Moving towards personalized cancer therapy
The “magic bullet” for the treatment of specific diseases has been the holy grail of medicine since the discovery of arsphenamine for the treatment of syphilis by Paul Erlich in the early 20th century. Over the last five decades, the cumulative efforts of
In the late 1990’s, the first designer targeted anti-cancer Glivec came into use as a result of understanding of the causative role of the fusion protein BCR-ABL in chronic myelogenous leukaemia (CML). Glivec specifically inhibits the tyrosine kinase domain of BCR-ABL, preventing the activation of intracellular signalling which is responsible for the malignant transformation of the CML cell. Glivec turned a disease with low cure rates and relatively toxic treatments, such as interferon and allogeneic stem cell transplants, into a highly curable and controllable disease with low treatment related toxicities.
Following the resounding success of Glivec, numerous advances have been made in the treatment of other cancers. Nowhere has the effect been as dramatic as non-small cell lung cancer. In the early part of the 21st century, the treatment of metastatic non-small cell lung cancer had made little advance over the previous two decades. A large trial involving over a thousand patients with stage IV non-small cell lung cancer comparing four different regimens of chemotherapy showed relatively uninspiring average survival times of eight to 10 months. Since then, a number of targetable oncogene drivers have been discovered in non-small cell lung cancer. Treatment of these oncogene driven tumours – with specific small molecules inhibiting activated enzymes resulting from these gene mutations – result in higher rates of cancer shrinkage and longer periods of cancer control with much less side effects than with traditional cytotoxic chemotherapy. The first of these mutations, those in the epidermal growth factor tyrosine kinase domain (EGFR TK), were found in 2005 and we now have
four such inhibitors in clinical use and four to five more in clinical development. Iressa and Tarceva are first generation EGFR TK inhibitors. Gilotrif and Tagrisso are second and third generation inhibitors. Use of these inhibitors have increased the survival of patients with metastatic EGFR TK mutated nonsmall cell lung cancer from an average of eight to 10 months to three to five years. A number of other driver oncogenes have been identified and small molecule inhibitors discovered. These driver oncogenes include rearrangements of EML4-ALK, RET, and ROS1 as well as mutations in Braf (V600E). Treatment of the lung cancers with these mutations with the specific inhibitors have similarly improved results as those with EGFR TK inhibitors in EGFR TK mutated lung
Another advancement in the treatment of metastatic lung cancer is the development of immunotherapy. Discovery of the regulators of the immune system and the factors that lead to an anti-tumour immune response has also led to the development of more effective and less toxic immunotherapies. Cytokines such as interferon and Interleukin-2 have been used for the last three decades to treat tumours such as CML and renal cell carcinoma with limited effectiveness and frequent serious side effects. AntiCTLA4 antibodies (Ipilumumab) demonstrated the ability to induce potent anti-tumour immune responses in patients with metastatic melanoma, resulting in cures in a subset of patients with a previously incurable disease. Antibodies against the programmed death-1 (PD1) molecule came into routine clinical use four years ago and is now a standard of care treatment for a number of different tumour types including lung cancer, melanoma, renal cell carcinoma, hepatocellular carcinoma, transitional cell carcinoma of the bladder, and squamous cell carcinoma of the head and neck.
The PD1 pathway is important in preventing autoimmunity and preventing the rejection of transplanted organs. However, tumours have co-opted the PD1 pathway to evade anti-tumour immune responses. Blockade of the PD1 pathway result in potent and long lasting anti-cancer immune responses in a subset of cancer patients with relatively few serious side effects. In about 20 per cent of patients with previously untreated metastatic lung cancer identified by high levels of expression of the programmed death ligand on tumour tissue, treatment with anti-PD1 antibodies is superior to chemotherapy in terms of rates of tumour shrinkage, disease control, and survival. Anti-PD1 antibodies are also better than other treatments in previously treated lung cancer. By adding Ipilumumab to anti-PD1 antibodies, one can improve the therapeutic benefit of immunotherapy at the cost of more side effects. However, further clinical trials are ongoing with novel combinations of immunotherapies to improve efficacy while reducing side effects. In addition to the advantages of good probability of disease control with low rates of serious side effects, immunotherapy also has the advantage of prolonged disease control which can last for a number of years after cessation of treatment due to an ongoing active immune response against the tumour.
Lung cancer is an important disease in Asia due to the epidemiology of the disease and the molecular characteristics of the lung cancer found in Asia.
Firstly, the large population in Asia, frequency of tobacco use and the environmental pollution associated with rapid industrialization will cause an epidemic of lung cancer in Asia in the coming years. Secondly, for reasons that are not completely clear, there is also a much higher rate of lung cancer in non-smokers in Asia which are often oncogene driven and can be treated molecularly targeted therapies as described above. The large trials which demonstrate the benefit of such therapies have largely been conducted in Asia. Due to these factors, the development of lung cancer therapy will become more focused in Asia.
None of these advances would be possible without carefully conducted basic and clinical research.
Having been involved in laboratory and clinical research for the last two decades, it has been gratifying to see the results of basic understanding of tumour biology translated into better testing and treatments for patients. It is an iterative process where hypothesis are tested in the laboratory and the results are applied to design treatments for patients. The clinical trials are then conducted to test for the safety and efficacy of the novel treatments, culminating in large randomized trials which test the novel treatment either in combination with standard therapy or in comparison with the current standard of care. Observations and hypothesis are then taken back to the laboratory to further improve outcomes. For example, the EGFR TK inhibitors were synthesized to target the EGFR pathway in general before EGFR TK mutation were even known. However, when only a subset of patients seem to respond to these medications, further testing was done and the EFGR TK mutations were discovered. The EGFR TK mutations are now the single predictor of benefit to EGFR TKIs. Through this process, we can achieve the goal of personalized cancer therapy.