug interfering