Cancer diagnosis and treatments today are undergoing deep-reaching changes. Therapeutic strategies, until recently, could be summarised as ablation of the diseased organs and destruction of cancerous cells, often leading to serious unwanted effects that weaken the patient or limit the efficiency of the cancer treatment. But innovative approaches are emerging. They target cell functions and its close environment.

Cancer occurrences are on the rise. According to projections made by WHO, mortality level will exceed 13.1 million cancer deaths yearly in 2030. Far upstream from these terrible figures, there is a destabilising fact: cancers always start from a single cell.

Transformation of that single cell into a tumour cell is the result of genetic or epi-genetic alterations that progressively deregulate normal cell division system (mitosis). The cell affected in this way starts replicating in a uncontrolled ‘rogue’ manner and the proliferation leads to a tumour.

These modifications may come from interactions between genetic factors, specific to a given patient and carcinogenic external agents. The latter can be physical (e.g., through over-exposure to UV (ultraviolet) radiation); or chemical (e.g., asbestos or nicotine in tobacco); or biological (infections caused by certain viruses, bacteria or parasites).

Faced with cancer, our natural defence mechanisms remain passive. The choice among therapeutic strategies is therefore primordial. For a long time, specialists concentrated on a single objective: destroying the cancer cell(s). This is the main function of chemotherapy, which uses chemical substances to interrupt the mitosis of the affected cells; the problem is that healthy cells are also destroyed in the process. Over the past 20 years, considerable progress has been recorded is terms of chemical dosing and drug administration protocols. But today, these methods have reached their limit. New therapies are now being assessed in this context.

Reasoning at cell level: the advent of targetable therapies
Practitioners are currently developing increasingly accurate therapies, the core objective of which is “to put the cell back at the heart of the debate”, according to Pierre Cordelier, senior research scientist with Inserm and a member of the Oncopole Programme (Toulouse). “The main problem with chemotherapies is that, as the term itself implies, the patient ingests chemical compounds and we are not focusing on gaining better knowledge about cell functions; in short, chemotherapy is non specific”. This is precisely where we see the arrival of a major innovation: research scientists are now investigating what makes a cell trigger a cancerous process, and what are the special characteristics of tumour cells. This approach underscores targetable therapies.

At a molecular level, the idea consists of exclusively targeting the contents of the cancerous cells, sparing the healthy cells and avoiding undesired side-effects. This protocol aims at specific molecular targets, such as the growth factor, necessary to initiate cell proliferation. As Prof. Hamouda Boussen (Abderrahaman Mami Hospital, Tunisia) explains, working at this molecular dimension brings real advantages: a higher level of efficiency with lower pharmacological doses, a limited toxicity and the possibility to tailor-design the treatment as a function of the patient’s pathology and molecular profile.

Today, there are over 500 medicinal compounds designed for use in targeted therapies being developed round the world. At the same time, we witness the advent of targeted bio-therapies that use products that already exist in the patient’s body but which undergo modification, or reinforcement, or are even diverted from their normal functions. In the case of hormone-dependent cancers, for example, such as prostate cancer or breast cancer, bio-therapy will call hormones into play. In contradistinction to administering medicinal drugs, bio-therapists will not be seeking to kill the cancerous cells but rather to restoring normal cellular functions. Notably, the aim here is to prevent cells from proliferating, by targeting what actually takes place when cells divide (mitosis) or when they attempt to repair themselves. Targeting is not just a bio-chemical approach: targeted bio-therapy can be combined with conventional radiotherapy.

As in surgery and contrary to chemotherapies, radiotherapy is “local.” But the question of undesired side-effects remains unsolved. In order for X-rays to reach a targeted zone in the body, the beam must penetrate through healthy tissue and they have a damaging effect as they do so. With this evidence in mind, the French start-up company Nanobiotix developed what could prove to be a major break-through is cancer treatment. Their product, which goes by the trade-name of NanoXRay, in fact uses hafnium oxide (HfO2), which offers a very high electron density. The aim investigated here was to have the HfO2 absorbed only by the cancerous cells. When this molecule is present in a cell, it multiplies by a factor 10 000 the probability of the cell absorbing X-rays, and this allows you to measure a better local efficiency for the radio-therapy, while diminishing the total dose received by the healthy cells of the patient that are adjacent to the tumour. This novel technology, inasmuch as it can be applied to almost every from of cancer, is raising a lot of interest at the moment (see video).

The opening the radiotherapy therapeutic window provided by NanoXray nanoparticles
Therapeutic-window
(Left: radiotherapy alone; right: radiotherapy in the presence of NanoXray nanoparticles. Image: Nanobiotix)

Activating our immune defences by cloning anti-bodies
The strategic “advantage” of most cancer cells lies in their ability to become unrecognised by the patient’s immune system as being abnormal. It is for this reason that we develop immunotherapy strategies that help the patients mobilise their immune defence mechanisms to fight the illness.

Immunotherapies are part of bio-therapies, viz., where the war against cancer is fought using living matter, at a cellular level.

To be more precise, the strategy consists of fighting cancer on its own ground. The reason for this is that cancer, in sense, manipulates our immune defence mechanisms. When a tumour forms, a certain category of white blood cells (the “T” leukocyte regulators) protect the cancer cells from attacks by other white cells, i.e., the latter are neutralised and rendered ineffective. The neutralisation process takes place via a molecule in the surface membrane of cells; it is a protein CTLA4, which slows down the activities of cytotoxic cells (the white cells). Immunotherapy consists of countering this phenomenon, by targeting the CTLA4 proteins.

How is this done? The answer lies in cloning anti-bodies. The strategy involves monoclonal anti-bodies, produced under laboratory conditions by cloning cells (hence the term monoclonal). The reference product here is ipilimumab (also known as MDX-010 and MDX-101, marketed as Yervoy), used to treat metastatic melanomas. This drug has been market approved by the American and European drug authorisation agencies and has spectacular effects on patients whose life expectancy horizon is doubled.

Immunotherapies have been used for the past 40 years to treat certain cancers, such as bladder cancer. But a more general use is fairly recent. There are 23 monoclonal antibodies on the market place today, with another 250 in development phases. Not only is there an measurable efficiency in solid tumours (melanomas, colorectal cancer, breast cancer), but we can observe an improved life-style for patents undergoing treatment. However, the treatments are very costly for the moment and not all are as yet authorised for market introduction.

Nano-medicine and nanorobots
Nano-medicinal drugs are every bit as innovative yet use a different approach. Jacques Lambrozo, Head of Clinical Studies at EDF, reminds us – if we wish to fully understand a central issue in cancerology – that medication in oncology is faced with the mechanisms of metabolism. “Inasmuch as everything goes systematically through out liver, this limits to a large extent the applications for ingested drugs. In a conventional protocol, acting on the tumour amounts to acting on the liver and here we are faced with a level of therapeutic toxicity which often is the reason for stopping the protocol.” The idea behind nano-medicinal drugs is simply to by-pass the liver and avoid impregnation the whole body with the molecule(s) administered.

Bio-pharmacist, Patrick Couvreur, titular holder of the Liliane Bettencourt Chair of Technological Innovation at the prestigious Collège de France, explains “a nano-medicinal drug takes the form of a molecule encapsulated is nano-dimensioned vector that is administered to the patient. These minute particles are equipped, so to speak, with marker detecting radars, viz., the monoclonal anti-bodies grafted to the surface of the nanoparticles and capable of recognising specific tumour markers.”

The process proves triply attractive: firstly, healthy tissues are preserved; secondly, the drug can be released into the patient over a period of time, contrary to what happens in radio-therapy, where the unwanted side-effects only allow you to use a short exposure time. And thirdly, the nano-technological delivery protocol of the drug allows you to side-step the tumour’s defence mechanisms, allowing direct access to the cancerous cells, sensitive to the active principle of the drug administered.

Although we can note that pharmaceutical laboratories are working wit intensity in this direction, there are for the moment only a few nano-drugs on the market. A mention can be made for Doxil, produced by Alza Corporation and prescribed for ovarian cancers resisting classic chemotherapeutical protocols.

This nano-therapeutic approach is not necessary based on use of a chemical reaction, as is the case in nano-drug administration. A recent technology breakthrough, using genetic engineering, with DNA fragments has been developed by the Wyss Institute for Biologically Inspired Engineering, University of Harvard. The idea announced by the research team (Dr Shawn Douglas and Dr Ido Bachelet) in February 2012 was to develop a nanorobot from a DNA strand, with the capacity to activate the call’s suicide gene – a natural biological process called apoptosis “a standard feature that allows aging or abnormal cells to be eliminate,” i.e., self-destruction in response to a signal.

The Wyss Institute’s nanorobot
Nanorobot Wyss

(The nanorobot looks like a barrel, holding molecules with encoded instructions. The barrel is normally held shut by special DNA latches. When they latches their targets, the two halves of the barrel swing open and expose the molecules. Image: Campbell Strong, Shawn Douglas & Gael McGill, Wyss Institute)

The process involved uses a known mechanism of the body’s immune system. Just like the white cells that circulate in permanence in our blood stream on ‘stand-by”, seeking out and destroying infected, damaged cells, as and when they are detected, the nanorobot will be programmed to identify certain protein combinations at a cell’s surface. The research scientists are trying to deliver instructions encoded on anti-body fragments to two type of cancerous cell: in leukaemia and the lymphoma. By intervening directly on the gene, this experimentation is truly noteworthy in that it bounds precisely the therapeutic action envisioned.

Genetic engineering therapies are promising but carry risks

Using DNA in the war against cancer, modifying the infected cells, using genetic engineering techniques to eliminate a carcinogenic source or restore anti-oncogenes, together constitute the very base of gene therapies. One of the assigned objectives is to repair gene functions, i.e., rather than attempt to externally destroy cancerous cells, the practitioner attempts to re-establish normal cell functions. Let us recall here that all the information for correct functioning of any living matter is registered in each of its cells. The information is stored in the cell’s DNA and must be replicated exactly each time the cell divides (mitosis). Even the most minute error in the replication process leads to the generation of sub-populations of daughter cells that can proliferate in the body. In short, a normal cell becomes cancerous when an error occurs in a genome replication process.

Gene therapy consists of re-educating the cancerous cells. The idea is to inject a gene, either to replace a deficient, functionally damaged gene, or to produce a substance which makes the target cell toxic, i.e., it becomes identifiable by the lymphocytes that ensure antitumor immunity.

In order to be able to inject the gene, you need a vector, which may be, surprisingly… a virus. Pierre Cordelier, who was head scientist for a first clinical in vivo test of a gene therapy protocol for a pancreas cancer, explains the underlying principle: “The virus penetrates the cells, and uses them assure production of its own specific proteins, used then to kill the cells or to place them in a stable state of dormancy. Given that we now know how to effectively penetrate the cell right to its nucleus, we can use the virus as a vector for the gene fragment was want to place in the nucleus. By the way, these are indeed GMBs.”

Implementing this same principle, Nathalie Carter – now a research scientist at Inserm (by training a paediatrician) – made a notable breakthrough in 2009 in the treatment of leukodystrophy. Using a viral vector derived from an HIV strain (deactivated and thus inoffensive), she demonstrated how to penetrate cells and deliver a therapeutic gene: “This was the first gene therapy application with this particular virus and we successfully treated 4 children patients; we now have 6 years return on experience for the first two children treated in this way;” the objective of Nathalie Cartier’s team is now to receive authorisation to carry out a larger scale test in Europe and in the USA.

In the field of gene therapy, the most significant progress has been seen in the US, the UK, Italy and France. In 2013, the count stands at 2000 in vivo tests on patients, 1200 in the USA, 500 in European countries and 300 elsewhere in the world. Two or three products in the marketplace today are sold as injection-ready doses, but there are also many test protocols in their early stages (technical feasibility and patient tolerance).

The approach here is not exempt from risk. As Jacques Lambrozo points out: “Cancers do not all carry the same molecular signature and it is not certain that the anomaly is located in the cell’s DNA. We are therefore faced with a targeting issue. Moreover, and above all, there is a risk of an interaction with undamaged DNA. For patients who do not yet have children, for example, the gene therapy could prove to be a highly risky, potentially dangerous, approach.”

A new challenge: the micro-environment of a cancer
What are the future prospects here? The innovative strategies described in this paper are articulated round two main mechanisms that lead to cancers: abnormal gene regulation and a run-away proliferation of cells. Over the past 5 years, basic research and clinical studies have focused on the second mechanism: the micro-environment of the cells themselves. This constitutes the major challenge in coming years.

Growth of a tumour, unfortunately, does not only depend on the mass of cells that compose the tumour, but also on the healthy cells that surround the tumour. The latter also orders new blood vessels (angiogenesis) needed to feed the growing numbers of cancerous cells. As Urszula Hibner, laboratory head at the Institute for Molecular Genetics, Montpellier, and specialist in the study of the impact of the micro-environment of liver cancers explains: “We must learn more about the role of healthy cells and blood vessels adjacent and connected to the tumour.”

There are new treatments that target notably the cancerous cells but also the blood vessels that ‘feed’ the tumour. Numerous new medicinal drugs are being developed, some of which are ready for market or even authorised for marketing, such as Avastin. This drug is composed of a monoclonal anti-body which inhibits the signal alert for blood and in this manner stops the growth and development of new blood vessels. It can be administered by intravenous injection for certain types of cancer (kidney and lung cancers, notably) in association with conventional chemotherapy protocols. According to Pierre Cordelier, this approach could prove advantageous to treat pancreas cancers, with 20% cancer cells in the pancreas and 80% of the micro-environment infected.

What conclusions may we draw from this overview? First point, we no longer discuss cancer in its general acceptance. We now address specific types of cancer and their treatments. The tremendous progress registered in targeted therapies, the combination of protocols, the ever-increasing promise of a la carte therapy, depending on the sub-category of a given cancer case, are all tending to considerably improving the patient’s well-being during treatment. Recovering one’s health can now call on a series of novel, promising approaches (nano-drugs, nanorobots, genetic engineering therapies and the micro-environment).

Several safety issues raised by these new therapeutic paths still remain to be clarified. In the meantime, the most efficient treatment for cancer is to know how to prevent it happening. Reducing behavioural risks through national campaigns must be doubled by addressing the major challenge in related basic research; the fields to be investigated are 1° understanding the early stages of the cell deregulation process; 2° improving our capacity to predict and identify those patients liable to develop a cancer.

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