R&D: The cutting edge of cancer research

07-03-2019

R&D: The cutting edge of cancer research

(Source: PharmaFile 2019-03-08)

While immunotherapies continue to be the darling of the industry, new, innovative and sometimes seemingly fantastical research is emerging that blurs the realms of possibility in cancer treatment, Matt Fellows discovers.

Cancer is without a doubt the biggest therapeutic area in medicine, presenting a huge lucrative opportunity and an insatiable pool for investment; in 2016, the market was worth around $80 billion, and is expected to double in size in less than a decade to reach $170 billion by 2023.But it isn’t just on a fiscal level; the treatment of cancer occupies a colossal societal and emotional space for many whose lives have been touched by the disease and those who will be affected in future. It’s a health issue that is crucial to all of us. So when an up and coming biotech unveils new, promising data on a potential new treatment method, it’s perhaps not surprising that media headlines excitedly follow, and not always in a responsible way.

The field is rife with some of the brightest minds and innovations are seemingly always churning away in labs around the world. Some are more conventional, others breach the realm of science fiction, and others are so promising as to invite scepticism. In recent months, a few from each of these categories have emerged, and we will shine the spotlight on some of the more exciting ones here.

Explosive research

The depths of human creativity and ingenuity never cease to amaze, and, especially in cancer, the thin line of what we consider ‘too good to be true’ is often pushed and blurred. And a team of researchers based at Hollings Cancer Center at the Medical University of South Carolina (MUSC) are certainly embodying this spirit with the announcement that they have discovered cell membrane complexes which can cause cancer cells to explode.

The complexes, known as ceramidosomes, were unexpectedly uncovered by the team while studying the cancer-killing effects of Novartis’ FDA-approved multiple sclerosis drug Gilenya, or FTY720 as it is also known. They are created when ceramides – lipid molecule chains located in the cell membrane which function in cell death – combine with other protein molecules to form large pores which cause the cell membrane to ripple and explode, killing the cell.

Part of Gilenya’s cancer-killing potential is derived in part from its function of inducing ceramidosomes into the cell membrane. The drug lowers immune system activity after being modified by the liver, activating molecules which induce tumour suppression. The team discovered that if ceramidosomes were prevented from forming, cell death did not occur, confirming that the complexes are a core element of the drug’s ability to induce cancer cell death.

The team is now working to develop the research to better understand these functions and to potentially hone more effective cancer drugs.

Transformative potential

Exploding cancer cells are one thing, but another team, based at the University of Basel’s Department of Biomedicine, are perhaps pushing the line between reality and science fiction in cancer research even further with the claim that they have discovered a way to transform malignant cancer cells into harmless fat cells.

Again, it sounds almost too good to be true. Pharmafocus caught up with Gerhard Christofori, Professor of Biochemistry at the University of Basel and first author on the paper Gain fat-lose metastasis: Converting invasive breast cancer cells into adipocytes inhibits cancer metastasis, to better understand how these exciting findings work.

“Malignant cancer cells - so cancer cells that seed in the body that are able to resist chemotherapy - have a high cell plasticity; that means these cells can adapt to challenges and to the environment much better than any other cells because they are less defined,” he explains. “We call them 'differentiated cells', like the cells of your skin or any type of organ, but when they become more like stem cells, they have a lot of potency and they can develop into other types of cells and they can react to environmental challenges.

“We have essentially found through this study that the cells undergo a transition from a differentiated epithelial situation into an invasive and malignant situation. So, when they become malignant they also become more stem cell-like, and what we did is we essentially abused this situation by triggering in the cells the differentiation into a completely different cell type. This is essentially what is impressive: that we were able to take breast cancer cells – mouse or human – in vitro, but also in mouse models, and treat them in such a way that they differentiate or trans-differentiate into another cell type. In this case, we have chosen adipocytes – fat cells. The advantage of these differentiated fat cells is that they are, as we call it, post-mytotic, meaning they do not divide anymore. Before, we had a breast cancer cell, or breast cancer cells, that divide very rapidly and proliferate and form a tumour. And now, all of a sudden, they turn into fat cells, and they just sit there and they cannot divide anymore; they are essentially harmless by doing so. The message is that we can devise therapeutic interventions that can use this high cell plasticity to attack or to inactivate these malignant and metastatic cancer cells.”

So how exactly is this remarkable process triggered? It’s surprisingly simple, but the discovery was anything but easy.

“This essentially was the hardest work,” Christofori continues. “We have used essentially a cocktail of growth factors and also drugs that can be used to trigger the cells to become fat cells. In the cell culture this is relatively easy, but then of course, how do you do this in a living organism, in a mouse? You cannot just put the whole cocktail of factors and drugs into the mouse. So we had to do major homework. We studied the changes in gene expression during this trans-differentiation of the cells in culture; we looked at which genes are activated, which pathways are inactivated, and then we figured out which pathways we have to manipulate – what is the minimum requirement to modulate the system? In the end we ended up using only two drugs, but that of course took a lot of work and optimisation, and also some trial-and-error experimentation in culture. One called rosiglitazone, a diabetes drug that actually has been used in the clinics very frequently and has been replaced by other optimised drugs, and the other is actually a cancer drug called trametinib, an inhibitor of a signalling pathway in cells. The combination of the two is sufficient to induce these malignant breast cancer cells to become fat cells. It is important to note also that only these malignant cells with high cell plasticity are converting into fat cells; the tumour cells that are not malignant, that do not have this high plasticity, they are unaffected, so they still proliferate, but they are benign cells.”

Christofori also explained how this methodology could be cleverly married to the conventional chemotherapy approach, boosting its effectiveness in eliminating cancer metastasis which can often complicate patient outcomes.

“When we think about translating these findings into the clinic, what we have to do now is combine our treatment protocol with conventional chemotherapy or cytostatic therapy; this is essentially where we would attack the proliferating cells – the benign tumour cells – and with our new treatment, we would essentially take away the malignant cells to prevent metastasis formation. We would expect and hope that then we would essentially have a double-effect by preventing metastasis, but at the same time, also shrinking the primary tumour. Then, of course, benign primary tumours in most cases can be surgically removed, depending where they are.

“The fat cells are harmless as far as we can tell from when we follow them up. Of course, we didn't do years of follow-up in the mice, that's not possible, but in culture we did tests to see if the cells revert back into cancer cells, and they did not. When we look in the tumours of the mice, the cells are really sitting in the periphery of the tumour. Essentially, these would be the cells that would have migrated away from the tumour into the bloodstream and disseminate in the body, but they essentially sit there outside of the tumour and are not moving away and not proliferating; there are not too many of them, because essentially we catch them in the act, so to say.”

While breast cancer cells were used in testing, the treatment could even work for other types: “We did not do major work yet on other kinds of types, but we know that this process of this epithelial-mesenchymal transition, this malignant progression, is happening in any solid cancer type – so any cancer type that is starting from an epithelial-like structure, and these are 90% of all cancers in humans,” Christofori adds. “We would expect that this should also work in other cancer types, but of course we have to test that now in the in the months to come.”

Like any promising research, the path to realisation is never smooth, but unfortunately, one of the main hurdles for the team here is not a scientific one – it’s monetary.

“One issue here is how to finance these clinical trials, because one problem we already realised is that we are using two drugs that are out there, and to just combine them, you don't have a very strong intellectual property standing, so this is not easy to patent or to get investors interested. You get the patients interested, you get the clinicians interested, but we need to find funding for the first clinical trials - this will probably be a major hurdle. This is what some people call the 'Death Valley' of translational research, because when the patent is not very strong and people cannot start a spin-off company, or do not have a lot of support, they would have to finance it out of donations of charity money, or of institutional grants. Clinical trials are very expensive, and this is beyond what can be just financed out of the running budget, so this will be an issue we have to address in the near future.”

Raising eyebrows

Perhaps the most striking new development in the field of cancer research, however, comes from Israeli biotech Accelerated Evolution Biotechnologies (AEBi), which didn’t pull any punches when it announced what it has been working on.

“We believe we will offer in a year’s time a complete cure for cancer,” said Dan Aridor, Chairman of the AEBI’s Board. “Our cancer cure will be effective from day one, will last a duration of a few weeks and will have no or minimal side-effects at a much lower cost than most other treatments on the market. Our solution will be both generic and personal.”

Needless to say, this raised some eyebrows in the industry, and really pushes the notion of ‘too good to be true’. Information is so far thin on the ground, with a full report on the drug, known as MuTaTo (multi-target toxin), still to be released. The company likened it to a cancer antibiotic, utilising its proprietary SoAP platform – a phage display technology. This technology works through the introduction of DNA coding for proteins such as antibodies into a bacteriophage, a bacteria-infecting virus. These proteins are then visible on the surface of the phage, and can be used to determine interactions with other proteins, DNA sequences and small molecules.

AEBi instead substituted proteins for peptides, which it argues are smaller, cheaper, and easier to produce and regulate. Cancer drugs can often be rendered ineffective due to mutations in their specific targets, or the target’s physiological pathways, the team said, meaning the targets are no longer relevant to defeating the cancer. By contrast, MuTaTo combines at least three targeting, cancer-killing peptides with a strong cancer cell-killing peptide toxin, which AEBi’s CEO Dr Ilan Morad argues ensures the treatment “will not be affected by mutations; cancer cells can mutate in such a way that targeted receptors are dropped by the cancer.”

“The probability of having multiple mutations that would modify all targeted receptors simultaneously decreases dramatically with the number of targets used,” he told The Jerusalem Post. “Instead of attacking receptors one at a time, we attack receptors three at a time – not even cancer can mutate three receptors at the same time.”

Great research, great responsibility

While the research certainly sounds promising, critics remain sceptical; reactions ranged from “spurious” and “highly irresponsible" to even “cruel.” Primarily, criticism was levied at the lack of published findings in medical journals, but AEBi insists it “can’t afford” to do so.

Christofori gave his thoughts: “Drugs have been generated and are now in the clinics, but they've worked for some cancer types, but not at all for other kinds of types. And it's not known why that is; maybe they run on different sectors, different pathways, so the drug is not perfect for the patient, which is usually the explanation. This is also why I think a story where people claim that they can treat any patient with any cancer type is kind of hard to believe because cancers run differently; there's a high heterogeneity of cancer cells within a tumour, even within a patient, so with one treatment, you may not get all of them. The cancer types differ quite a lot from each other in terms of pathways, in terms of how you can interfere with them.”

While the legitimacy of AEBI’s research is still to be determined, it raises the question of the responsibility of researchers, in cancer and beyond, when it comes to publishing their data and reporting back to the public. Cancer is a very emotive disease area, and with good reason – it is currently the second-leading cause of death worldwide after cardiovascular disease – so it is crucial that researchers are transparent with their findings and seek to regulate expectations.

Christofori also touched on this issue: “I think we need to be very careful, because I can tell you, we have published this paper and I now get emails from patients asking 'is there a clinical trial? Can I join the trial?' and then you realise there's a huge responsibility, because we give people hope, but we cannot, in most cases, deliver right away. So we have to be very careful. In our reports that we publish, we are very careful in how to word these things and just hint at the options in the future. But, of course, this is immediately then translated into 'cancer researchers in Basel cure cancer' and things like that, and that's not the way it should be.”

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