Taxol is an cytotoxic drug that has immense potential. Unfortunately, getting taxol is not so easy. Its history has been racked with environmental concerns and supply issues that delay Phase I, II, and III clinical trials. Because of the nature of the illness this disease targets--cancer is fatal and many people are willing to spend immense amounts of money for just marginal impacts--time is quite sensitive.[6] An initial Phase II trial at Johns Hopkins University found an activity rate of 30% of taxol against ovarian cancer, [2] and later reports showed 20-50% activity, mostly partial remission [6.] Taxol is unique in its mechanism of microtubule stabilization, disrupting mitosis and leading to cell death. [2] Ovarian cancer results in the death of 12500 women in the US per year, so these results generated strong interest. [6] Taxol was also found to have activity in a variety of other cancers: breast, non-small cell lung, pancreatic, and AIDS-related Kaposi sarcoma. [1] Despite the strong results and urgent need, it took 30 years for taxol to get from nature to being prescribed in clinics. [13] The two main barriers preventing taxol from reaching its full capabilities are supply, as well as safety of its administration.

The Pacific Yew Tree

Taxol was originally isolated from the bark of Pacific Yew tree in 1962 by botanist Arthur Barclay. [1] Pacific Yews are found in Washington and Oregon, slow growing, and not abundant enough to keep up with clinical trial demands. [2] 20,000 pounds of bark--equalling two to four thousand trees--makes 1 kg of taxol.[2] There is about 100 mg of taxol per kg dried bark. This is enough to do in vitro testing, but amounts on the magnitude of grams are needed for tests to officiate taxol as a drug candidate. [3] Not only are yields low from trees, the process of collecting takes time, from waiting to collect in the spring and summer months when park peels easily, to the more than nine months for drying, extraction and recrystallization process. [6] Furthermore, harvesting bark will cause the tree to die, so the process is ecologically expensive. [1] There are many possible solutions to the the supply problem, including producing semisynthetic compounds and isolating taxol derivatives from other parts of the tree. However, each of these methods come with their own barriers.

The active ingredient in Pacific Yew trees is paclitaxel; about three mature trees are needed for one patient. One method discovered to circumvent harvesting Yew bark from the fragile Pacific tree species was harvesting docetaxel from the more common European Yew, Taux Baccata. [8] As a drug, docetaxel is newer, semisynthetic. Taxol can also be synthesized from this precursor in a four step process. Docetaxel, however, is also slightly different that it is more effective in breast cancer, while paclitaxel is more active in ovarian. [8] [2] Though the ecological cost of docetaxel is lower, it brings much higher rates of negative side effects, including hematologic toxicity and neurotoxicity. [13] Another potential is plant tissue culture; however, taxol has 11 chiral centers and its biosynthetic pathway is difficult to define. [6] Natural molecules in general are very complex, however as drugs they tend to have less contaminants and toxic side effects compared to chemotherapy, and don’t hurt healthy cells of the patient as much. [13] Total synthesis of taxol was produced by the Nicolaou and Holton groups, but the process was too long to be of commercial value. [3] Instead, the discovery of the pathway may be more useful in manipulating genes that affect enzyme activity involved in biosynthesis. This pathway can be transferred into a biofactory, such as E. Coli, a rapidly growing bacterium, which is what our team aims to tackle.

Other Barriers: Low Solubility

Another barrier and contributor to taxol’s unusual path of clinical development is insolubility of the molecule in aqueous solvents and high dosage requirements causing high toxicity, which almost caused the drug to be dropped from clinical trials. Eventually, to create a feasible parenteral formula, Cremophor EL was added as a large component of the drug. [6] However, Cremophor EL is believed to cause hypersensitivity to other drugs. This is an issue because most cancer drugs are used in sequence or in combination with other drugs because cancer is incurable. [16] 80% of women with ovarian cancer use adjuvant chemotherapy, [13] and Cremophor EL could intensify the already strong side effects of chemotherapy. We used homology modeling to develop protein models for the five necessary genes to determine active site architecture and catalytic functions. These models were then used to consider possible mutations to the genes in order to produce alternative taxane products with enhanced solubility. Enhanced solubility would allow us to use the great cytotoxic potential of taxanes in the future while alleviating the problematic toxic side effects.

Social and Political Involvement

The drug gained a lot of political attention in 1989, with main controversies stemming from the uniqueness of the activity of taxol (microtubule stabilization instead of destabilization) verses the preservation of biological diversity. Environmentalists attempted to classify the Pacific Yew as a threatened species. This failed, but resulted in the Pacific Yew Act of 1992, which outlines specific harvest policies. However, there was also the issue of privatization of scientific property. In 1991, the National Cancer Institute (NCI, the main organization responsible for development and funding of taxol as a cancer drug), the Bureau of Land Management, and Bristol-Myers Squibb created the CRADAs (Co-operative Research and Development Agreements), essentially giving BMS exclusive rights to publicly funded research of taxol from Pacific Yew trees. This event, coinciding with increasing costs of pharmaceuticals, sparked a movement for ‘lay participation in biomedical practice.’ [13] So, instead of seeing this as a fight between biodiversity and drugs, this can also be viewed as an attempt to gain more participation in the policy of medicine. In thinking about our project, and its impacts on society, we would like to support more participation and patient rights in the clinical process of drug development. There should be more transparency, more patient input, and to foster this we held a seminar to invite public opinion on genome editing. We want to encourage public participation and hope in the future, knowledge about the process and decisions that go into drug research and pricing are made more publicly available.

Economics of Cancer Drugs

In the last decade, there has been a phenomenon of cancer drug shortages, especially older generic drugs. Paclitaxel is currently on the shortage list, and docetaxel has often been used in place. However, docetaxel is five times more expensive, and paclitaxel shortages could cost an additional $11000 per patient with ovarian cancer in a 6 cycle docetaxel/carboplatin combined chemotherapy session. [13] These shortages can mean delay in treatment of a fatal disease; a 2011 Society of Gynecologic Oncology survey reported 98% of members who responded reported a delay in receiving cancer drugs, and 77% of those delays lasted a month or more.[13] Along with the shortage is a trend of prices increasing for cytotoxic drugs, rising steadily by 10% or on average $8,500 annually from 1995 to 2013. [13] Globally, the most money is spent on anticancer drugs compared to other types of medication. [13] Unfortunately, the process that manufacturers use to decide prices is completely opaque to the public, which is a firing point for biomedicine activists. Because of the lack of transparency, approval and production of new drugs is unpredictable, so in turn it is hard for insurance companies to price policies. [16] This leads to huge out-of-pocket expenditures that can be very detrimental to less wealthy households, and in some cases can be the largest source of spending of family income. Our system would make pacitaxel and taxane derivatives much more available for clinical trials, which would greatly alleviate the shortage issue as well as stabilize the price, as the biggest barrier to smooth clinical trial phases is simply lack of supply. Additionally, the cancer drug market functions as monopolies. This is due to drugs being used in combination with each other because most cancers are incurable, and is reinforced when new drugs and improved drugs are produced that replace generic versions. [16] This could be especially essential to recognize the full potential of taxanes, as low doses have been demonstrated to be effective against non-cancer diseases as well, such as skin disorders, renal and hepatic fibrosis, inflammation, axon regeneration, limb salvage, and coronary artery restenosis. [16]

Our Project and Next Generation Taxanes

Today, the pharmaceutical industry is expanding on the production of taxane derivatives, and defining which taxanes are more effective for which cancers. For example, Cabazitaxel has been shown to be stronger against Prostate cancer than docetaxel. [13] These modified taxol molecules have enhanced properties such as reduced toxicity and the potential to be taken orally, addressing two large barriers that are often come across during clinical trials. Though synthesizing taxol from plant tissue culture would produce more natural compounds with less toxic side effects, the process is long and arduous while the disease to be treated is time sensitive. It is much easier to make derivatives because we know more about E. Coli metabolism and biosynthesis mechanisms than plants. And though more patient input in the drug development process is essential, this method of production will enable clinical trials while the ecological perspective may be slowed by politicization, saving precious time. The ability to produce a wide range and volume of taxanes will ultimately open up the potential of the unique abilities of microtubule stabilization of taxol, allowing rapid clinical trials to broad applications. This stabilization reduces out-of-pocket spending and overall spending on taxane-derived anticancer drugs by providing more and cheaper alternatives.

Sources:

[1] A Story of Discovery: Natural Compound Helps Treat Breast and Ovarian Cancers. (n.d.). Retrieved June 7, 2018, from https://www.cancer.gov/research/progress/discovery/taxol

[2] Blume, E. (1989). Investigators Seek To Increase Taxol Supply. JNCI Journal of the National Cancer Institute, 81(15), 1122–1123. https://doi.org/10.1093/jnci/81.15.1122

[3] Bocca, C. (1998). Taxol: A short history of a promising anticancer drug. Minerva Biotecnologica, 10(2), 81–83. Retrieved from https://search.proquest.com/openview/4c6efd9558dc875652d67e904c89ef6a/1?pq-origsite=gscholar&cbl=30380

[4] Budd, G. T., Barlow, W. E., Moore, H. C. F., Hobday, T. J., Stewart, J. A., Isaacs, C., … Hortobagyi, G. N. (2013). S0221: Comparison of two schedules of paclitaxel as adjuvant therapy for breast cancer. Journal of Clinical Oncology, 31(18_suppl), CRA1008-CRA1008. https://doi.org/10.1200/jco.2013.31.18_suppl.cra1008

[5] Cancer Facts and Figures. (2018). Atlanta. Retrieved from https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf

[6] Cragg, G. M., Schepartz, S. A., Suffness, M., & Greyer, M. R. (1993). THE TAXOL SUPPLY CRISIS. NEW NCI POLICIES FOR HANDLING THE LARGE-SCALE PRODUCTION OF NOVEL NATURAL PRODUCT ANTICANCER AND ANTI-HIV AGENTS. Journal of Natural Products, 56(10), 1657–1668. Retrieved from https://pubs-acs-org.proxy.lib.duke.edu/doi/pdf/10.1021/np50100a001

[7] Gatesman, M. L., & Smith, T. J. (2011). The Shortage of Essential Chemotherapy Drugs in the United States. New England Journal of Medicine, 365(18), 1653–1655. https://doi.org/10.1056/NEJMp1109772

[8] Hardon, A., & Sanabria, E. (2017). Fluid Drugs: Revisiting the Anthropology of Pharmaceuticals. Annu. Rev. Anthropol, 46, 117–132. https://doi.org/10.1146/annurev-anthro-102116

[9] Havrilesky, L. J., Garfield, C. F., Barnett, J. C., & Cohn, D. E. (2012). Economic impact of paclitaxel shortage in patients with newly diagnosed ovarian cancer. Gynecologic Oncology, 125(3), 631–634. https://doi.org/10.1016/j.ygyno.2012.03.028

[10] Howard, D. H., Bach, P. B., Berndt, E. R., & Conti, R. M. (2015). Pricing in the Market for Anticancer Drugs. Journal of Economic Perspectives—Volume, 29(1—Winter), 139–162. https://doi.org/10.1257/jep.29.1.139

[11] https://www.pharmaceutical-journal.com/news-and-analysis/news/how-bark-from-the-pacific-yew-tree-improved-the-treatment-of-breast-cancer/11084729.article?firstPass=false

[12] Maxwell Gordon. (1996). Taxol Supply Problem? What Problem? Nature Biotechnology, 14, 1635. Retrieved from https://www.nature.com/articles/nbt1296-1635b

[13] Novel actions of next generation taxanes benefit advanced stages of prostate cancer (2) doi:10.1158/1078-0432.CCR-14-1358

[14] Siddiqui, M., & Rajkumar, S. V. (2012). The High Cost of Cancer Drugs and What We Can Do About It. Mayo Clinic Proceedings, 87(10), 935–943. https://doi.org/10.1016/j.mayocp.2012.07.007

[15] Walsh, V., & Goodman, J. (1999). Cancer chemotherapy, biodiversity, public and private property: The case of the anti-cancer drug taxol doi://doi.org/10.1016/S0277-9536(99)00161-6

[16] Zhang, D., Yang, R., Wang, S., & Dong, Z. (2014). Paclitaxel: new uses for an old drug. Drug Design, Development and Therapy, 8, 279–284. https://doi.org/10.2147/DDDT.S56801

Team:Duke/Human Practices