Cancer Therapeutics

Research into cancer signalling has paved the way for the development of numerous cancer therapeutics, which act at different stages/sites in the cell-cycle to arrest/suppress signalling in cancer cells and induce cell death. Molecularly targeted drugs based on rational drug design have been developed to target and inhibit isolated genes or pathways crucial to the disease mechanism. Many of the earlier targeted therapeutics utilised cancer vaccines, siRNA and antisense oligonucleotides, however, novel therapies now employ monoclonal antibodies (MoAbs) and small-molecule protein-kinase inhibitors (SMPKIs), and have been more successful. MoAbs are bulky and target membrane-bound receptors and act through interfering with ligand-receptor interactions, complement-mediated cytotoxicity, immune modulation and antibody-dependent cellular toxicity. SMPKIs are dual specific and target both membrane-bound and internal targets via binding catalytic domains, allosteric binders, inactive kinase binding ligands, and ATP analogues. Because of the structural homology shared by many protein kinases, a single SMPKI can inhibit multiple protein kinases, which is quite advantageous in anticancer therapy.

Molecularly targeted drugs can be placed into several categories based on their mode of action and the specific disease mechanism targeted. Some of the major categories include (i) Aromatase inhibitors, block aromatase in oestrogen-sensitive breast cancer (Drugs: Anastrozole/Arimidex®, exemestane/Aromasin®). (ii) Signal transduction inhibitors; e.g. HER receptor inhibitors, protein kinase inhibitors (scr inhibitors e.g. Dasatinib/Spryce®, Bosutinib), aurora kinase inhibitors (AZD-1152), MAPK inhibitors (Tipifarnib/Zarnestral, Sorafenib/Nexavar, ARRY-142886), PI3k/Akt/mTOR inhibitors (Temsirolimus/Torisel, Rapamycin/Rapamune, Perifosine), etc. (iii) Gene expression modifiers/epigenetic modulators; e.g. histone deacetylases (HDACs) inhibitors and DNA methyltransferase inhibitors (Vorinostat/Zolinza®, Romidepsin (Istodax®), which increase gene expression leading to the induction of tumour cell differentiation, cell-cycle arrest, and apoptosis (Rountree et al., 2000). (iv) Cell death enhancers; these interfere with the action of proteasomes and DNA synthesis thus triggering cell death (Bortezomib/Velcade®, Pralatrexate/Folotyn®) (v) Angiogenesis blockers, which block the growth of blood vessels to tumours, integrin agents that inhibit metastasis (Volociximab), and anti-VEGF/VEGFR (Vascular Endothelial Growth Factor) agents (Bevacizumab/Avastin®, Sorafenib/Nexavar®, Sunitinib/Sutent®).

EGF signalling is crucial in cancer since it integrates many cascades and also that tumour cells produce EGF-related growth factors (e.g. TGF-α is a ligand for EGFR), which makes EGFR constitutively active. For this reason and the fact the EGFR was the first receptor TK directly linked to human cancers, many MoAbs and SMPKIs and been developed and approved for EGFR/HER2/ErbB targeted therapies in many cancers. However, since most signalling pathways interact through extensive cross-talk with other pathways, the use of drugs that target a single pathway has shown limited success. After initial responsiveness patient tumours then become resistant or re-occur, as seen with some ErbB-targeted drugs and Gleevec targeting of Bcr-Abl. The authors showed that after initial success, the tumour cells developed a mechanism to circumvent the actions of these drugs, either by mutations (allelic adaptive changes) such that the drugs cannot bind catalytic domains or via by-passing that route in the cascade. As a result of this, back-up inhibitors and combination therapies have been developed. These therapeutics target several receptors and/or signalling pathways, thereby reducing the chance of drug resistance. Lapatinib, which targets both EGFR and HER2/neu receptors and Sunitinib/Sutent®, which targets PDGFR, VEGFR, c-kit and Flt3 are good examples of such drugs.

The future of targeted therapeutics will be based on multi-component drugs having combination effects since oncogenesis is a multi-genic, multi-stage process. New drugs being developed induce apoptosis in cancer stem cells to arrest cancer proliferation. However, with the increase use of structural and systems biology, and knowledge of the disease process, the development of many new drugs that target several processes in cell-cycle dysfunction/dysregulation will culminate in better treatment options and eventually a cure.

For More Detail:

Free Cancer Information