Developing a new class of cancer combo drugs

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t’s a familiar problem within oncology: how can we develop treatments that kill cancer cells while leaving healthy tissue unscathed? Many types of treatments, which would otherwise prove effective, are limited by their toxicity and side effects.

“The way cancer drugs for the most part are administered is systematically, so they go everywhere throughout the body,” says Per Hellsund, president and CEO of biotech start-up Cybrexa. “While they have more of an effect on the cancer cells than they do the healthy cells, nearly all cancer drugs do have off-target toxic effects.”

While this problem is associated particularly with chemotherapy, it also applies to other types of treatment, such as PARP inhibitors. In essence, these drugs work by blocking the action of a protein (PARP1) that fixes damaged DNA. Although they are effective in treating certain cancers, they can affect normal cells too.

The situation is compounded when we look at combination treatments. PARP inhibitors have enormous potential in combination with chemotherapy, as this provides a double blow to the cancer cells. First the chemotherapy damages their DNA, and then the PARP inhibitor prevents the cells from repairing.

However, these combinations are often associated with life-threatening toxicity and bone-marrow suppression, meaning their potential remains unrealised. In trials, it has been necessary to de-escalate the dose to the point where the drugs become ineffective.

“If you look at the current landscape of PARP inhibitors, they are successful, powerful effective anticancer drugs – however, they’re only effective in patients with certain mutations,” says Hellsund. “This is because, in order for the DNA repair inhibitors to work there has to be an inherent defect in the DNA of the cancer cells. While you can create these defects artificially throughout the use of chemotherapy, you quickly run into toxicities.”

His company, Cybrexa, is working to develop a solution to this problem. Currently in the early stages of development, its alphalex platform technology could one day enable combinations of chemotherapy and PARP inhibitors without the dangerous side effects.

Launched at the start of 2017, Cybrexa is a privately held company dedicated to developing a new class of cancer therapies. The ambition is clear – to target DNA repair inhibitors, making them more effective and suitable for a broader patient population.

“I got together with Dr Ranjit Bindra, rising star at Yale, and started talking about various ideas,” says Hellsund. “He’d been working on DNA repair inhibitors, and he felt that they were underutilised and that the true potential of these drugs could be exploited by combining them with chemotherapy. He was aware of a tumour targeting technology that had been developed at Yale by Donald Engelman, and was potentially available for license. So that was the nucleus of the company.”

The technology in question, which became Cybrexa’s alphalex platform, is based on a chemical compound that forms a corkscrew-like structure when it comes into contact with acidic (low pH) cells.

“This is important because the surface of cancer cells and the microbe environment surrounding these cells is very acidic,” says Hellsund. “This is pretty much a universal phenomenon across all cancer types, particularly solid tumours, so it’s a fairly universal tumour-targeting mechanism.”

When placed in an acidic environment (i.e. a tumour), the compound forms an alpha helix shape. It then bores its way through the cell membrane and deposits an anticancer drug in the cell.

“This technology has the ability to deliver the anticancer agent intracellularly as opposed to extracellularly,” says Hellsund. “We attach anti cancer agents to the peptide via a self-immolating linker, so the peptide drags the anticancer agent and the linker into the cell and then the linker dissolves, releasing the anticancer agent. Obviously the big benefit is that it reduces or eliminates toxicity to other organs.”

As Dr Ranjit Bindra, chief scientific advisor, explains, the technology works similarly to an antibody-drug conjugate (ADC) – another form of targeted therapy for cancer patients.

“It has some similarities, but many more advantages,” he says. “Unlike an ADC, which has a specific antigen that needs to be developed for a specific tumour type, we target a universal feature of tumours. The second consideration is these are very small peptides in comparison to ADCs, and as such they can penetrate deeper into the tumours. The third is that these are simpler molecules to design.”

Dr Vishwas Paralkar, chief scientific officer, adds that with ADCs, you can only administer a limited volume of the drug.

“With ADCs, around 0.2% of the total molecule is the drug itself and 99.8% is the antibody,” he says. “Here, about 10%-20% of the total conjugate is the drug itself. So the amount of drug you can give to the patient is significantly greater than ADCs will ever achieve.”

Recently, the company announced the results of a preclinical study into its technology. A PARP inhibitor named talazoparib, developed by Pfizer, was attached to the alphalex peptide, and tested in animal models. The technology could be combined with chemotherapy without any bone marrow toxicity.

“We showed that we could use very high doses of the PARP inhibitor and not have the toxicity,” says Hellsund. “We believe this has the potential to change the narrative of PARP inhibitors and enable us to address patient populations that currently have few, if any, options for treatment.”

The technology might also be used in conjunction with radiation therapies. In this case, you would use a different kind of DNA repair inhibitor (such as an ATM inhibitor) that also has radiosensitising effects. If this radiosensitiser is deposited inside the cancer cells, the radiation is magnified in the tumour, allowing you to reduce the radiation dose and minimise damage to the surrounding tissue.

“These drugs are unbelievably potent, but the elephant in the room is that a really good radiosensitiser is no good if you can’t find some way to target the tumour,” says Bindra.

Over the coming months, Cybrexa plans to move forward with its lead alphalex-PARP inhibitor combination, initiating a Phase I trial in patients by the start of 2020. If clinical trials prove successful, the implications could be radical – many different patient groups, with many different kinds of cancers, could benefit.

“We think this has potential to improve cancer care by being able to address patient populations that currently don’t have any options,” says Hellsund. “It could affect large groups of patients just looking at the PARP inhibitor, and then there are the radiosensitisers – DNA-PK, ATM and potentially ATR inhibitors. So looking forward the plan would be to expand the portfolio to other classes of molecules.”

The platform might also be used with standalone drugs that are too toxic to be used without a targeting mechanism.

“We have an opportunity here now to take so many drugs either alone or in combination with chemotherapy and radiation,” says Bindra. “Right now they’re very promising in terms of efficacy but we’re limited by toxicity. And Cybrexa’s offering a solution to that problem because there are dozens of drugs out there – we can fix them and give options to patients who desperately need them.”