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European Biopharmaceutical Review

Hitting the Mark

In the 70 years since the anti-cancer properties of nitrogen mustards were first made public, cancer treatment has become almost unrecognisable, having developed from these humble beginnings into a multi-billion dollar industry. Today, approximately half of patients diagnosed with cancer are expected to survive at least 10 years: double the odds of 40 years ago (1). Furthermore, 85-95% of those suffering from common indications – such as breast, bowel and prostate – can expect to attain five-year survival. For other tumours – like cancer of the brain, lung or oesophagus – there has been little improvement in five-year survival and, for pancreatic cancer, no change at all.

Improvements in prognosis are due to a number of factors, with early detection and diagnosis, increased understanding of treatment modalities and disease stratifi cation all playing a role in increased survival. However, lung cancer is one of the most common indications, accounting for 13% of worldwide cancer cases and 22% of cancer-related deaths, and has seen little improvement in 10-year survival since the 1970s (2). Clearly, some cancers are still not being adequately cured by present-day chemotherapy. Thus, in order to improve patient survival, there needs to be improved therapies, new classes of anticancer drugs and, importantly, greater selectivity in current treatments.

Today’s Approaches


There is a large repertoire of anti-cancer drugs and combination therapies available. Multiple studies have demonstrated the potent anti-proliferative properties of these therapies; nonetheless, their inherent lack of specifi city towards malignant cells results in unwanted side-effects, preventing these agents from being fully effective in man (3).

Cancer therapy is normally delivered systemically and the drugs do not distinguish between healthy and malignant tissues, which results in the off-target side-effects commonly associated with this form of treatment. Specific targeting of drug therapy to malignant cells would be the solution, making this the holy grail of many research groups. Targeted anti-cancer approaches would not only reduce the uptake of drugs into healthy cells, thereby preventing toxicity and off-target effects, but also lower the dosage required for successful treatment. This would further decrease the likelihood of toxicity and possible secondary occurrence.

Monoclonal Antibody Conjugates

The development of tumour-specific drugs has focused primarily on over-expression of receptors or the dysregulation of signal transduction pathways with antibodies, which are able to target the differences between diseased and healthy cells (4,5). A number of cancer-specific antigens have now been identified, and monoclonal antibodies (mAbs) have been generated successfully to bind specifically to them (6). These agents are designed to strengthen the immune response to cancer cells by ‘tagging’ them for removal. mAbs are well-established in the treatment of breast cancer, with antibodies targeting cell surface molecules – such as, glycoproteins that become overexpressed in cancer cells.

While these antibodies are highly specific to malignant cells, mAbs confer limited anti-cancer effects when administered alone and, therefore, are often used in combination with other therapies (6). The anti-cancer activity of these antibodies can be enhanced by conjugation to radioactive isotopes or cytotoxic drugs, which then act as a drug delivery vehicle. Meanwhile, antibodies raised against specific overexpressed receptors are internalised through receptor-mediated endocytosis, resulting in the internalisation of the conjugated cytotoxic moiety. Membrane molecules are internalised constitutively, so antibodies targeted to cancer-specific surface membrane molecules will be internalised with their cytotoxic cargo. Once inside the cell, the drug will be cleaved from the antibody and have its cytotoxic effect on the cancer cell (6).

The specific nature of mAb therapy has allowed for conjugation of highly potent drugs that have toxicities too severe to be delivered systemically. For example, brentuximab vedotin – a mAb drug conjugate – has been approved for use in treatment of Hodgkin’s lymphoma, and other such therapies are in clinical trials. These antibody-drug conjugates (ADCs) have enormous potential; however, if the cancer cell changes its cell surface antigens, then these highly specific ADCs may be of limited use.

Prodrug Targeting

mAbs can also be used to target prodrug therapies to cancer cells, akin to the approach described above. A prodrug is a pharmacologically inert molecule that is converted to an active drug in vivo, where it can exert its therapeutic effect. Tissue-specific prodrug targeting can be achieved through antibody-directed enzyme prodrug therapy (ADEPT) or gene-directed enzyme prodrug therapy (GDEPT). Targeting specific membrane transporters is an additional method for prodrug therapy, which aims to improve the bioavailability of compounds, but this has limited application in targeted cancer therapy (7).

In ADEPT, to prevent non-specific drug activation, the prodrug is normally activated by an enzyme that is not found in the extracellular fluid or cell membrane. These prodrug-activating enzymes are conjugated to cancer-specific mAbs and administered systemically. The conjugates will then localise in the tumour microenvironment, and the remaining conjugates will be cleared from the blood and non-tumour tissues. Following administration, again systemically, the prodrug will only be activated in the tumour microenvironment when it is metabolised by the prodrugactivating enzymes.

GDEPT works using a similar principle to ADEPT, instead utilising a viral vector for delivery of genes encoding prodrugactivating enzyme into the malignant cells. Enzymes used are commonly non-human or non-mammalian to allow activation and ensure the prodrugs are not activated by endogenous enzymes (7). Prodrug administration would, therefore, result in activation only in the malignant cells that express the required prodrug-activating enzymes.

While targeted prodrug anti-cancer therapy is appealing, there are drawbacks to these methods. ADEPT prodrug activation occurs outside the cell, meaning healthy cells can be exposed to drug therapy – although at lower doses than conventional chemotherapy. The immunogenicity of the non-human enzymes used in both ADEPT and GDEPT also limits their potential use, and these issues must be overcome in order to employ these targeting methods more successfully.

Peptide Conjugates

Another potential delivery system conjugates cytotoxic compounds to cell-specific targeting peptides. These targeting peptides can be broadly divided into two categories: homing peptides (HPs) and cell-penetrating homing peptides (CPHPs). While HP conjugates lack the inherent ability to undergo internalisation, these peptides deliver their cytotoxic cargo to the cell surface, much like ADEPT targeting. CPHPs, meanwhile, can target overexpressed receptors on the cell surface of cancer cells and, therefore, undergo receptor-mediated endocytosis, allowing internalisation of the drug molecule and facilitating efficacy (8).

As a tumour grows, it requires the formation of new blood vessels, or angiogenesis, in order to sustain continued growth. Angiogenic growth factors are increased in many cancerous tissues, and CPHPs have been successfully targeted to the cancer vasculature, but not healthy tissue (9). This presents new targeted drug delivery opportunities. In addition, well-characterised cytotoxic compounds – such as doxorubicin and paclitaxel – have been targeted successfully towards a human melanoma cell line (8). Peptideconjugated drug molecules, therefore, have potential as an anti-cancer therapy to reduce the toxicity and off-target effects seen in cancer. These agents are promising, but are at an early stage and still undergoing clinical trials.

Nanotechnology


Nanomedicine is a rapidly developing field – particularly in oncology – with several treatments having been developed and entering the clinic in recent years. Abraxane – an albumin-bound form of paclitaxel – and DOXIL – liposomal doxorubicin – have been used in breast and ovarian cancer, respectively (10). Nanotechnology has been a point of interest, thanks to the advances in detection, diagnosis and treatment this technology offers, as a result of its interactions at the molecular level.

Numerous drug delivery mechanisms have been developed in the field, including liposomes, micelles and nanocapsules (10). Liposomes are lipid bilayers with a core that can carry drug molecules and be conjugated with ligands for selective targeting. Micelles are spherical structures similar to liposomes, which are able to carry water-insoluble compounds, and their surface can be modified with ligands for endogenous targets to provide selectivity. Nanocapsules, meanwhile, have drug compounds confined to a central core surrounded by a polymeric membrane and – just as with liposomes and micelles – are targeted to cells by antibodies attached to the surface (10). There is no doubt that this research will revolutionise therapeutics, with the advances having profound implications for all drug development – not just anticancer indications. At present, however, the potential toxicity of these nanodrugs remains unclear.

Polyamine Conjugates

In a different approach, drugs tagged with agents that have specific uptake transporters have been investigated – in particular, polyamine tails attached to agents to deliver cytotoxic cargo to cancer cells (11). The polyamines putrescine, spermine and spermidine make up a family of polycations that are found in all human cells. They are essential regulators of cell growth, with high concentrations observed in rapidly proliferating and cancer cells. These molecules are essential for normal cell division, and disruption of the polyamine content can lead to cancer development (12).

Polyamines are imported into cells through the polyamine transport system (PTS), with data suggesting differing systems exist across all cell types – although the exact mechanism of transport is, as yet, unclear. The PTS is an area of interest as higher uptake of polyamines has been observed in cancer cells. As this increase is specific, the rise in PTS activity can be used to promote the delivery of cytotoxic compounds into cancer cells by attaching them to polyamines. These polyamine conjugates would not only target cancer cells selectively, but also, thanks to their positive charge, will be directed to both DNA and RNA (13). One huge advantage of using the PTS is that it is capable of transporting large molecules – like polyamine analogues with cycloheptyl side chains – and so is able to transport polyamine conjugates (14).

F14512, an etoposide-spermine conjugate, has been developed to utilise the increased PTS in cancer cells. The anti-cancer activity of etoposide, as with most cancer therapeutics, is limited by its toxicity and off-target effects, but it is still a front-line treatment for many indications. F14512 demonstrated a 73-fold rise in cytotoxicity compared to etoposide alone in in vitro studies and was successful in Phase 1 trials, with Phase 2 trials currently under way (15,16). Although this method of selective drug targeting shows great potential, the development of polyamine conjugates is hindered by the lack of molecular characterisation of the PTS.

Lipid Conjugates


While the previously mentioned techniques describe drug targeting towards specific cells, cellular internalisation of drugs may not always result in a therapeutic effect. Once a drug is inside a cell, it may still need to reach its desired target site. Many anti-cancer drugs act within the nucleus, and so will be required to permeate the nuclear membrane to be effective. This adds to the complexity of developing successful drug delivery approaches; due to the essential nature of the nucleus, the membrane is not freely permeable to many substances, in order to protect the cell’s genetic material.

To achieve drug delivery to these subcellular compartments within a cell, drug molecules have been conjugated with lipids. Telomerase has long been an attractive target as this enzyme is, at least in part, responsible for cancer cell immortality. Since telomerase resides within the nuclear membrane, drug entry into this subcellular compartment presents a major hurdle. However, short nucleotide polymers can be conjugated with lipids. This allows the oligonucleotide to permeate across the membrane and target the telomerase enzyme. The use of such lipid modification has been shown to increase affinity in in vitro and in vivo studies, compared to telomerase inhibitors lacking lipid conjugates (17).

The inhibition of DNA and RNA synthesis is also possible through the use of nucleoside analogues, but this treatment is limited in therapeutic efficacy due to the lipid insolubility of such analogues preventing cell entry. CP4055, a lipidconjugated nucleotide analogue, effectively blocks DNA replication and is currently in Phase 1 clinical trials (17).

Lipids conjugated to cytotoxic compounds confer obvious benefits for the subcellular targeting of drugs, but unlike other methods, this technique is yet to successfully target physiological differences between healthy and diseased cells. The primary disadvantage of this method is that these lipid modifications increase the subcellular targeting of compounds in healthy cells – in addition to diseased cells – though continued research may overcome this inherent problem.

Positive Prognosis

As our knowledge of cancer cell biology has advanced, therapeutics have been designed to exploit the biochemical differences between diseased and healthy cells. Conventional chemotherapy is associated with a wide range of off-target effects, which is fundamentally due to the inability of anti-cancer drugs to distinguish between cancer and non-cancer cells. However, the use of more complex technologies has allowed for specific targeting of drugs to the cancer cell, thereby limiting the toxic side-effects associated with treatment.

Continuing R&D into more specifically targeted anti-cancer treatments will hopefully improve patient prospects and response to therapy, while at the same time, decreasing the off-target effects. This will improve the quality of life for those undergoing therapy, and should increase survival rates for cancers where the five-year prognosis has remained almost unchanged for the last 40 years.

References

1. Cancer Research UK, Cancer statistics report: Cancer survival, 2014
2. Cancer Research UK, Cancer statistics report: Key stats all cancers combined, 2015
3. Urruticoechea A et al, Recent advances in cancer therapy: An overview, Current Pharmaceutical Design 16: pp3-10, 2010
4. Akhtar MJ et al, Targeted anticancer therapy: Overexpressed receptors and nanotechnology, Clinica Chimica Acta 436: pp78-92, 2014
5. Teicher BA, Linehan WM and Lee JH, Targeting cancer metabolism, Clinical Cancer Research 18(20): pp5,537-5,545, 2012
6. Chari RV, Targeted cancer therapy: Conferring specificity to cytotoxic drugs, Accounts of Chemical Research 41(1): pp98-107, 2008
7. Han HK and Amidon GL, Targeted prodrug design to optimize drug delivery, AAPS PharmSci 2(1): pp48-58, 2000
8. Svensen N, Walton JG and Bradley M, Peptides for cell-selective drug delivery, Trends in Pharmacological Sciences 33(4): pp186-192, 2012
9. Li ZJ and Cho CH, Peptides as targeting probes against tumor vasculature for diagnosis and drug delivery, Journal of Translational Medicine 10(Suppl 1): p1, 2012
10. Sutradhar KB and Amin L, Nanotechnology in cancer drug delivery and selective targeting, ISRN Nanotechnology, Article ID 939378, 2014
11. Palmer AJ and Wallace HM, The polyamine transport system as a target for anticancer drug development, Amino Acids 38(2): pp415-422, 2010
12. Wallace HM, Fraser AV and Hughes A, A perspective on polyamine metabolism, Biochemical Journal 376: pp1-14, 2003
13. Traquete R and Wallace HM, Developing vector systems: Targeting tumours, Biochemist 34(1): pp22-25, 2012
14. Wallace HM, Targeting polyamine metabolism: A viable therapeutic/ preventative solution for cancer? Expert Opinion on Pharmacotherapy 8(13): pp2,109-2,116, 2007
15. Xie S, Wang J, Zhang Y and Wang C, Antitumor conjugates with polyamine vectors and their molecular mechanisms, Expert Opinion on Drug Delivery 7(9): pp1,049-1,061, 2010
16. Bahleda R et al, Tackling leukemia: Phase 1 study of F14512 in replapsed or refractory AML patients, 2014. Visit: http://tatcongress.org/wpcontent/ uploads/2014/05/140305- bahleda-f14512.pdf
17. Rajendran L, Udayar V and Goodger ZV, Lipid-anchored drugs for delivery into subcellular compartments, Trends in Pharmacological Sciences 33(4): pp215-222, 2012


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Aidan Seeley recently graduated from the University of Aberdeen in Biomedical Sciences (Pharmacology) and was awarded the Pharmacology Prize. He is the founding President of the Aberdeen Medical Science Network, a student-run organisation aimed at promoting networking between staff and students. Aidan has previously worked with Professor Heather Wallace on novel multidrug resistance modifiers and, later this year, is due to begin his PhD studies at Queen’s University Belfast, where he will focus on receptormediated endocytosis in cancer cells.

Heather Wallace is Professor of Biochemical Pharmacology and Toxicology at the University of Aberdeen, Scotland. She is President of the British Toxicology Society, as well as a professional development advisor at the Royal College of Pathologists. Heather’s research interests are in the mechanisms of cell death associated with anti-cancer drugs and potential chemopreventative agents and, in particular, drugs targeting the polyamine pathway. She is a Deputy Chair of the Biochemical Journal and has seven years of experience as a non-executive director of a publishing company.
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