This article is republished with permission, courtesy of Oxbridge Biotech Roundtable Review. Authors: Ross Cloney and Kelvin Chan.
The natural world and the bounty of the forest have long been sources of medicines for the cultures that recognized and harvested their potential. One of the best known examples is that of the willow tree. Its key active compound, salicylic acid, was first mentioned in Ancient Greek and Egyptian texts as a treatment for fever. A derivative of salicylic acid is now mass manufactured as aspirin. One of the areas where interest in plant-derived compounds is particularly strong is the search for new chemotherapeutic drugs in the treatment of cancer.
Human cancer cells displaying markers of DNA damage. Image by Ross Cloney.
As our understanding of cancer has improved, we have come to recognise that cancer is not so much a single disease as a varied set of diseases that share a common set of characteristics. Cancer is a ‘disease of the genes’: the accumulation of genetic errors, hastened by biological predisposition or lifestyle choices, that results in a population of cells freeing itself from the growth restraints imposed on healthy cells. Cancers, unfortunately, display a fantastic range of genomic heterogeneity between people, tissue type and even among cells in the same tumour. However, all cancers are defined by ten hallmarks: dysregulated metabolism, replicative immortality, insensitivity to anti-growth signals, self-sufficiency in growth signals, the ability to evade apoptosis, genomic instability, the ability to evade immune system detection, sustaining an inflammatory environment, promoting angiogenesis and, particularly in highly aggressive cancers, metastasis [1].
Since cancer is caused by the accumulation of mutations, it is primarily a disease of the elderly for the simple reason that they have had longer to build up a critical level of genetic errors. Currently, one in three people are predicted to be diagnosed with cancer in their lifetime with the expectation that as the population ages, the rate will rise to one in two [2]. With increasing knowledge of lifestyle choices that reduce the risk of cancer and the identification of risk factors in the population, such as testing for a BRCA1 or BRCA2 mutant allele in women with a family history of breast cancer, success rates for survival are increasing year by year [3]. However, different cancers have different levels of success for treatment outcome. Several cancers are still highly difficult to treat and illustrate the importance of developing novel chemotherapy drugs.
The molecular structure of Taxol® with a Chinese Yew Tree. Image by KC Nicolaou, used with permission.
Several natural plant compounds have already been isolated from their sources and put to use in the laboratory and the clinic. Paclitaxel (Taxol®) is a famous natural plant-derived compound, widely used in the UK for treatment of lung, breast, ovarian and other solid state tumours. Originally derived from the bark of the Pacific Yew Tree Taxus brevifolia, it is now understood that a symbiotic fungus in the bark produces the drug. Taxol functions as a microtubule stabilizer, preventing the depolymerization of the established cytoskeleton and the formation of the spindle structures required for mitosis. These are both required in proliferating cells, including rapidly dividing cancer cells. With their microtubules locked into an artificially stable structure, cells cannot appropriately segregate their genetic material and finish mitosis, leading to cell death. Interestingly, Taxol functions in the opposite manner to a wide range of chemotherapy drugs that prevent cell division by destabilising microtubule structures.
The story of Taxol is illustrative of the path taken by natural compounds as they progress from discovery to the clinic and the care that must be taken in harvesting naturally occurring compounds. The journey begins in 1962 with samples from Taxus brevifolia being harvested by Arthur S Barclay as part of the American National Cancer Institute initiative to identify novel plant compounds. Of the 110,000 compounds identified by the survey, Taxol showed the most promise but was ignored until 1979 when Susan Horwitz’s team demonstrated its microtubule-stabilizing properties in a key Nature publication [4]. The anti-cancer potential combined with the environmental impact of harvesting led to a flurry of interest from chemists keen to synthesise the drug. The problem was cracked by the Nicolaou group in 1994, and was followed by a succession of alternative synthesis pathways throughout the mid-90s [5].
One of the key discoveries for securing a long-term sustainable supply of Taxol was the identification of closely related plant compounds. The Yew tree was unsuitable for the large-scale harvesting that the widespread use of a promising anti-cancer drug would require. The tree grows slowly in difficult-to-access forest ecosystems, and large-scale manufacturing of Taxol to treat 12,000 patients for clinical trials required the sacrifice of 38,000 trees. The discovery that a closely related tree, Taxus baccata or the common European Yew, could be used to isolate the closely related starting compound 10-deacetylbaccatin III from its needles without killing the tree allowed the widespread adoption of this potent anticancer drug. Today, Taxol and related compounds are mass-manufactured industrially and are leading compounds in the anti-cancer market.
As our finesse with chemotherapy matures, is there still a role for natural plant compounds in the clinic or will they be supplemented by targeted, designed drugs based on our knowledge of the molecular biology of the cell? We were fortunate enough to be able to directly ask a leading researcher in the field, Prof Phil Baran of The Scripps Research Institute, for his insights into the future of natural product synthesis and cancer therapeutics.
RC & KC: You currently consult for numerous pharmaceutical companies; how much interest does pharma still have in identifying natural products as a starting point for general drug discovery?
PB: They are making a comeback. I think the trend these days is to focus on pursuing validated biological targets that will lead to positive clinical outcomes. Once a company has identified that, most are pretty agnostic as to the type of small molecule that will get the job done. Advances in the synthesis of complex natural products are making medicinal chemists more open to using them as a starting point for drug discovery. The surge of interest in antibody-drug conjugates is also fueling a renewed focus on natural products in some companies.
RC & KC: Much of your chemistry illustrates practical aspects of natural product synthesis, including scalable reactions. How successful do you think the synthetic community has been in synthesizing viable quantities of natural plant products that can be used towards discovery of novel chemotherapy drugs?
PB: The community has a long way to go. The era of feasibility demonstrated that anything is possible but now we have entered the age of practicality where the value of a synthesis is measured in terms of one’s ability to make large quantities in an economically viable fashion (in terms of time, effort and cost of goods). Slowly but surely, the community will demonstrate that it is possible to routinely access viable quantities of natural products (derived from marine or terrestrial sources).
RC & KC: There is significant attention in the scientific literature concerned with analogues and structure-activity relationships. What are your thoughts about the direction of the field of new drug discovery – towards analogues or towards new natural products?
PB: I don’t think it’s one or the other. It’s never wise to dismiss one area of science as being better or more likely to succeed than another. In my view, one needs to apply common sense in the interrogation of a biological target and be agnostic as to the small molecule starting point.
Dr Ross Cloney is a post-doctoral research fellow in Genome Damage and Stability at the University of Sussex. Kelvin Chan is a PhD student in Organic Chemistry at The Scripps Research Institute in La Jolla, California, USA.
This article is jointly published with Phenotype.
References:
1. Hanahan D & Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57-70.
2. CRUK (2012) Lifetime Risk of Cancer. Available at http://www.cancerresearchuk.org/cancer-info/cancerstats/incidence/risk/ [Accessed March 2014].
3. CRUK (2013) Cancer Mortality for Common Cancers. Available at http://www.cancerresearchuk.org/cancer-info/cancerstats/mortality/cancerdeaths/ [Accessed March 2014].
4. Schiff PB, et al. (1979) Promotion of Microtubule Assembly in vitro by Taxol. Nature 277(5698):665-667.
5. Nicolaou KC, et al. (1994) Total synthesis of taxol. Nature 367(6464):630-634.