Alternative Cancer Treatments

Extracellular growth factors are proteins that control mammalian cell proliferation and/or differentiation through the binding of receptors on cell surfaces to initiate a cascade of events. Many growth factors dictate the balance between proliferation and cell death within organs. For normal cells to remain viable, they require stimulation from growth factors. However, when cells become transformed and tumorigenic, this requirement is circumvented as their growth and survival pathways have become hyperactivated by oncogenes, thereby freeing them from the need for exogenous growth factor signals.

DNA damage through environmental factors, which mutate DNA, and inherited genetic mutations have been shown to be involved in the production of oncogenes that lead to cell transformation and ultimately cancer. Oncogenes arise through several mechanisms.

(1) DNA rearrangements, the most common mutation as seen in the translocation of c-myc to sites where it is over-expressed, bcr-abl fusion as in the case of chronic myeloid leukemia (CML) or proteins may be truncated making them constitutively active.

(2) Gene amplification.

(3) Point mutations, e.g. mutations at position 12 and 61 in ras making it constitutively active.

(4) Integration of viral DNA next to a proto-oncogene.

Through these processes, normal cellular genes may be inappropriately expressed resulting in loss of control over the cell-cycle then cell transformation. Oncogenes encode proteins involved in cell-cycle control or have high homology with TK growth factor receptors (e.g. v-fms, v-ros, v-sis, v-erb B), and may code for factors involved at all the important mitogenic stages. Another important oncogene src (non-receptor TK) has sequence homology with EGFR and is able to activate over 50 distinct substrates through its TK. Permanent activation/over-expression of scr has been identified in many cancers. While many of these oncogenes are membrane associated, myc, myb and fos act on transcription in the nucleus. Unlike myc and ras, many oncogenes are tissue-specific and their role in cancer development and progression has been the source of targets for cancer therapeutics, since different oncogenes act at different stages. In addition to gain of function mutations mentioned, loss of function mutations particularly with genes that carryout DNA-repair, and tumour suppressors such as the retinoblastoma protein – pRB, p53, phosphatase and tensin homolog – PTEN, BRACA etc. also give rise to cancers. PTEN is mutated in many cancers as it dephosphorylates PIP3 in PI3K/PKB signalling controlling cell proliferation and apoptosis. Similarly, p53, which coordinates signals to determine whether or not a cell goes through the cell-cycle or is destroyed, is frequently mutated in many cancers. Mutations in genes accounting for more than 1% of the human genome contribute to cancer, which makes these genes attractive targets for drug development.

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.