Where We Are and What Lies Ahead
“Cancer's life is a recapitulation of the body's life, its existence a pathological mirror of our own”- renowned physician Dr Siddhartha Mukherjee eloquently describes cancer’s intricate identity. Interestingly, this similarity also forms the fundamental challenge in cancer therapies – the ability to kill cancer cells vs normal cells. Traditional chemotherapy drugs that attack rapidly dividing cancer cells also affect similar cells essential for normal body functions, like blood cells, and those in the hair and stomach lining. Such undesirable side effects associated with conventional cancer drugs have led to the emergence of targeted therapies that attack properties unique to cancer cells.
Targeted therapies have been a significant milestone in rational drug design and have come a long way in improving cancer treatments. According to the National Cancer Institute, there have been 8.2 million cancer-related deaths worldwide in 2012 and the number of new cancer cases in the next two decades is estimated to be 22 million. In the light of the current and estimated cancer mortalities, rapid development of targeted therapies – encompassing both chemical and biological approaches – are imperative to managing the global cancer-related healthcare burden.
Targeted therapies: Purpose and Principle
The 1997 FDA approval of RITUXIMAB – the first molecularly targeted cancer drug – has dramatically transformed the oncology drug market. Targeted cancer therapies are designed to interfere with molecular targets, e.g. proteins, or pathways that help specifically in the growth and sustenance of cancer cells. Identification of these targets thus forms the cornerstone of such therapies – the primary target may even vary across sub-types of cancers of the same organ.
On the one hand, cell growth and proliferation are enhanced by the mutation of cell cycle regulating proteins like kinases. On the other hand, cell death pathways like apoptosis are inhibited by the mutation tumour suppressor proteins like p53. Cancer is typically seen to manifest in a synergy of such dysregulated pathways that either promote cell growth and/or evade the regular cell death mechanisms. Cancer cells cleverly derive essential nutrients and oxygen by manipulating different pathways for their survival. Targeted therapies aim to attack these very pathways by: a) preventing the production of hormones involved in tumour growth; b) blocking the growth of blood vessels that provide nutrients for cancer cell growth; c) promoting apoptosis; and d) signalling the immune system to kill cancer cells.
Based on the size of drug molecules, targeted therapies are broadly classified into: 1) small molecule inhibitor drugs that penetrate the cell; and 2) larger monoclonal antibodies that act on the proteins or receptors on the cellular surface.
1. Small Molecule Inhibitor drugs
A therapy developed by rigorous and iterative cycles of chemical synthesis and pharmacological evaluation finds its ‘lead candidate’ through the initial-most high throughput screening (HTS). With the 3-D structure of the target (protein) known, the small-molecule lead can be decorated with chemical functionalities that favour drug-protein interactions leading protein activity inhibition. This small molecule is tested first on rodents, and subsequently elevated to the status of ‘drugs’ upon successful results in humans (clinical trials). Animal testing data like efficacy and toxicity often do not translate similarly in humans. Drug induced toxicities identified in Phase I clinical trials are one of the top reasons for a drug’s failure and its withdrawal from the trial. A recent comprehensive study that compared the ‘Likelihood of Approval’ (LOA) of various drugs in clinical trials ranked oncology drugs the lowest (5.1% LOA in Phase I). This emphasizes the various challenges, mainly toxicities (or side effects), that can act as a significant hindrance in the way of an effective cancer cell-killing molecule to becoming an anticancer drug.
Success story of the first small molecule inhibitor anticancer drug
The pioneering ‘targeted small molecule’ IMATINIB (Gleevac™), revolutionized the treatment of Chronic Myeloid Leukemia (CML) – which was previously considered to be an impending death statement. CML affects the blood and bone marrow, and is usually (90% likelihood) accompanied by the over-activity of the enzyme tyrosine kinase (Bcr-Abl fusion gene). This rare form of enzyme – a cell cycle regulator – behaves abnormally to sustain leukemic cells, and thus serves as an attractive CML target. Imatinib binds to Bcr-Abl tyrosine kinase, inhibits its activity and leads specifically to the death of leukemic cells.
The effects in the first CML clinical trials were astounding – a five-year survival rate leapt from 31% to a whopping 59%. Consequently, the FDA approval of Imatinib – 2.5 months from review – was among the fastest in the history of oncology drugs. By selectively targeting cancer cells with rather mild side effects, Imatinib successfully navigated the main hurdles faced by most anticancer drugs. The success of Imtanib has been attributed primarily to the prior knowledge of the structural biology of its target tyrosine kinase. This success story highlights the vital role of early stage target identification and validation in establishing the framework for successful rational drug design.
The knowledge of other similar protein targets has subsequently extended the use of Imatinib to other types of leukemias and gastrointestinal tumours. In fact, second generation drugs like Dasitinib, Nilotinib etc. have also been developed to combat Imatanib-resistance cancers. However, Imatinib, due to its optimal clinical profile, remains the first line therapy for CML.
Apart from kinases, small molecule inhibitors of other proteins like Epidermal Growth Factor Receptor (EGFR) and HER2 have also been explored for a variety of cancers. Epigenetics – dealing with chemical modifications of DNA and histones – is a nascent yet rapidly developing area in the oncology space. VORINOSTAT™, inhibitor of an epigenetic target (histone deacetylase), was the first FDA approved small molecule in this category. However, to achieve a trade-off between drug efficacy and clinical response durability, small molecule targeted therapies in conjunction with chemotherapy are also being studied.
2. Immunotherapy: Monoclonal antibodies
Immunotherapy has been one of the exciting and promising avenues in targeted cancer therapies, with many significant advances expected in the coming decade. In contrast to chemically designed small molecule drugs, this approach utilises the immune system of the individual to make the drugs (monoclonal antibodies or mAbs). This approach is analogous to how our body fights infections – i.e. by producing antibodies in response to foreign antigens. For cancer therapies, proteins (antigens) present on the surface of cancer cells are isolated and injected in mice for producing the corresponding antibodies. These mAbs are injected into a patient’s body which triggers their immune system – this in turn kills the cancer cells. Identifying the right target (antigen) specific to cancer cells is the crucial step in these therapies.
Programmed cell death protein (PD-1) Inhibitors: PD-1 protein, which is present on the surface of T cells (immune cells), plays an important role in the functioning of the immune system. Cancer cells inactivate the immune system by making proteins that bind to PD-1. Drugs like PEMBROLIZUMAB (Keytruda™) – an extensively used PD-1 inhibitor – block this binding, and reactivate the immune system to kill cancer cells. This mAb – initially approved for the treatment of metastatic melanoma – is also being used as a second line therapy for other types of cancers. While the success rates in immunotherapy have been much raved about, its applicability is limited and immune-dysnfunction related side effects are often accompanying in such treatments.
More recently, other cell surface receptors specific to myeloma cells, such as SLAMF7, CD38 etc. have been explored, with drugs like Elotuzumab, Daratumumab in the market. While mAbs as a single therapy have shown more durable responses for certain types of cancers, their use in combination with standard chemotherapy drugs like Docetaxel has shown improved survival rates in more general cases.
Antibody-Drug Conjugates (ADC): Several efforts have focused on making targeted therapies more cancer cell specific. One of the prominent strategies links the two approaches - chemotherapy and immunotherapy - that form the backbone of existing cancer therapies and has over 40 candidates under clinical investigation. ADC connects a mAb to a chemotherapy drug via a linker; each of the three components have a specific function (illustrated in Figure 3). After mAb identifies the specific cancer antigen and binds to the tumour cell, the linker releases the cytotoxic drug into the cell.
T-DM1 is the only approved ADC for non-haemotological malignancies; it links trastuzumab (anti-HER-2 mAb) to maytansinoid (cytotoxic drug) through a stable linker. ADC provides multiple avenues for further investigation, although it also presents challenges associated with optimizing three diverse components in developing a single optimal therapy.
Precision Medicine – is it the way to go?
While targeted therapies have taken a step forward in oncology therapy, Precision or personalized medicine aims to further tailor cancer treatments by accounting for genetic changes in patients. It is well known that individuals suffering from the same cancer type respond differently to the same therapy due to differences in their genetic makeup. Precision medicine involves analysing every patient’s genetic identity – DNA sequences, mutations and related abnormalities. Analysis of these data is then used to prescribe the most appropriate targeted therapy. While improving the toxicity profile is one of the main aims, precision medicine is also likely to reduce cancer mortality rates.
Widespread sharing of cancer research data and standardizing of patient data analysis would enable the rapid development of precision medicine and widen its applicability. For example, a recently developed comprehensive bioinformatics tool iCAGES claims to predict the implicated genes and prescribe the best treatments to patients. This promising tool, developed by Columbia University Medical Centre (CUMC), should soon be tested in clinical trials.
Targeted therapy research and precision medicine are in symbiosis; the evolution of one field will help in the advancement of the other and eventually oncology healthcare. While research on various targeted therapies continue, precision medicine will focus effectively utilizing these therapies judiciously.
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About the Author
PhD candidate, Department of Pharmacy, National University of Singapore
Uttara's PhD focusses on development of inhibitors targeting epigenetic proteins: G9a methyltransferase and Histone deacetylases. Her research involves synthesizing small molecules against breast cancer and looking at the gene expression changes caused by these inhibitors.